September 1997 Volume 23 - Number 7 July 2019 - Revues ...

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Volume 23, Number 7, July 2019

Table of contents

Gene Section

BIRC5 (baculoviral IAP repeat containing 5) 168 Paola Cristina Branco, Paula Christine Jimenez, João Agostinho Machado-Neto, Letícia Veras Costa-Lotufo

SLC45A2 (solute carrier family 45 member 2) 187 Mainak Sengupta, Tithi Dutta, Kunal Ray

Leukaemia Section

Burkitt's lymphoma (BL) 190 Luis Miguel Juárez Salcedo, Ana Corazón Monzón, Samir Dalia

t(X;14)(p22;q32) or t(Y;14)(p11;q32) IGH/CRLF2 194 Daniel Martinez-Anaya, Rocio Juárez-Velázquez, Dafné Moreno-Lorenzana, Patricia Pérez-Vera

Case Report Section

Isolated 1q21 rearrangement der(20)t(1;20)(q21;p13) with telomere involvement of 20p in a case of longstanding myelodysplastic syndrome 200 Lubomir Mitev, Liliya Grahlyova, Aselina Asenova, Verginia Uzunova, Julian Raynov

A new case of adult Acute Myeloid Leukemia with t(3;3)(p24;q26) 204 Bo Yuan, Janice Smith, April Ewton, Sai Ravi Pingali, Arthur Zieske, Amy Breman

t(4;11)(q23;p15) in paediatric early T cell precursor acute lymphoblastic leukemia 207 Anurag Gupta, Sirisharani Siddaiahgari, Nagaraju Nalla, Mukkanteeswara Rao Kasaragadda, Manu Goyal

t(6;17)(p21;p13) and acquisition of the Philadelphia chromosome translocation with p190 BCR-ABL1 transcript during the course of myelodysplastic syndrome Adriana Zamecnikova 210

t(6;17)(p21;p13) associated with t(3;3)(q21;q26.2) in AML 213 Adriana Zamecnikova

Gene Section Review

Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7) 168




BIRC5 (baculoviral IAP repeat containing 5) Paola Cristina Branco, Paula Christine Jimenez, João Agostinho Machado-Neto, Letícia

Veras Costa-Lotufo

Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo, São

Paulo, [email protected] (PCB); [email protected] (JAM-N); [email protected] (LVC-L) Brazil;

Department of Marine Sciences, Federal University of Sao Paulo, Santos, [email protected]

(PCJ), Brazil.

Published in Atlas Database: January 2019

Online updated version : http://AtlasGeneticsOncology.org/Genes/BIRC5ID797ch17q25.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70468/01-2019-BIRC5ID797ch17q25.pdf DOI: 10.4267/2042/70468

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract BIRC5, also known as survivin, has been implicated

in cell cycle progression and apoptosis avoidance.

BIRC5 is highly expressed in embryonic tissues,

however very low or absent in adult tissues. BIRC5

overexpression has been frequently associated to

cancer development, a poor prognosis and

chemoresistance. Besides that, different BIRC5

isoforms has been characterized and related to better

or worse chemotherapy responses depending on the

isoform and the cancer type. So far, many efforts

have been conducted in order to deplete BIRC5 in

cancer cells, including gene therapy,

pharmacological and nanotechnological approaches.

In this review, we will discuss the role of BIRC5 in

cancer cell biology and its clinical significance,

demonstrating its DNA/RNA and protein aspects,

also its relevance for diagnosis and prognosis, and

advances as a target for the treatment of different

cancer types.

Keywords

BIRC5; Cell cycle progression; Apoptosis; Cancer

Identity

Other names: API4, EPR-1

HGNC (Hugo): BIRC5

DNA/RNA

Description

The entire BIRC5 gene is approximately 11.4 Kb

(start: 78214186 and end: 78225636 bp; orientation:

Plus strand).

Transcription

There are three transcript variants deposited in the

NCBI database

(https://www.ncbi.nlm.nih.gov/gene).

In general, they present three exons (exon 1, 2 and 3)

that are responsible for encoding the BIR domain,

which is conserved in all BIRC family members, and

the exon 4 that is related to the coiled-coil (CC)

domain.

Variant 1 is the predominant transcript (cDNA: 2574

bp), and encodes isoform 1 (142 amino acids [aa]).

Variant 2 lacks an exon in the 3' coding region,

which results in a frameshift (cDNA: 2537 bp) and,

thus, in a changed protein (143 aa) with a different

C-terminus from that of isoform 1 (isoform 2, also

known survivin-ΔEx3). Variant 3 exhibits an

alternate in-frame segment (cDNA: 2724 bp) and

generates a longer (165 aa) and distinct protein

(isoform 3, also known survivin-2B), compared to

isoform 1.

https://www.ncbi.nlm.nih.gov/gene

BIRC5 (baculoviral IAP repeat containing 5) Branco PC et al.


Figure 1. BIRC5 structure and its splices variants. BIRC5 (also kwon as survivin) presents at least five variants with biological relevance for cancer. A. The protein structure of the most common variant observed presents 142 aa and is composed of a BIR

domain that is responsible for its anti-apoptotic activity and a coiled coil. B. The BIRC5 pre mRNA of the most common expressed variant is composed of 3 exons that codifies the BIR domain and the exon 4 that codifies the coiled coil. This variant present anti-apoptotic activity. Survivin Ex3 has its exon 3 deleted and an insertion of a 3'UTR, this isoform codes a protein of 143 aa and also exerts anti-apoptotic functions. Survivin-2B presents an insertion of an exon 2b located between exon 2 and

exon 3, generates a protein of 165 aa with pro-apoptotic characteristics. Survivin-2α is characterized by the presence of exon 1 and 2 and the insertion of a 3'UTR, this isoform codifies a protein of 74 aa with pro-apoptotic functions. Survivin-3B presents the insertion of exon 3 b between exon 3 and exon 4, which generates a protein of 165 aa with anti-apoptotic properties. Survivin-3α

presents a deletion of exon 3 and generates a protein of 78 aa whose function remain controversial. Arrows indicate the stop codon. UTR- untranslated region. Red line indicates the BIR structure.

Moreover, three additional transcript variants are

reported in Ensembl (http://www.ensembl.org/): a

transcript variant containing 568 bp, which generates

a protein of 74 aa (also known as Survivin-2α); a

transcript variant with 492 bp (cDNA) that produces

a protein of 121 aa (also known as Survivin-3B); and

a transcript variant comprised of 386 bp (cDNA) that

gives a protein of 78 aa (also known as Survivin-3α)

(Figure 1).

Protein

Description

The IAPs (Inhibitors of Apoptosis Proteins) are a

family of proteins primarily known for inhibiting

caspase activity, either directly or indirectly, thus

preventing apoptotic cell death (Gyrd-Hansen and

Meier, 2010). Still, the IAPs are further implicated

in key roles in other processes, such as cell cycle, cell

migration, inflammation and, even, in the innate

immune response (de Almagro and Vucic, 2012).

Structurally, members of the IAPs are characterized

by the presence of at least one BIR (Baculovirus IAP

repeat) domain, which contains nearly 80 amino acid

residues and carries Zn2+ in the center. Such domain

is a highly conserved sequence that mediates

protein-protein interactions, an essential feature for

their anti-apoptotic function. Within the eight human

IAPs recognized ( NAIP [BIRC1], BIRC2 [cIAP1],

BIRC3 [cIAP2], XIAP [BIRC4], survivin [BIRC5],

BIRC6 [bruce], BIRC7 [livin] and BIRC8 [ILP-2])

there may be between one and three BIR domains,

typically arranged in their N-terminal portion

(Budhidarmo and Day, 2015; Lopez and Meier,

2010).

BIRC5 (survivin), the smallest among the IAPs (16.5

kDa), was discovered in 1997 (Ambrosini et al.,

1997), is 142 amino acids (aa) long and has a single

BIR domain (Peery et al., 2017). This protein is

presented as a stable loop-shaped homodimer,

formed by interactions of the N-terminal region

through a predominantly hydrophobic interface

(Chantalat et al., 2000; Verdecia et al., 2000).

Furthermore, on the C-terminal portion, survivin

carries an alpha-helix CC (coiled coil) domain, its

unique structure (Chantalat et al., 2000; Coumar et

al., 2013) which convenes the ability to associate to

microtubules and a range of other proteins involved,

mainly, in the process of mitosis, and further

allowing for translocation among the different

cellular compartments, such as mitochondria,

cytoplasm and nucleus (Rodel et al., 2012) (Figure

1).

Since BIRC5 is connected to a diverse network of

biochemical processes and therefore has remarkable

multifunctionality, its modulation in cancer therapy

continues to be extensively explored. Several

survivin inhibitors have been identified by in vitro

and in silico methods, such as antisense

oligonucleotides, siRNA, dominant-negative



mutants, peptidomimetic molecules and other small

inhibitory molecules, and even as anticancer vaccine

(Fenstermaker et al., 2016; Sarvagalla et al., 2016).

Expression

BIRC5 is normally expressed in embryonic tissues

and during fetal development, as well as in fast

dividing normal cells (like bone marrow stem cells,

basal epithelial cells and thymocytes, even if at lower

concentrations), but is virtually undetectable in fully

differentiated and healthy adult tissues (Adida et al.,

1998; Sah et al., 2006; Stauber et al., 2007).

Throughout the cell cycle, BIRC5 is expressed only

during mitosis, in a highly regulated manner

comprising the chromosomal passenger complex

(CPC), as it interacts with tubulin and kinetochores

during metaphase, then participates in central

spindle organization and cytokinesis, throughout

anaphase (Szafer-Glusman et al., 2011).

However, BIRC5 is expressed in cells that undergo

malignant transformation, being overexpressed in

numerous tumors (Altieri, 2001; LaCasse et al.,

2008). Recent studies evidenced that transcriptional

activation is not the only cause for BIRC5

overexpression, but also post-transcriptional

regulation, specially coordinated by many

alternative polyadenylation (APA) sites. For

instance, in ovarian cancer, aberrant APA leads to

shortening of the 3'-UTR region, enabling escape

from negative regulation of miRNAs and causing

up-regulation of BIRC5 (He et al., 2016).

Clinically, overexpression of BIRC5 has been

correlated with a poor prognosis of cancer, resistance

to apoptosis induced by chemotherapy, decreased

survival of patients and greater chances of relapse

(Islam et al., 2000; Rodel et al., 2012).

Localisation

BIRC5 is located both in the cytoplasm and in the

nucleus. Nuclear expression has been associated

with a poor prognosis and chemoresistance (Du et

al., 2015), which may differ among the different

types of cancers (Shintani et al., 2013). BIRC5 splice

variants were also related to subcellular localization.

This has been shown in samples from acute myeloid

leukemia patients, where wild-type survivin and the

2B splice variant were expressed in the nucleus,

cytoplasm or both, whereas the ΔEx3 isoform was

only expressed in the nucleus (Serrano-Lopez et al.,

2013). However, considering pro-survival factors,

localization is not the only relevant feature: it has

been recently demonstrated that BIRC5 can be

packaged into extracellular vesicles (endosomes)

and its delivery may be guided by antiapoptosis

stimuli from cancer cells and tumor

microenvironment, inducing pro-survival

competences in fibroblasts after treatment with

paclitaxel. Conversely, knockdown of BIRC5 in

those vesicles promoted increased cell sensitivity to

chemotherapeutic agents (Kreger et al., 2016).

Function

Studies have shown that overexpression of BIRC5

inhibits both the intrinsic and extrinsic pathways of

apoptosis and the depletion of survivin in human cell

culture impairs apoptosis and triggers cell division

defects (Li et al., 1998; Roy et al., 2015). The

antiapoptotic mechanism of BIRC5 still needs to be

better clarified, however, both the direct or indirect

binding of BIRC5 to caspases are proposed (Figure

2) (Altieri, 2013; Garg et al., 2016; Li et al., 1998).

Evidences also indicate that BIRC5 binds to XIAP,

one of the best studied IAPs, forming a complex that

protects XIAP against ubiquitination and

proteosomal degradation.

This complex then activates multiple signaling

pathways, including NF-κB, inhibits caspases

CASP3, CASP7 and CASP9, suppresses apoptosis

and accelerates tumor progression. Other

cytoprotective mechanisms have been proposed for

BIRC5, including the ability of mitochondrial

BIRC5 to sequester the pro-apoptotic DIABLO

(Smac) protein from its binding to BIRC4 (also

known as XIAP), or even preventing its release from

mitochondria (Altieri, 2013; Coumar et al., 2013;

Song et al., 2003).

Interaction of BIRC5 with CDK4 has been

associated with progression of the cell cycle. In

mitosis, BIRC5 plays a key role in integrating the

transient chromosome complex (CPC), along with

INCENP, CDCA8 (borealin) and AURKB, which

controls the formation and stabilization of the

mitotic spindle (Altieri, 2013; Coumar et al., 2013).

Activation of Wnt signaling induces β-catenin (

CTNNB1) and BIRC5 nuclear translocation, which

contributes in mitotic spindle formation, further

regulating CPC, β-catenin, STAT3 and HIF1A

(Figure 2). BIRC5 also appears to be involved in the

cellular response to stress through the interaction

with various chaperones, such as AIP, HSPD1

(HSP60) and HSP90AA1 (HSP90) (Altieri, 2013;

Fortugno et al., 2003). Moreover, BIRC5 also

partakes in the process of autophagy (Wang et al.,

2011) and in DNA repair among several tumor cell

lines (Jiang et al., 2009).

BIRC5 has also been shown to induce cell motility,

metastasis and increased colonization capacity by

AKT-mediated upregulation of the α5 integrin

pathway in a melanoma model (McKenzie et al.,

2013).

Additionally, BIRC5 plays an important role in

angiogenesis, contributing to endothelial cell

proliferation and migration, which was then linked

to increased β-catenin protein levels that

consequently promotes an elevated expression of

BIRC5 and VEGF (Fernandez et al., 2014).



Figure 2. BIRC5: a multitask protein. BIRC5 (survivin) acts on cytoplasm and nucleus and is involved different cellular functions: cell survival, cell cycle progression, mitotic spindle formation and transcription activation. In cytoplasm, BIRC5 modulates

apoptosis pathway by binding to and blocking initiator caspase 9 and effectors caspases 3 and 7, demonstrating to be involved in extrinsic and intrinsic apoptosis and contributing to cell survival. BIRC5 may be blocked by SMAC/DIABLO, a factor released by mitochondria. Also BIRC5 potentiates apoptosis inhibition through stabilization of BIRC4 (also kwon as XIAP). TGF-β signaling negatively regulates BIRC 5 by phosphorylating SMAD protein. p53-mediated signaling also downregulates BIRC5 functions.

CDC phosphorylates BIRC5 and promotes its binding to CDK4 that may be translocated to nucleus, and thus promotes cell cycle progression. In nucleus, BIRC5 is involved in the mitotic spindle formation modulated by Wnt pathway through the

phosphorylation inhibiton and nuclear translocation of β-catenin activating BIRC5 and associated to other proteins (not shown) form the Chromosomal Passenger Complex (CPC). The transcription activation of BIRC5 mRNA is mainly promoted by β-

catenin, STAT3 (signal transducer and activator of transcription-3) and HIF 1 α (hypoxia-inducible factor-1α).

BIRC5 is also directly involved in enhancing anoikis

resistance through miR-141/KLF12/Sp1/survivin

axis. It is a consensus that anoikis resistance is

crucial for establishing a metastatic niche and

consequently promoting cancer progression and

dissemination (Mak et al., 2017). Dissimilar

functions have been attributed to the different

isoforms of BIRC5. Survivin-2α and survivin-2B

portray a proapoptotic activity profile, whereas

Survivin-ΔEx3 and Survivin-3B show prominent

antiapoptotic activity, with similar activities to those

of survivin itself. These distinct variants can predict

aggressiveness of cancer phenotype, thus

contributing to prognosis (Caldas et al., 2005).

BIRC5 can be released from tumor cells in exosomes

(Khan et al., 2011). This information provided new

insights into biomarkers for determination of early

diagnosis and also to predict prognosis. In this

context, the splice variant survivin-2B, in breast

cancer, was shown to be expressed mostly in primary

tumors and exclusively in early stage disease.

Conversely, Survivin-ΔEx3 variant was most

commonly expressed in late stages of breast cancer

(Khan et al., 2014). Survivin-2B has been further

reported to promote cell death in some cancer cells

by promoting

autophagy followed by cell death induced by

accumulation and stabilization of IKBKB (IKKB) in

the nucleus (Shi et al., 2014).

Homology

The BIRC5 gene is highly homologous among

different species, as shown in Table 1, which

demonstrates the comparison of variant 1 among

different species.

% Identity for: Homo

sapiens BIRC5 Symbol Protein DNA

vs. P. troglodytes BIRC5 98.3 98.8

vs. M. mulatta BIRC5 97.9 97.9

vs. C. lupus BIRC5 90.8 90.1

vs. B. taurus BIRC5 90.1 90.1

vs. M. musculus Birc5 83.6 82.6

vs. R. norvegicus Birc5 83.0 81.3

vs. G. gallus BIRC5 60.6 65.7

vs. X. tropicalis birc5.2 57.8 64.2

vs. D. rerio Birc5a 54.3 58.0

Table 1. Comparative identity of human BIRC5 with other species (Source: http://www.ncbi.nlm.nih.gov/homologene)

http://www.ncbi.nlm.nih.gov/homologene



Mutations

Somatic

Recurrent mutations in the BIRC5 gene are rare.

Among the 47,119 unique samples reported in

COSMIC (Catalogue of Somatic Mutations in

Cancer;

http://cancer.sanger.ac.uk/cancergenome/projects/c

osmic), only 43 presented BIRC5 mutations (29

missense substitutions, 8 synonymous substitutions,

3 nonsense substitutions and 2 frameshift insertions).

Similar findings are reported in cBioPortal

(http://www.cbioportal.org) among the 55,481

cancer samples accessed, that show somatic

mutations in BIRC5 occur in merely 0.2% of the

tested samples (corresponding to 116 mutations, of

which 65 are missense substitutions, 50 truncated

genes or 1 other mutation). When mutations,

amplifications, deep deletions and multiple

alterations were considered, the total of cancer

samples with any type of genetic alteration in BIRC5

was 969 (1.7%).

Implicated in

Angiosarcoma

In a cohort including 85 samples from angiosarcoma

patients and 88 controls (54 hemangioma and 34

pyogenic granuloma), nuclear BIRC5 expression

was observed in all angiosarcoma patients, but in

fewer than 7% of the control group. This data

indicates that BIRC5 expression may be used as a

diagnosis tool in angiosarcoma (Tsuneki et al.,

2017). In addition, genetic or pharmacological

BIRC5 inhibition reduces cell proliferation in ISO-

HAS-B human angiosarcoma cells (Tsuneki et al.,

2017).

Brain cancer

Western blot analysis revealed that BIRC5 was

expressed in 60.3% of glioma samples, which was

associated with a reduced apoptosis ratio and high-

grade tumors (Bae et al., 2017). In agreement,

samples obtained from gliosarcoma patients

presented elevated expression of BIRC5 in the

nucleus of tumor cells collected from brain lesions,

when compared to normal brain cells (Chen et al.,

2010).

BIRC5 expression was also associated to

radioresistance: ionization of glioblastoma cell lines

promoted BIRC5 upregulation, which mediated

dedifferentiation to a stem-like phenotype and,

consequently, induced a radioresistant phenotype

(Dahan et al., 2014).

Treatment of glioma cells with the survivin inhibitor

YM155 overcomes resistance to TRAIL-induced

apoptosis, by downregulating MCL1 and BIRC5

(Premkumar et al., 2013). In glioblastoma cell lines,

YM155 treatment reduced BIRC5 expression, and

induced apoptosis and DNA fragmentation (Lai et

al., 2012). Similar results were reported by Jane and

colleagues (Jane et al., 2013), where YM155

downregulated BIRC5 and MCL1 expression and

inhibited cell growth in malignant human glioma

cells. Interestingly, in resistant glioma cell lines

attributed to EGFR activation, YM155 alone did not

present any significant effects, however in

combination with ABT-373, a BH3-only mimetic

that targets the prosurvival members of the BCL2

family, a synergic effect mediated by caspase

activation was observed (Jane et al., 2013).

Depletion of BIRC5 levels mediated by parthenolide

treatment induced apoptosis and cell cycle arrest in

glioblastoma cell lines (Tang et al., 2015).

Cucurbitacin-I, another natural product, induced cell

death in malignant glioma cells, while promoting

G2/M accumulation, depletion of p-STAT3, p-

STAT5, p-JAK1 and p- JAK2 levels, and

downregulation of AURKA, AURKB and BIRC5

(Premkumar et al., 2015). Medulloblastoma also

presents elevated level of BIRC5 expression, as

observed for other brain cancers. Similarly,

antagonists of BIRC5 impaired proliferation and

survival of both murine and human medulloblastoma

cells (Brun et al., 2015). High BIRC5 expression was

associated to advanced stages and sporadic tumors in

patients aged greater than 12 months (Islam et al.,

2000), which negatively impacted clinical outcomes

(Azuhata et al., 2001). In addition, BIRC5/p53 and

BIRC5/FAS ratios have been implicated in

neuroblastoma prognosis (Sandler et al., 2002; Tajiri

et al., 2001). In neuroblastoma and

oligodendroglioma cell lines, BIRC5 silencing

reduced cell viability while further inducing mitotic

catastrophe and cell death by caspase-dependent and

-independent pathways (Shankar et al., 2001).

Breast cancer

BIRC5 protein expression was found in 78% of high-

grade and 21.4% of low-grade patients with ductal

carcinoma in situ, indicating that BIRC5 expression

is associated with an advanced stage phenotype in

breast cancer (Chade et al., 2018). In addition,

increased

Estrogen positive breast cancer subtypes have been

connected to increased BIRC5 regulation, w levels

of BIRC5 mRNA (2.24 fold) were observed in whole

blood samples from breast cancer patients when

compared to healthy donors (Wang et al., 2016).

Estrogen positive breast cancer subtypes have been

connected to increased BIRC5 regulation, which was

reverted by treatment with the natural compound

myricetin, enhancing apoptosis (Jiao and Zhang,

2016). In triple negative breast cancer,

chemoresistance and metastasis were associated to

elevated DEPTOR protein expression that, in turn,

induced a higher expression of BIRC5, both in vitro



and in vivo (Parvani et al., 2015). Survivin and

survivin-ΔEx3 were overexpressed and associated to

chemoresistance in non-responder samples using ex

vivo organotypic cultures of primary human breast

tumors (Faversani et al., 2014). Using shRNA

targeting BIRC5 splice variants isoforms, Zheng and

colleagues (Zheng et al., 2011) demonstrated that

apoptosis rates were improved considerably by

survivin depletion, but survivin-ϚEx3 isoform

silencing only moderately inhibited cell survival and

growth in a breast cancer model.

In breast cancer cells, combined therapy using

panobinostat with gemcitabine markedly diminished

BIRC5 expression (Budman et al., 2012). Similarly,

SMAC mimetics (BV6, Birinapant) and BH3-

mimetics (ABT-737/263) combined with paclitaxel

treatment demonstrated positive results regarding

BIRC5 downregulation (Panayotopoulou et al.,

2017).

Chemoresistance was also related to the extracellular

LGALS1 (galectin-1) expression that, moreover,

contributes to cancer progression and doxorubicin

resistance in triple negative breast cancer. It must be

stated, herein, that galectin-1 expression is mediated

by STAT3 activation, which is a transcription factor

that culminates in BIRC5 upregulation,

corroborating the role of BIRC5 in chemoresistance

in breast cancer cells (Nam et al., 2017). The

function for STAT3 in BIRC5 upregulation in breast

cancer cells was also confirmed by Wang and

colleagues (Wang et al., 2015), who demonstrated

that MIR204 inhibits STAT3 activation and BIRC5

expression.

BIRC5 also participates on the invasive phenotype

by regulating the expression of the vascular

endothelial growth factor-C ( VEGFC) at both

protein and mRNA levels, which culminates in a

raised metastasis rate in breast cancer (Cai et al.,

2012). In agreement, elevated BIRC5 expression

was associated with poor prognostic in stage II/III

breast cancer patients (Hamy et al., 2016). The

authors proposed that BIRC5 expression might be

theranostic, and suggest that high BIRC5-expressing

breast cancer patients would be randomized to

receive BIRC5 targeting drugs (Hamy et al., 2016).

A recent study that evaluate the transcriptome of

primary breast cancer patients, demonstrated that,

along with NEK2 and TOP2A, BIRC5 gene was

amplified in obese breast cancer patients, reinforcing

that this gene may be druggable for this population

(Nuncia-Cantarero et al., 2018). One factor that may

explain such observation is the synthesis of visfatin,

an adipokine secreted by adipocytes, macrophages

and inflamed endothelial tissue, which was found to

be increased in obese and breast cancer patients,

while exerting a protective effect on BIRC5, raising

its levels and, thus, contributing to tumor

progression (Gholinejad et al., 2017).

In breast cancer cell lines, including triple negative

phenotype and tamoxifen-resistant cells, YM155, a

BIRC5 inhibitor, as previously mentioned, reduces

cell viability, with IC50 values in the low nanomolar

range, and induced autophagy (Cheng et al., 2015).

In breast cancer cell lines, ABT-263 (navitoclax), a

BCL2 family protein inhibitor, promoted a negative

modulation of BIRC5 levels in MDA-MB-231, but

not in MCF-7, which was associated with a higher

sensitivity to the drug (Lee et al., 2018).

Cervical carcinoma

In a recent meta-analysis including eleven studies

and a total of 865 cervical carcinoma patients, Cheng

and colleagues (Cheng et al., 2016) reported that

elevated BIRC5 expression was positively

associated with aggressive clinicopathological

features, lymph node metastasis and poor survival

outcomes.

Colorectal cancer

Immunohistochemical analysis evidenced that

patients with colorectal adenocarcinomas exhibited

higher BIRC5 levels compared to adjacent non-

tumor colorectal mucosa. In the same study, the

authors demonstrated that BIRC5 silencing, by

siRNA, suppressed survival and cell invasion, and

induced cell cycle G0/G1 arrest and apoptosis in

colorectal cancer cells (Wang et al., 2017b). BIRC5

splice variants were also evaluated in colorectal

cancer, and the distribution of mRNA observed was

the following: 48% of wild-type survivin, 38% of

survivin-2B isoform and 29% of survivin-ΔEx3

isoform. The mRNA expression of wild-survivin and

survivin-ΔEx3 was related with tumor size and

invasion, respectively (Pavlidou et al., 2011). In

contrast, BIRC5 levels were not associated with

patients with advanced colorectal adenoma (Choi et

al., 2017).

Elevated expression of BIRC5 was also correlated

with levels of CD133+, which is associated to

chemoresistance to 5-fluorouracil, in colon cancer

cells. The elevated expression of BIRC5 induced by

activation of the CXCL12/ CXCR4 signaling

pathway in cells exposed to radiation may be a

crucial factor for the acquisition of chemoresistance

in this cancer type (Wang et al., 2017a). However,

no association was found between expression of

BIRC5 and invasion, lymph node metastasis, nor

histologic differentiation (Li et al., 2017). Survivin

depletion by the EpCAM-aptamer-guided BIRC5

RNAi enhanced colorectal cancer stem cells

sensitivity to 5-FU and oxaliplatin, further inducing

apoptosis, reducing tumor growth and improving the

overall survival in a colorectal cancer xenograft

model (AlShamaileh et al., 2017).

The use of natural products was also implicated in

reduction of BIRC5 levels, such as tanshinone I, an

active compound from traditional Chinese herbal



medicine (Lu et al., 2016), and the Pinus roxburghii

essential oil (Sajid et al., 2018). Additionally,

treatment with tamoxifen β-estradiol or a

combination of these two agents promoted decreased

BIRC5 levels and impaired cell migration in

colorectal cancer cells (Ou et al., 2017). In colon

cancer cells, dimethoxy curcumin inhibited cell

growth, increased apoptosis, reduced cell migration,

downregulated BIRC5 expression and enhanced

CDH1 (E-cadherin) in vitro and in vivo (Chen et al.,

2016).

Treatment failure in colorectal cancer was

previously associated to the presence of stem cells

bearing a KRAS mutation, which, then, become

resistant to chemotherapy. Treatment with Omega-3

fatty acid DHA promoted a reduction of cell

viability, with caspase-3 activation mediated by a

decrease in transcript and protein levels of BIRC5

and, moreover, an increase in MIR16-1 expression

levels, suggesting that BIRC5 and microRNA-16-1

to be promising molecular targets of DHA (Sam et

al., 2018).

Endometrial cancer

In endometrial cancer, BIRC5 was identified to be

critical for NEF2-driven progestin resistance. The

authors also demonstrated that BIRC5 silencing

enabled restoration of progestin sensitivity in NRF2-

overexpressing RL-95-2 cells (Fan et al., 2017).

Gastric cancer

Gastric adenocarcinoma patients undergoing

gastrectomy were evaluated for the expression of

markers with relevance for tumor progression and

prognosis. Among them, 93.9 % of samples from

gastric cancer patients presented nuclear sub-

localization of BIRC5, which was associated with a

poor prognosis (Lins et al., 2016). It has been

demonstrated that BIRC5 upregulation increased

VEGF expression in gastric cancer (Zhang et al.,

2014). The authors also demonstrated that 51.3% of

gastric carcinoma samples presented BIRC5

expression, which was located mainly in the

cytoplasm of tumor cells, associated with lymph

node metastasis and reduction of overall survival in

the univariate analysis (Zhang et al., 2014).

BIRC5 knockdown using shRNA promoted an

elevated sensitivity to radiation and chemotherapy

using 5-FU, demonstrating that the modulation of

BIRC5 levels may be an important adjuvant therapy

for gastric cancer patients (Shen et al., 2012). In

agreement, BIRC5 silencing mediated by siRNA

increased apoptosis rates, inhibited cell proliferation

in a cisplatin-resistant cell line (Li et al., 2014) and

impaired cell migration in gastric cancer cells (Li et

al., 2015).

Head and neck squamous cell carcinoma

Hih levels of BIRC5 was observed in samples from

head and neck squamous cell carcinoma patients,

which was associated with poor survival outcomes

and chemotherapy resistance (Zhang et al., 2015a) In

head and neck squamous cell carcinoma cells, a

treatment targeting BIRC5 by using YM155

increased apoptotic and autophagic cell deaths,

suppressing pro-survival pathways (Zhang et al.,

2015a).

Similarly, treatment with an aliphatic hydroxamate-

based compound targeting BIRC5 reduced survivin

levels through LKB1/AMPK/p38MAPK signaling,

and further enhanced p63 phosphorylation and p21

activation (Yen et al., 2018).

Hepatocellular carcinoma

In SMMC-7721 hepatocellular carcinoma cells,

treatment with berbamine, a natural compound from

Chinese medicine, promoted upregulation of p53

expression and downregulation of BIRC5, which

further triggered mitochondria signaling pathway-

mediated apoptosis (Cao et al., 2018).

Kidney cancer

In renal cell carcinoma patients, high BIRC5

expression was associated with increased TNM stage

and high Fuhrman grade, which indicates that

BIRC5 may be a good prognosis predictor (Ma et al.,

2017).

Furthermore, BIRC5 has been associated with tumor

progression and chemoresistance to temsirolimus, an

MTOR inhibitor. Strategies that abrogate survivin

expression, such as shRNA-mediated BIRC5

silencing or pharmacological approach (YM155),

reduced chemoresistance of renal cell carcinoma

cells in vitro and in vivo (Carew et al., 2015).

Other signaling pathways seem to converge to the

induction of BIRC5 expression in renal cell

carcinoma.

For instance, combined treatment between the

histone deacetylase (HDAC) inhibitor OBP-801 and

the phosphatidylinositol 3-kinase (PI3K) inhibitor

LY294002 synergistically inhibited cell growth and

induced apoptosis in renal cell carcinoma through

BIRC5 downregulation (Yamada et al., 2013).

Leukemia

In chronic myeloid leukemia, the oncogenic

signaling induced byBCR/ ABL1 leads to BIRC5

upregulation by activating the JAK2/STAT3

pathway.

Moreover, BIRC5 silencing promoted pronounced

cytotoxic effect in both imatinib-sensitive and -

resistant chronic myeloid leukemia cell lines, a

similar effect to that observed after treatment with



shepherdin, a cell-permeable peptidomimetic

compound that downregulates BIRC5. These

findings indicate that survivin may be a target in

BIRC5-overexpressing leukemias (Stella et al.,

2013). The combined use of C82 (a Wnt/β-catenin

signaling modulator) and nilotinib in chronic

myeloid leukemia progenitor cells inhibited the

expression of CD44, MYC, BIRC5, p-CRKL and p-

STAT5 (Zhou et al., 2017)

In acute myeloid leukemia, BIRC5 overexpression is

involved in drug resistance of leukemia stem cells,

regulated by the ERK/MSK/Sp1/MYC axis (Zhang

et al., 2015b). Interestingly, BIRC5 depletion, by

siRNA, reduced cell proliferation, induced

apoptosis, and synergistically enhanced cytotoxicity

of etoposide in acute myeloid leukemia cells

(Karami et al., 2013). Other molecular signaling that

has been involved in acute myeloid leukemia

resistance is the expression of MUC1 (MUC1-C), an

oncoprotein critical for the onset of tumorigenesis,

which is overexpressed in acute myeloid leukemia

blasts and leukemia stem cells. It has been

demonstrated that targeting MUC1-C reduced

BIRC5 levels and increased sensitivity to cytarabine,

indicating that BIRC5 is involved in multiple

signaling pathways required for survival in leukemia

cells (Stroopinsky et al., 2018).

Acute lymphoblastic leukemia (ALL) patients also

presented elevated levels of BIRC5 and VEGF,

especially prior to treatment with an association of

idarubicin, cytosine arabinoside and etoposide.

Nevertheless, those levels decreased after treatment

(Yang et al., 2013). In children diagnosed with acute

lymphoblastic leukemia, BIRC5 expression was

higher compared to healthy donors. The same group

of patients was monitored during the entire treatment

period and those who went in to complete remission

of the disease presented decreased levels of BIRC5,

compared to diagnosis sample. In contrast, BIRC5

protein levels were elevated in non-survived ALL

patients (Yahya et al., 2012). In acute lymphoblastic

leukemia primary samples and cell lines, treatment

with YM155 exhibited elevated cytotoxicity by

induction of DNA damage, leading to

phosphorylation of CHEK2 and H2AFX and

promoting suppression of BIRC5 expression (Chang

et al., 2015).

It is well accepted that leukemia stem cells

contribute to a reduced treatment efficacy and also to

chemoresistance. The natural product curcumin

decreased BIRC5 levels in leukemia stem cell-like

KG1a in a combined treatment with busulfan, which

may overcome such chemoresistant of leukemia

stem cells (Weng et al., 2015).

Furthermore, Li and colleagues (Li et al., 2018)

observed an association between the presence of C

allele of BIRC5 polymorphism rs9904341, but not of

rs8073069, and an increased risk of acute leukemia

development in a cohort including 182 childhood

acute leukemia patients and 200 controls.

Liver cancer

In samples from hepatocarcinoma patients, 55.4% of

tumor tissues were positive for BIRC5 expression,

which was higher when compared to non-tumor

adjacent tissues (2%). Additionally, BIRC5

expression has been directly correlated with

unfavorable clinical staging and tumor score, and the

presence of extrahepatic metastasis. The authors also

demonstrated a positive correlation between BIRC5

and VEGF expression, implying that besides

avoiding apoptosis, BIRC5 may induces

angiogenesis contribute to tumor dissemination

(Tian et al., 2018).

Lung cancer

A meta-analysis study including 3,206 non-small

cells lung cancer (NSCLC) patients and 816 normal

controls, BIRC5 was found to be overexpressed in

tumor samples and strongly correlated with

histological differentiation, tumor-node-metastasis

stage and lymph node metastasis, which indicates

that BIRC5 may be a tumor progression marker for

such cancer type (Duan et al., 2016). Another study

indicated that BIRC5 may be involved in

chemoresistance of NSCLC cells (Hu et al., 2016).

Additionally, it was demonstrated that the GC+CC

genotypes in the promoter region (-31) of the BIRC5

gene (polymorphism rs9904341) were significantly

associated with EGFR mutations in a cohort of 360

lung cancer patients (Liu et al., 2016).

Recently, BIRC5 was identified as a target of

MIR195, a microRNA that induced apoptosis and

senescence in NSCLC cells (Yu et al., 2018). A

combined therapy using the natural product

resveratrol and the epidermal growth factor receptor

(EGFR) inhibitor erlotinib promoted an increase in

cell death mediated by BIRC5 depletion in NSCLC

cells (Nie et al., 2015). Similarly, depletion of

BIRC5 induced by treatment with YM155 increased

the sensitivity of such cells to radiation (Hu et al.,

2015).

Treatment with the natural product fisetin also

increased sensitivity to cisplatin in cisplatin-resistant

NSCLC cells by modulation of

MAPK/BIRC5/Caspase axis (Zhuo et al., 2015).

Lung cancer stem cells were more sensitive to

FL118, a BIRC5 inhibitor, than cisplatin.

Additionally, FL118 downregulated cancer stem cell

related markers, which may improve drug-sensitivity

in this kind of tumor cells (Wang et al., 2017c).

Lymphoma

In non-Hodgkin lymphoma, specifically the

aggressive subtype extranodal natural killer/T-cell

lymphoma, which is frequently associated with

resistance to anthracyclines, presence of BIRC5



serum levels were detected in approximately 25% of

patients, which is associated with advanced stages of

the disease. In addition, the percentage of lymphoma

cells that demonstrated BIRC5 nuclear localization

was significantly associated with BIRC5 serum

concentration (Kim et al., 2015).

BIRC5 expression was positive in 40% of lymph

node biopsy of diffuse large B-cell lymphoma

patients. Such observation correlated with

unfavorable factors for therapy response and

predicted shorter survival outcomes (Markovic et al.,

2012). A meta-analysis, including 17 studies and

1,352 diffuse large B-cell lymphoma patients, found

positive BIRC5 expression to be associated with

advanced clinical stages and reduced overall survival

(Zhang et al., 2015c).

The combinatory use of bendamustine and rituximab

associated with BIRC5 inhibitor, YM155, presented

potentiating effects on induction of cell death by

triggering DNA damage and cell cycle arrest in

lymphoma cells, and, moreover, reduced tumor size

and metastatic capacity in diffuse large B-cell

lymphoma xenograft murine models (Kaneko et al.,

2014). A combined treatment of rituximab and

YM155 was shown to reduce tumor growth more

effectively than monotherapy (Kita et al., 2012). In

B and T cell lymphoma cells, BIRC5 abrogation

using the non-toxic tellurium compound, AS101, has

overcome chemoresistance, sensitizing these cells to

paclitaxel (Danoch et al., 2015). BIRC5 expression

presented anti-apoptotic functions and is regulated

by NF-κB and PI3K/AKT signaling pathways in

nasal NK/T-cell lymphoma cells (Sun et al., 2015).

Malignant pleural mesothelioma

In two independent cohorts of malignant pleural

mesothelioma patients, nuclear BIRC5 expression in

both, pre- and post-chemotherapy tissues, was

associated with shorter freedom from recurrence and

overall survival, indicating that BIRC5 expression

may be a prognostic factor for poor clinical

outcomes in this cancer type (Meerang et al., 2016).

Melanoma

BIRC5 expression was previously demonstrated in

melanoma and melanocytic nevus, which

demonstrated all nevi, regardless of histologic type,

expressed detectable levels of BIRC5 (Yan et al.,

2006). Additionally, a cytoplasmic staining of

BIRC5 was evidenced in dysplastic nevi (Florell et

al., 2005). In normal melanocytes, it was

demonstrated that p53 and RB1 are required to

repress BIRC5 expression. A role for E2F2 in the

negative regulation of BIRC5 expression was also

pointed out (Raj et al., 2008). Increased BIRC5

expression was observed in vivo in melanocytes that

were more resistant to UV-induced apoptosis, which

was further associated to lower rates of spontaneous

apoptosis, earlier melanocytic tumor development

and increased tendency for lymph node and lung

metastasis (Thomas et al., 2007). Furthermore,

BIRC5 overexpression in melanocytes activated the

AKT and MAPK signaling pathways, acquiring a

more invasive phenotype, and demonstrating the

involvement of BIRC5 on the onset and progression

of melanoma (McKenzie et al., 2013).

In melanoma cells, BIRC5 was associated to

enhanced AKT and MAPK signaling dependent

migration and invasion, as well as to the

upregulation of ITGA5 (α5 integrin) (McKenzie et

al., 2010). BIRC5 silencing through RNA

interference promoted cell cycle arrest and reduced

cell proliferation and metastasis in vivo and in vitro

in melanoma models. Moreover, as observed for

other tumor types, BIRC5 inhibition led to increased

sensitivity to chemotherapy in melanoma cells

(Kedinger et al., 2013). In another study, a proposed

strategy to overcome chemoresistance and to

promote melanoma cell death was the combination

of vemurafenib and Nutlin-3, whose synergism was

responsible for BIRC5 depletion and apoptosis

induction (Ji et al., 2013).

Pharmacological suppression of BIRC5 expression,

using YM155, increased apoptosis induction and

tumor regression in melanoma xenograft models. In

the same study, combined treatment of YM155 and

docetaxel presented potentiating effects in induction

of apoptosis compared to monotherapy,

corroborating the notion that targeting BIRC5 may

be an interesting approach in melanoma

management (Yamanaka et al., 2011). Similar

results were obtained using natural compounds

extracted from plants that target BIRC5 through β-

catenin and STAT3 suppression (Habibie et al.,

2014).

Another alternative approach for targeting BIRC5

was the generation of recombinant fusion proteins

containing the TAT protein transduction domain and

either wild-type survivin (TAT-Surv-WT) or a

dominant- negative mutant (TAT-Surv-T34A). The

mutant promoted in vitro cell death through

apoptosis and DNA fragmentation in melanoma

cells. In vivo injections of such mutant in melanoma

xenograft mice increased apoptosis, induced

aberrant nuclei formation and impaired tumor

growth (Yan et al., 2006).

BIRC5 mRNA was detected in 98% of samples from

metastatic melanoma patients. High BIRC5 mRNA

levels were significantly associated with poor overall

survival (Takeuchi et al., 2005).

Multiple myeloma

BIRC5 expression was positive in 35% of samples

from newly diagnosed multiple myeloma patients,

but no association with clinical and laboratorial

characteristics, treatment response and survival

outcomes was found (Zeng et al., 2014). On the other

hand, Yang and colleagues (Yang et al., 2016b), in a



study that evaluated the efficacy of a combination

treatment with fludarabine, vincristine, epirubicin,

dexamethasone and thalidomide (FVADT)

chemotherapy regimen for refractory multiple

myeloma patients, reported that complete remission

and efficacy rates were significantly lower in the

BIRC5-positive group, when compared with the

BIRC5-negative group.

Myxoid liposarcoma

Using high-throughput drug screen and myxoid

liposarcoma cell lines, BIRC5 has been identified as

a relevant protein important for cell survival (de

Graaff et al., 2017).

Oral squamous cell carcinoma

Elevated BIRC5 mRNA expression was observed in

samples from oral squamous cell carcinoma patients

compared to peritumoral or normal tissues (Li et al.,

2012). Still, such increase was shown to be

insufficient to drive tumor progression in oral

squamous cell carcinoma, however nuclear

expression of BIRC5 was correlated with tumor

stage and differentiation grade (Liu et al., 2017).

Additionally, the authors suggested that nuclear

localization of BIRC5 has been due to the acetylation

at K129 in the protein C-terminal region (Liu et al.,

2017). In oral squamous cell carcinoma cells,

treatment with YM155 reduced BIRC5 levels and

increased apoptosis rates (Yan and Su, 2017).

Ovarian cancer

High BIRC5 levels correlate with advanced stage,

metastasis and poor disease-free survival in ovarian

cancer (Aune et al., 2011; No et al., 2011).

Moreover, BIRC5 serum levels were significantly

higher, while DIABLO (Smac) levels were

significantly lower in patients with serous ovarian

carcinoma when compared to healthy controls

(Dobrzycka et al., 2015).

The association of nuclear and cytoplasmic BIRC5

expression and prognosis remains controversial in

ovarian cancer. The evaluation of BIRC5 expression

in patients treated with taxane and platinum agents

concluded that, in this treatment regimen, higher

nuclear BIRC5 expression was associated with

reduced risk of disease recurrence and death

(Felisiak-Golabek et al., 2011). By contrast, another

study reported that nuclear BIRC5 was significantly

associated with chemoresistance to taxane-based

chemotherapy, predicting poor progression-free

survival (Du et al., 2015). Immunohistochemistry

analysis revealed that BIRC5 expression presented a

positive correlation with FIGO stage in epithelial

ovarian cancer, benign epithelial ovarian tumor

tissue and borderline ovarian tumor tissues (Ju et al.,

2016).

BIRC5 splices variants were also correlated to the

development of ovarian cancer and resistance to

chemotherapy. Taxane-resistant ovarian cancer cells

expressed higher BIRC5 mRNA levels than their

taxane-sensitive counterparts. Survivin-2B

expression was significantly higher in taxane-

resistant cells, when compared to sensitive cells

(Vivas-Mejia et al., 2011).

YM155 treatment induced BIRC5 downregulation,

cell growth inhibition, cell cycle arrest, reactive

oxygen species formation and apoptosis, and

enhanced docetaxel efficacy in ovarian cancer cell

lines (Hou et al., 2018). In agreement, in ovarian

cancer cells, BIRC5 knockdown enhanced cisplatin

sensitivity in resistant cancer cells, inducing

apoptosis and inhibiting the invasive process through

downregulation of MMP2 (Jiang et al., 2013).

Pancreatic cancer

In a cohort of 51 pancreatic adenocarcinoma

patients, BIRC5 expression was found in 49% of

samples and was associated with poor survival

outcomes (Contis et al., 2018). Similar results were

reported by Zhou and colleagues (Zhou et al., 2018),

who described that nuclear BIRC5 was higher in

tumor compared to non-tumor pancreatic tissues,

and a high nuclear BIRC5 expression was an

independent predictor of disease-specific survival in

ductal pancreatic adenocarcinoma patients. In

pancreatic cancer models, FL118, a BIRC5 inhibitor,

reduced cell viability, including for stem cell like and

cisplatin-resistant cells, and decreased xenograft

tumor growth and metastasis (Ling et al., 2018).

Prostate cancer

BIRC5 levels was not detected in normal tissues,

slightly detected in benign prostate hyperplasia

tissues and considerably higher in prostate

adenocarcinoma, which was positively correlated

with higher tumor stage (Eslami et al., 2016). In

agreement, increased BIRC5 levels were also

associated with poor survival outcomes in prostate

cancer patients (Xu et al., 2015).

In a cohort including 157 prostate cancer patients

and 145 controls, genetic polymorphisms c.-31G>C

(rs9904341), c.454G>A (rs2071214), and c. *148T>C (rs1042489) of BIRC5 were associated

with risk for prostate cancer development (Karimian

et al., 2018).

Treatment with BIRC5 inhibitor (YM155) inhibited

cell growth, cell migration and invasion in prostate

cancer cells (Xu et al., 2015). Overexpression of

miR-494 (a microRNA targeting BIRC5) and/or

BIRC5 silencing using shRNA attenuated cell

growth in vitro and in vivo (Zhu et al., 2016).

Moreover, treatment of prostate cancer cells with a

selective inhibitor of nuclear export, KPT-330,

inhibited proliferation and promoted apoptosis of

tumor cells, by increasing protein degradation of

exportin XPO1, BIRC5 and CCND1, further leading

to cell cycle arrest and apoptosis (Gravina et al.,

2015). Natural products, such as the triterpenoid



pristimerin, demonstrated that BIRC5 levels may

modulate therapeutic responses, once BIRC5-

overexpressing prostate cancer cells became

resistant to pristimerin (Liu et al., 2014).

Salivary adenoid cystic carcinoma In SACC-83 salivary adenoid cystic carcinoma cells,

treatment with simvastatin reduced cell viability and

induced apoptosis by decreasing BIRC5 levels (Cai

et al., 2018).

Thyroid cancer Nicotinamide phosphorybosiltransferase (NAMPT),

a marker for thyroid cancer that is positively

associated with tumor stage and metastasis,

presented a positive correlation with BIRC5

(survivin) and survivin splice variant º, but not with

survivin-2B, expressions, reinforcing that survivin

and its variant ΔEx3 are associated with poor

prognosis and advanced stage cancer (Sawicka-

Gutaj et al., 2015).

Urinary tract cancer In SK-NEP-1 Wilms tumor cells, YM155 treatment

reduced cell proliferation, induced apoptosis and

inhibited growth of xenograft tumors. Interestingly,

YM155 treatment promoted an elevation in levels of

other BIRC-related genes, such as BIRC3 and

BIRC8, suggesting that the regulation of cell death

induced by BIRC5 suppression is highly

orchestrated with other members of the IAP family

(Tao et al., 2012).

To be noted

Pharmacological Advances for BIRC5 inhibition YM155, a small-molecule BIRC5 inhibitor, was

developed in 2007 and tested in multiple cancer

models. YM155 caused a concentration-dependent

cytotoxic effect with IC50 values reaching nanomolar

concentrations (Nakahara et al., 2007; Rauch et al.,

2014). The mechanism of action for YM155

involves a selective inhibition of BIRC5 promoter

activity by disrupting Sp1 interaction in a specific

region of the BIRC5 core promoter. Such repression

occurs in a cell cycle-independent manner (Cheng et

al., 2012).

A novel survivin inhibitor developed in 2012,

FL118, presents structural similarities to irinotecan.

Such molecule selectively inhibits survivin promoter

activity and gene expression in a TP53 status-

independent manner.

Additionally, it promotes the inhibition of three

additional cancer-associated survival genes (MCL1,

BIRC4 and BIRC3) (Ling et al., 2012). FL118 was

able to suppress BIRC5 expression in cancer stem

cells in a lung cancer model (Wang et al., 2017c),

which are known to be a cell population that presents

chemoresistance and are responsible for disease

recurrence in multiple type of cancer (Zhao, 2016).

Vaccines against BIRC5 Survivin-2B80-88 (AYACNTSTL) is an antigenic

peptide that can be recognized by CD8+ cells and

demonstrated promising results as a potent

immunogenic cancer vaccine (Idenoue et al., 2005).

By using an HLA-A24/survivin-2B80-88 tetramer,

the number of cytotoxic T-lymphocytes precursors

in peripheral blood mononuclear cells of HLA-A24+

cancer patients was increased. Interestingly,

cytotoxic cells positive for this peptide were found

among peripheral blood mononuclear cells obtained

from 100% of patients with breast cancers (n=7),

83% with colorectal cancers (n=7) and 57% with

gastric cancers (n=7) (Idenoue et al., 2005).

Dendritic cells vaccines using recombinant BIRC5

were tested in hormone refractory prostate cancer

patients and results revealed cellular response,

disease stabilization, partial tumor remission and no

adverse events (Xi et al., 2015).

Using the DepoVax platform, a BIRC5 vaccine was

developed (DPX-Survivac) and produced antigen-

specific immune responses in ovarian cancer

patients. Of note, 12 out of 18 ovarian patients

remained without clinical progression after a 6-

month treatment (Berinstein et al., 2015).

A study using vaccination with a long BIRC5

peptide demonstrated a BIRC5-specific CD8-

mediated tumor cell lysis and, more importantly, the

presence of circulating anti-BIRC5 antibodies was

found in both, murine glioblastoma models and

human glioblastoma patients following vaccination.

The same vaccine showed promising results in

GL261 glioma and B16 melanoma murine models

(Fenstermaker et al., 2018).

Gene Therapy targeting BIRC5 Gene therapy has already been used as an approach

for inhibiting the expression of BIRC5 and to

improve cell death induction in cancer. A combined

gene therapy using BIRC5 siRNA and the fusion

suicide gene yCDglyTK system displayed a relevant

antitumor effect, inducing apoptosis more efficiently

and eradicating colon cancer cells. Furthermore, this

therapeutic system was able to inhibit the migration

of colon cancer cells in vitro (Ye et al., 2017).

Pharmacological approaches

Drug Clade Cancer type References

YM155 Small-molecule survivin inhibitor Multiple cancer

types

Cheng et al., 2014; Jane

et al., 2013; Kita et al.,

2012; Lai et al., 2012



FL118 Small-molecule survivin inhibitor Cancer Stem Cell Wang et al., 2017

Vaccines

Vaccine Clade Cancer Type References

Survivin-2B80-88 Antigenic peptide

Breast cancer;

Gastric cancer;

Colorectal cancer

Idonoue et al., 2005

Dendritic Cell

Vaccines

Dendritic cells vaccines using recombinant

BIRC5

Hormone

refractory prostate

cancer patients

Xi et al., 2015

DPX-Survivac BIRC 5 vaccine developed based on

DepoVax platform Ovarian cancer Berinstein et al., 2015

SurVaxM Long BIRC5 peptide Gliobastoma Fernstermarker et al.,

2018

Gene Therapy

Strategy Cancer Type References

Suicide gene yCDglyTK combined with BIRC5 siRNA Colon cancer cells Ye et al., 2017

Heparin-polyethyleneimine (HPEI) nanoparticles to deliver a

dominant-negative human BIRC5 T34A (hs-T34A) Ovarian carcinoma Luo et al.,2016

Packaging RNA (pRNA) of bacteriophage phi29 DNA-

packaging motor to carry BIRC 5 and methallotionein siRNA Ovarian carcinoma Tarapore et al., 2011

Adeno-associated virus (aaV)-mediated the dominant-negative

human BIRC5 T34A (raaV-Sur- Mut(T34a) Gastric cancer Dang et al., 2015

Nanotechnology

Strategy of use Nanoparticle Cancer Type References

Nanoparticles for

siRNA delivery

Fe3O4 core covered respectively by

polyacrylate (PA) and polyethyleneimine

(PEI) layer (Fe3O4-PA-PEI)

Breast cancer Arami et al., 2016

Magnetic nanoparticles containing

polyethyleneglycol-lactate polymer (PEG-

LAC), chitosan, and polyethyleneimine

(PEI)

Breast cancer and

Leukemia Arami et al., 2017

Poly(ethylene glycol)-modified chitosan

(PEG-CS)

Murine breast

cancer Sun et al., 2016

NDCONH(CH2)2NH-VDGR/survivin Breast cancer Bi et al., 2016

Nanoparticles for

shRNA delivery

Monomethoxypolyethylene glycol-chitosan

(mPEG-CS) Prostate cancer Yang et al., 2015

Nanoparticles for

combinatory

treatment

Nanoparticles were also developed for co-

delivery of siRNA targeting BIRC5 and

paclitaxel

Murine cancer

models

Jin et al., 2018; Salzano

et al., 2015

Table 2. Summary of BIRC5 targeting strategies in cancer.

Gene therapy using degradable heparin-

polyethyleneimine (HPEI) nanoparticles to deliver a

dominant-negative human BIRC5 T34A (hs-T34A)

gene was also used in ovarian cancer with promising

results. HPEI nanoparticles effectively delivered the

hs-T34A into ovarian carcinoma cells with low

systemic cytotoxicity. Additionally, intraperitoneal

administration of HPEI/hs-T34A complexes

inhibited tumor growth in ovarian cancer xenograft

murine model (Luo et al., 2016). The use of

packaging RNA (pRNA) of bacteriophage phi29

DNA-packaging motor to carry siRNA for combined

BIRC5 and metallothionein silencing presented a

stronger effect on reducing cell proliferation and

aggressiveness in ovarian tumor cell lines than either

one applied alone (Tarapore et al., 2011).

Adeno-associated virus (aaV)-mediated the

dominant-negative human BIRC5 T34A (raaV-Sur-

Mut(T34a)) delivery inhibited cell proliferation,

induced apoptosis and sensitized gastric cancer cells



to 5-FU in vitro and impaired tumor growth in vivo

(Dang et al., 2015).

Nanotechonology for BIRC5 depletion Several nanotechnology-based systems were

developed to improve the delivery of siRNA or

shRNA targeting BIRC5 in cancer cells, including a

Fe3O4 core covered respectively by a polyacrylate

(PA) or polyethyleneimine (PEI) layer (Fe3O4-PA-

PEI) (Arami et al., 2016). Moreover, magnetic

nanoparticles containing polyethyleneglycol-lactate

polymer (PEG-LAC) have also been used for such

means, as well as other systems, like chitosan and

polyethyleneimine (PEI) (Arami et al., 2017),

poly(ethylene glycol)-modified chitosan (PEG-CS)

(Sun et al., 2016), NDCONH(CH2) 2NH-

VDGR/survivin (Bi et al., 2016) and

monomethoxypolyethylene glycol-chitosan (mPEG-

CS) (Yang et al., 2016a). These systems have been

shown to inhibit expression of BIRC5, increase

apoptosis, reduce cell proliferation and metastasis,

and to shrink tumor size in multiple cancer models.

Nanoparticles were also developed for co-delivery of

siRNA targeting BIRC5 and paclitaxel, which

constrained tumor growth, prolonged survival and

augmented anticancer properties of paclitaxel in

murine cancer models (Jin et al., 2018; Salzano et al.,

2015).

A summary of approaches to BIRC5 targeting in

cancer is described in Table 2.

Funding: Process numbers: 2017/09022-8 and

2015/17177-6, Fundação de Amparo à Pesquisa do

Estado de São Paulo (FAPESP)

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This article should be referenced as such:

Branco PC, Jimenez PC, Machado-Neto JA, Costa-Lotufo LV. BIRC5 (baculoviral IAP repeat containing 5). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):168-186.

Gene Section Short Communication




SLC45A2 (solute carrier family 45 member 2) Mainak Sengupta, Tithi Dutta, Kunal Ray

University of Calcutta, Department of Genetics, 35, Ballygunge Circular Road, Kolkata - 700 019,

India. [email protected]; [email protected] (MS, TD) ATGC Diagnostics Private

Limited, Kolkata, India, [email protected] (KR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC45A2ID41306ch5p13.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70469/01-2019-SLC45A2ID41306ch5p13.pdf DOI: 10.4267/2042/70469


Abstract SLC45A2 gene, having a chromosomal location

5p13.2, encodes a membrane associated transporter

protein (MATP). MATP is a transmembrane protein.

It is present in the melanosomal membrane in the

melanocytes. It maintains the osmotic potential by

regulating the pH of the melanosomal lumen.

Defects in the SLC45A2 gene causes

oculocutaneous albinism type IV; OCA IV

Keywords

SLC45A2, MATP, albinism, OCA IV

Identity

Other names: AIM1, SHEP5; OCA4

HGNC (Hugo): SLC45A2

Location: 5p13.2

DNA/RNA

Description

In Chromosome 5, the 40,529 bases of DNA starts

from 33,944,616 and ends at

33,985,144(GRCh38/hg38). Orientation: Minus

strand. It contains 7 exons.

Transcription

The gene after transcription produces 7 different

mRNAs, 6 alternatively spliced variants and 1

unspliced form. There are 4 non overlapping

alternative last exons

(https://www.ncbi.nlm.nih.gov/IEB/Research/Acem

bly/av.cgi?db=humanterm=slc45a2submit=Go).

Protein

Description

The human SLC45A2 protein is a 530-amino acid

polypeptide that contains 12 putative trans-

membrane domains, and is only expressed in the

melanosomes in the melanocytes (Newton et al.,

2001).

The SLC45A2 gene initially identified as AIM1

(absent in melanoma 1) by Newton et al, 2001

encodes a Membrane-Associated Transporter

Protein (MATP). It acts as a transporter and

regulates the melanosomal pH using a proton

gradient.

Figure 1. SLC45A2 Gene in genomic location: Cytogenetic band: 5p13.2 by Entrez Gene, 5p13.2 by HGNC, 5p13.2. The figure represents the cytogenetic banding of SLC45A2 locus (Ref https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC45A2)

https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=humanterm=slc45a2submit=Go

https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=humanterm=slc45a2submit=Go

SLC45A2 (solute carrier family 45 member 2) Sengupta M et al.


Figure 2. The SLC45A2 (MATP) acts as a transporter present on the melanosomal membrane. Under normal condition it controls the pH by using a proton gradient. Thus helps in Copper to bind to Apo-Tyrosinase and convert it to active Tyrosinase.

In oculocutaneous albinism type IV (OCA4), any deleterious mutation in melanosomal MATP transporter protein makes the melanosomal lumen acidic. Under this condition, the Cu fails to bind to the Apo-Tyr and Tyrosinase activity is reduced. (Bin et al,

2015).

Expression

The MATP protein (58 kDa) is expressed in most

melanoma cell lines and melanocytes and sorted into

the melanosomal membrane. The highest expression

level has been observed in the pigmented layer of

retina (https://www.uniprot.org/uniprot/Q9UMX9).

Localisation

It is a transmembrane protein present in the

melanosomal membrane in melanin producing

melanocytes.

Function

SLC45A2 (MATP) allows the transport of sugar

molecule across the membrane into the cytoplasm

and maintains osmotic potential of the melanosomes

(Rabea Bartolke, 2014, Reinders et al 2015). It

maintains the pH of the melanosome which

facilitates the binding of Copper to Tyrosinase

resulting in the conversion of Apo-Tyrosinase to

Tyrosinase. (Newton et al, 2011).

Homology

The human MATP shows syntenic homology with

the proximal region of mouse chromosome 15. The

human orthologue for the mouse underwhite gene

locus (uw gene) is encoded by SLC45A2 gene. The

predicted mouse MATP protein is 82% identical and

87% similar to the human MATP protein.

The highest degree of homology was found between

MATP and sucrose/proton symporters found in

plants. The homologous region of MATP includes

the sucrose-transporter signature sequence: R-X-G-

R-[K/R], found in between the transmembrane

domains 2 and 3 (Meyer H et al, 2011, Newton et al,

2011).

The sucrose transporter Slc45-1 in Drosophila shows

significant similarity to mammalian SLC45A2 and

plays a role in melanin synthesis.

Mutations

Germinal

Homozygous mutation or Compound Heterozygote

mutations in SLC45A2 gene has been found

responsible for causing Oculocutaneous Albinism

Type 4 (OCA4). To date around 80 mutations have

been reported in SLC45A2 responsible for OCA4.

(Kamaraj et al. 2014, Toth et al. 2017). OCA4 was

first observed in Turkish population, it is rare among

Caucasians and Africans and in Japan it is diagnosed

in one of four persons affected with OCA.

There are several non-pathogenic polymorphisms

which result into mild pigmentation.

The haplotypes at SLC45A2 is significantly

associated in determination of dark or light

pigmentation features in human population.

(Fracasso et al.2017)

Epigenetics

In an attempt to identify genetic and epigenetic

marks involved in population structure, a coding

SNP: rs16891982 (p.L374F) of SLC45A2, known to

play a role in normal pigmentation variation, was

found to positively correlate with the methylation

level of PM20D1 gene. The minor allele A was been

found to be associated with lower methylation of the

target gene.

(https://www.ncbi.nlm.nih.gov/pubmed/20949057).

Implicated in

Oculocutaneous albinism type IV (OCA IV)

Disease

OCA IV is an autosomal recessive disorder of

melanin biosynthesis that results in congenital

hypopigmentation of ocular and cutaneous tissues.

Common developmental abnormalities of the eye

like decreased visual acuity, macular hypoplasia,

optic dysplasia, atypical choroidal vessels, and

nystagmus are observed in patient suffering from

OCA type IV.

SLC45A2 (solute carrier family 45 member 2) Sengupta M et al.


The severity of hypopigmentation is correlated with

melanosome size, shape, melanin content and

maturity of the melanosomal structures

demonstrating that the encoded protein is a major

determinant of mammalian pigmentation.

Melanoma

In 2017, Park et al reported that a few variants

present in SLC45A2 gene can be a promising

immune therapeutic target for melanoma with high

tumor selectivity and reduced potential for

autoimmune toxicity.

It is associated with an increased risk for melanoma

in light-skinned populations, and the encoded

protein can elicit immune recognition.

The Cancer Genome Atlas Research Network

(TCGA) database reported that it is expressed by

approximately 80% of cutaneous melanomas.

In the same year Hafner et al showed that SLC45A2

(also called AIM1, absent in melanoma 1) function

as a key suppressor of invasive phenotypes by

working in association with the actin cytoskeleton.

SLC45A2 becomes dysregulated and suppresses

cytoskeletal remodelling in primary and metastatic

prostate cancer and in non-malignant prostate

epithelial cells.

In 2012, Fernandez et al reported in a family that

adult siblings presented with congenital neutropenia

which later developed into Crohn's Disease.

Molecular characterisation revealed homozygous

mutations both in G6PC3 and SLC45A2 in the sister

and mutation in single allele for both genes in the

brother.

References

Bartölke R, Heinisch JJ, Wieczorek H, Vitavska O. Proton-associated sucrose transport of mammalian solute carrier family 45: an analysis in Saccharomyces cerevisiae. Biochem J. 2014 Dec 1;464(2):193-201

Bin BH, Bhin J, Yang SH, Shin M, Nam YJ, Choi DH, Shin DW, Lee AY, Hwang D, Cho EG, Lee TR. Membrane-Associated Transporter Protein (MATP) Regulates Melanosomal pH and Influences Tyrosinase Activity. PLoS One. 2015;10(6):e0129273

Kamaraj B, Purohit R. Mutational analysis of oculocutaneous albinism: a compact review. Biomed Res Int. 2014;2014:905472

Lamason RL, Mohideen MA, Mest JR, Wong AC, Norton HL, Aros MC, Jurynec MJ, Mao X, Humphreville VR, Humbert JE, Sinha S, Moore JL, Jagadeeswaran P, Zhao W, Ning G, Makalowska I, McKeigue PM, O'donnell D, Kittles R, Parra EJ, Mangini NJ, Grunwald DJ, Shriver MD, Canfield VA, Cheng KC. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science. 2005 Dec 16;310(5755):1782-6

Meyer H, Vitavska O, Wieczorek H. Identification of an animal sucrose transporter. J Cell Sci. 2011 Jun 15;124(Pt 12):1984-91

Newton JM, Cohen-Barak O, Hagiwara N, Gardner JM, Davisson MT, King RA, Brilliant MH. Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Am J Hum Genet. 2001 Nov;69(5):981-8

Reinders A, Ward JM. Investigating polymorphisms in membrane-associated transporter protein SLC45A2, using sucrose transporters as a model. Mol Med Rep. 2015 Jul;12(1):1393-8

Tóth L, Fábos B, Farkas K, Sulák A, Tripolszki K, Széll M, Nagy N. Identification of two novel mutations in the SLC45A2 gene in a Hungarian pedigree affected by unusual OCA type 4. BMC Med Genet. 2017 Mar 15;18(1):27


Sengupta M, Dutta T, Ray K. SLC45A2 (solute carrier family 45 member 2). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):187-189.

Leukaemia Section Short Communication




Burkitt's lymphoma (BL) Luis Miguel Juárez Salcedo, Ana Corazón Monzón, Samir Dalia

Principe de Asturias University Hospital, Madrid, Spain (LMJS); Clinic Valladolid University

Hospital, Valladolid, Spain (ACM); Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO,

USA [email protected] (SD).


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/BurkittID2077.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70470/01-2018-BurkittID2077.pdf DOI: 10.4267/2042/70470

This article is an update of : Cuneo A, Castoldi GL. Burkitt's lymphoma (BL). Atlas Genet Cytogenet Oncol Haematol 2001;5(2)


Abstract Review on Burkitt's lymphoma, with data on clinics,

and the genes involved.

Keywords

Burkitt's lymphoma; MYC; IGH; IGK; IGL

Identity Other names: Burkitt's tumor; Malignant

lymphoma Burkitt's type

Clinics and pathology

Phenotype/cell stem origin

Pan-B antigens positive (CD19, CD20, CD21, CD22

and CD79a); co-expression of CD10 and Bcl-6.

TdT-, CD5-, CD23-, Bcl-2- and CD138-; sIgM+.

The cell of origin is a peripheral IgM+ memory B-

cell (presence of somatic hypermutation of the Ig

gene). Ki67 expression is close to 100% of

neoplastic cells.

Etiology

Burkitt lymphoma (BL) originates from germinal or

post-germinal center B cells. The three clinical

subtypes are: endemic, sporadic and

immunodeficiency-related. All of these likely arise

from B cells at different stages of development.

The development of BL is dependent upon the

constitutive expression of the MYC proto-oncogene

located at chromosome 8q24. The transcription of

MYC protein modulates the expression of target

genes that regulate many cell processes including

cell growth, division, metabolism and apoptosis.

Chronic Epstein-Barr virus (EVB) infection appears

to play a role in all cases of endemic BL and minority

of sporadic and immunodeficiency-associated BL

(Klapproth and Wirth, 2010).

Epidemiology

Most common in children (1/3 of lymphomas).

Endemic BL is mainly confined to equatorial Africa

where it accounts for 30-50% of all childhood

cancers diagnosed each year (3-6 cases per 100.000

children).

Sporadic variant is mostly seen in the US and

Western Europe. 30% of pediatric lymphomas and

3 distinct peaks at around age 10, 40 and in the

elderly. In all groups, most patients are male with a

3:1 or 4:1 male to female ratio (Magrath, 2012).

Clinics

African endemic variant usually develops in

children with a jaw or facial bone tumor; initial

involvement of the abdomen is less common.

The primary tumor can spread to mesentery, ovary,

testis, kidney, breast, and meninges, spreading to

lymph nodes, mediastinum, and spleen less

frequently.

The non-endemic variant may be associated with

immunodeficiency states and usually presents with

abdominal involvement (distal ileum, ciecum,

mesentery). Presenting symptoms can be related to

bowel obstruction or gastrointestinal bleeding,

Burkitt's lymphoma (BL) Juárez Salcedo LM et al.


mimicking acute appendicitis or intussusception.

Lymphadenopathy is generally localized.

The disease is very aggressive and requires prompt

treatment with appropriate regimens.

Cytology

The blast cells in the peripheral blood and bone

marrow display a basophilic cytoplasm with

characteristic vacuolization, a picture

indisinguishable from acute lymphoblastic leukemia

(ALL) L3 of the FAB classification, which

represents the leukemic counterpart of BL.

WHO recognize three different types of Burkitt

Lymphoma:

Classic Burkitt lymphoma: Characterized for the

monomorphic medium-size blast proliferation, with

lax chromatin, multiple nucleolis and intense

basophilic cytoplasm.

Plasmablastic Burkitt Lymphoma and Atypical

Burkitt lymphoma: Cells with nuclear

pleomorphism and nucleoli of big size but in inferior

number to the observed in the classic form.

The three variants, blastic cells can be associated

with plenty mitotic images.

Pathology

The tumor mass demonstrate complete effacement of

the normal architecture by sheets of atypical

lymphoid cells.

At low power, the tumor has a 'mouth-eaten'

appearance, often with interspersed areas of

coagulative necrosis or hemorrhage. High rate of

proliferation and high rate of apoptotic cell death is

observed. A classic 'starry-sky' pattern is usually

present, imparted by numerous benign macrophages

that have ingested apoptotic tumor cells. The benign

histiocytes are large with abundant, clear cytoplasm

and are dispersed throughout of basophilic tumor

cells.

At high power, classically are monomorphic,

medium-size cells with round nuclei, multiple dark

nucleoli, and basophilic cytoplasm.

The related form 'Burkitt-like' lymphoma shows

intermediate features between diffuse large cell

lymphoma and BL and probably includes different

disease entities. It was suggested by the WHO panel

that only those cases with MYC rearrangement

and/or a >99% proliferation fraction as demonstrated

by Ki-67 positivity should be classified as Burkitt-

like lymphoma.

Treatment

Aggressive regimens specifically designed for this

lymphoma must be used.

Multiple intensive regimens demonstrate excellent

activity in BL and are composed of doxorubicin,

alkylators, vincristine, and etoposide combined with

therapy directed at the eradication and/or

prevention of central nervous system disease.

In patients younger than 60 years of age, including

those with well-controlled HIV, and those up to 70

years of age with good baseline functional status,

CODOX-M is recommended.

Patients with extensive disease and elevated LDH, 2

cycles each of R-CODOX-M and R-IVAC can be

used.

For patients with low-risk disease (a single site of

disease and normal LDH) 3 cycles of R-CODOX-M.

For patients with preexisting organ dysfunction, or

significant comorbidities and patients older than 60

years of age with low-risk disease, DA-REPOCH

could be considering a great option associated with

IT therapy or systemic methotrexate upon the

completion of cycle 6.

The addition of rituximab to hyper-CVAD may

improve outcome in adult BL or B-ALL, particularly

in elderly patients (Castillo et al., 2013; Jacobson

and LaCasce, 2014; Dozzo et al., 2016).

Evolution

Apart from the occasional refractory case, a few

responsive BL patients will relapse soon after

treatment completion and generally within the first 6

months of follow-up.

Results in refractory/relapsed BL are extremely

poor, and new options are urgently needed.

Relapse and progression frequency varies according

to first-line treatment used.

In chemoresistant disease cases, experimental

therapies, due to the globally poor results of

traditional salvage programs, should be considered

in all refractory or relapsed cases.

Prognosis

If treated promptly with appropriate regimens the

majority of patients can be cured.

Cytogenetics

Cytogenetics morphological

The molecular hallmark of BL is the translocation of

the MYC proto-oncogene to the Ig heavy or 1 light

chain genes, leading to constitutive MYC activation.

In classic BL, either endemic type or sporadic type,

90-95% of Ig loci are involved, 85% for t(8:14)/ IgH-

MYC, 10% for t(8;22)(q24;q11) /Ig-lambda /MYC

and approximately 5% for t(2;8)(p12;q24) /Ig-

kappa/MYC.

In the Burkitt-like form there are at least 3

cytogenetic categories: one with an 8q24/MYC

translocation, one with an 8q24 and 18q21/ BCL2

translocation and another with "miscellaneous"

rearrangements, frequently including an 18q21 break

(Bellan et al., 2005).



Additional anomalies

Recurrent chromosome aberrations associated with

the 8q24 translocations include 1q21-25

duplications, deletions of 6q11-14, 17p deletions and

trisomy 12, +7, +8 and +18.

Genes involved and proteins

MYC

Location 8q24.21

Protein

MYC functions as a transcriptional regulator. MYC

binds to MAX that is an obligate heterodimeric

partner for MYC in mediating its functions.

The MYC-MAX complex is a potent activator of

transcription. Thousands of MYC target genes have

been identified. Genes targeted by MYC include

mediators of metabolism, biosynthesis, and cell

cycle progression (Mohamed 2017).

IGH

Location 14q32.33

Note

Alternatively: IGK, located in 2p11.2 or IGL,

located in 22q11.22

Result of the chromosomal anomaly

Fusion protein

Oncogenesis

Constitutive expression of MYC is crucial for the

pathogenesis of BL, this protein being a key

transcriptional regulator, controlling cell

proliferation, differentiation and death.

The deregulated expression of MYC, caused by the

8q24 translocations, is achieved through multiple

mechanisms: a) juxtaposition to regulatory elements

of the Ig loci, b) mutations in the MYC 5' regulatory

regions and, c) aminoacid substitutions occurring in

exon 2, making the MYC transactivation domain less

susceptible to modulation (Hecht and Aster, 2000).

Additional gene alterations include the following:

truncating mutations of ARID1A and amplification

of MCL1; point mutations of LRP6; truncating

alterations of LRP1B, PTPRD, PTEN, NOTCH1,

and ATM; amplifications of RAF1, MDM4, MDM2,

KRAS, IKBKE, and CDK6; deletion of CDKN2A;

overexpression ofMIR17HG; activating mutations

of TCF3 and/or inactivating mutations of its negative

regulator ID3; and CCND3 activating mutations

(Havelange et al., 2016).

References

Bellan C, Lazzi S, Hummel M, Palummo N, de Santi M, Amato T, Nyagol J, Sabattini E, Lazure T, Pileri SA, Raphael M, Stein H, Tosi P, Leoncini L. Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas. Blood. 2005 Aug 1;106(3):1031-6

Castillo JJ, Winer ES, Olszewski AJ. Population-based prognostic factors for survival in patients with Burkitt lymphoma: an analysis from the Surveillance, Epidemiology, and End Results database. Cancer. 2013 Oct 15;119(20):3672-9

Gaidano G. Molecular genetics of malignant lymphoma. In: Fo R (ed): Reviews in clinical and experimental hematology. Forum Service Editore, Genova and Martin Dunitz, London,. 1997. Catalogue of chromosome aberrations in cancer (5th edition). Mitelmam F ed Wiley Liss, New York. 1994.

Gibbs RF. The present and future medicolegal importance of record keeping in anesthesia and intensive care: the case for automation J Clin Monit 1989 Oct;5(4):251-5

Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997 J Clin Oncol 1999 Dec;17(12):3835-49

Havelange V, Pepermans X, Ameye G, Théate I, Callet-Bauchu E, Barin C, Penther D, Lippert E, Michaux L, Mugneret F, Dastugue N, Raphaül M, Vikkula M, Poirel HA. Genetic differences between paediatric and adult Burkitt lymphomas Br J Haematol 2016 Apr;173(1):137-44

Hecht JL, Aster JC. Molecular biology of Burkitt's lymphoma J Clin Oncol 2000 Nov 1;18(21):3707-21

Jacobson C, LaCasce A. How I treat Burkitt lymphoma in adults Blood 2014 Nov 6;124(19):2913-20

Klapproth K, Wirth T. Advances in the understanding of MYC-induced lymphomagenesis Br J Haematol 2010 May;149(4):484-97

Kornblau SM, Goodacre A, Cabanillas F. Chromosomal abnormalities in adult non-endemic Burkitt's lymphoma and leukemia: 22 new reports and a review of 148 cases from the literature Hematol Oncol 1991 Mar-Apr;9(2):63-78

Macpherson N, Lesack D, Klasa R, Horsman D, Connors JM, Barnett M, Gascoyne RD. Small noncleaved, non-Burkitt's (Burkit-Like) lymphoma: cytogenetics predict outcome and reflect clinical presentation J Clin Oncol 1999 May;17(5):1558-67

Mohamed AN. MYC (MYC proto-oncogene, bHLH transcription factor) Atlas Genet Cytogenet Oncol Haematol. in press. On line version : http://AtlasGeneticsOncology.org/Genes/MYCID27.html

Polito P, Cilia AM, Gloghini A, Cozzi M, Perin T, De Paoli P, Gaidano G, Carbone A. High frequency of EBV association with non-random abnormalities of the chromosome region 1q21-25 in AIDS-related Burkitt's lymphoma-derived cell lines Int J Cancer 1995 May 4;61(3):370-4

Schlegelberger B, Zwingers T, Harder L, Nowotny H, Siebert R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Nader A, Ott G, Müller-Hermelink K, Feller A, Heinz R. Clinicopathogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma Kiel-Wien-Lymphoma Study Group Blood



Siebert R, Matthiesen P, Harder S, Zhang Y, Borowski A, Zühlke-Jenisch R, Metzke S, Joos S, Weber-Matthiesen K, Grote W, Schlegelberger B. Application of interphase

fluorescence in situ Hybridization for the detection of the Burkitt translocation t(8;14)(q24;q32) in B-cell lymphomas Blood 1998 Feb 1;91(3):984-90


Juárez Salcedo LM, Corazón Monzón A, Dalia S. Burkitt's lymphoma (BL). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):190-193.

Leukaemia Section Review




t(X;14)(p22;q32) or t(Y;14)(p11;q32) IGH/CRLF2 Daniel Martinez-Anaya, Rocio Juárez-Velázquez, Dafné Moreno-Lorenzana, Patricia

Pérez-Vera

Laboratorio de Genética y Cáncer. Instituto Nacional de PediatrÍa (DMA, RJV, PPV), Posgrado en

Ciencias Biolgicas, Universidad Nacional Autnoma de México (DMA), Cátedra CONACYT-Instituto

Nacional de PediatrÍa (DML); [email protected]

Published in Atlas Database: December 2017

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0X14p22q32IGHCRLF2ID1769.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70471/12-2017-t0X14p22q32IGHCRLF2ID1769.pdf DOI: 10.4267/2042/70471


Abstract Review on t(X;14)(p22;q32) or t(Y;14)(p11;q32)

with data on the genes involved, and clinics.

Keywords

IGH; CRLF2, B cell precursor Acute Lymphoblastic

Leukemia (ALL), Ph-like, BCR/ABL1ñlike ALL.

Clinics and pathology

Disease

Provisional entity: B-lymphoblastic

leukemia/lymphoma, BCR/ABL1ñlike (Arber et al.

2016)

Etiology

The translocation IGH/CRLF2 involves a CpG break

at CRLF2 and a V(D)J break at IGH locus, and

produce overexpression of the CRLF2 protein

(Schmäh et al. 2017).

Epidemiology

Reports about the IGH/CRLF2 prevalence have been

obtained from selected and unselected patients,

mostly from retrospective cohorts; as a consequence

contrasting results have been informed. The Medical

Research Council (MRC) found IGH/CRLF2 in 1%

of paediatric patients (Ensor et al. 2011); in adults

with Ph-like this translocation has been detected in

57.6% of cases (Roberts et al. 2017). A recent study

reports in ALL

children and adolescents (1-18 years-old) the higher

incidence of IGH/CRLF2 in patients with median

age of 14 years (Schmäh et al. 2017). Another report

describes a cohort of pre B-ALL patients, ranging

from 1-60 years-old, with IGH/CRLF2 in 37.2% of

cases (Russell et al. 2017). In general, the prevalence

of IGH/CRLF2 increases with age.

Clinics

ALL with BCP immunophenotype with

rearrangement involving a cytokine receptor,

included in the BCR/ABL1ñlike ALL subgroup.

Treatment

The IGH/CRLF2 translocation results in kinase-

activating lesion that causes the constitutive

activation of the Jak2/STAT5 signalling pathway.

The patients that harbour IGH/CRLF2 ALL could

benefit from the treatment with Ruxolitinib, which

blocks Jak2/STAT5 pathway (Figure 5).

This treatment could potentially improve their

survival (Harrison 2013)).

Prognosis

IGH/CRLF2 is associated with high risk National

Cancer Institute (NCI) characteristics in contrast to

P2RY8/CRLF2 positive patients. IGH/CRLF2 is

also present in patients with high levels of minimal

residual disease (MRD) (≥ 10-3) which are consider

MRD-slow early responders, based on this the group

is prone to suffer relapses (Schmäh et al. 2017;

Attarbaschi et al. 2012).

t(X;14)(p22;q32) or t(Y;14)(p11;q32) IGH/CRLF2

Martinez-Anaya D et al.


Figure 1. CRLF2 Flow cytometry analysis in an ALL patient with IGH/CRLF2 rearrangement. The figure shows the strategy

applied to analyze by flow cytometry the CRLF2 overexpression and activation in blasts population (CD34+ CD19+), compared with unstained control (A). In this patient almost 100% of blasts are positive to CRLF2 protein, (B) and its signaling pathway is active since the phosphorylation of STAT5 at tyrosine residue (pY694) is present and (C) was reversible by the Jak2 inhibitor

Ruxolitinib.

Figure 2. Chromosomes obtained from MHH-CALL-4 cell line positive to IGH/CRLF2 translocation detected by fluorescence in situ hybridization (FISH). The der(Y) chromosome is lost in the cell line. (A) Metaphase hybridized with CRLF2 break-apart probe

(Cytocell Aquarius) with a normal chromosome X (yellow arrow) and the der(14) (green arrow). (B) Metaphase hybridized with IGH break-apart probe (Vysis-Abbott) with the normal chromosome 14 (yellow arrow) and the der(14) (red arrow).

Cytogenetics

Cytogenetics morphological


is a cryptic rearrangement (Figures 2 and 3). It is

present in patients with extra copies of the X

chromosome produced by high hyperdiploidy in

19.8% of cases. To date, only one patient who

presented both a PAR1 deletion (P2RY8/CRLF2)

and IGH/CRLF2 translocation has been reported

(Harvey et al. 2010). Recently, two patients with

coexistence of IGH/CRLF2 and BCR/ ABL1

rearrangements have been described. One patient

presented both rearrangements in different clones

(Russell et al. 2017); the other case showed the

translocation t(Y;14) harbouring the CRLF2

rearrangement in 90% of interphases, and presented

BCR/ABL1 fusion in a subset of the CRLF2-

rearranged cells (Jain et al. 2017).

IGH/CRLF2 positive cells also have a high

frequency (94%) of additional deletions which may

reflect chromosomal instability (Schmäh et al.

2017).

The most common deletions in addition to this

rearrangement are found in IKZF1 (53%), ADD3

(46%) and SLX4IP (41%). Similar to patients

P2RY8/CRLF2 positive, deletions in JAK1/ JAK2

(17%) are also present (Russell et al. 2017).

Although IGH/CRLF2 is part of the BCR/ABL1-like

ALL subtype this rearrangement is not associated

with it in all cases; however, those patients with the

rearrangement in coexistence with JAK2 mutations

have been found that present the expression

signature of the subtype (Herold et al. 2017).

Although in Down syndrome patients the

P2RY8/CRLF2 deletion is more frequent,

IGH/CRLF2 rearrangement is also observed (35%

vs. 20% respectively) (Russell et al. 2017).

t(X;14)(p22;q32) or t(Y;14)(p11;q32) IGH/CRLF2 Martinez-Anaya D et al.


Figure 3. (A-B) FISH in interphase nuclei with the IGH break apart-probe, and (C-D) with the CRLF2 break-apart probe. The yellow arrows indicate normal alleles and the red and green arrows indicate monoallelic breakages.

Genes involved and proteins

IGH (immunoglobulin heavy locus)

Location

14q32.33

Protein-coding gene. Others names: D (diversity)

region of heavy chains; J (joining) region of heavy

chains; immunoglobulin heavy chain variable

region; immunoglobulin heavy diversity group;

immunoglobulin heavy diversity locus;

immunoglobulin heavy joining cluster;

immunoglobulin heavy joining group;

immunoglobulin heavy polypeptide, joining region;

immunoglobulin heavy variable cluster;

immunoglobulin heavy variable group. Other

symbols: IGHDY1; IGH@; IGD1; IGHV; IGHD@;

IGHJ@; IGHV@; IGH1@

DNA/RNA

The genomic location of IGH starts at 105,536,746

pb from 14pter and ends in 106,879,844pb from

14pter. The size is 1,343,098 bases, with minus

strand orientation NC_000014.9

CRLF2 (cytokine receptor like factor 2)

Location

It is located at the PAR1 of chromosome X,

Xp22.33, and chromosome Y, Yp11.

Protein-coding gene. Other names and symbols:

Thymic Stromal Lymphopoietin Protein Receptor,

TSLP Receptor, Thymic Stromal-Derived

Lymphopoietin Receptor, Cytokine Receptor-Like

2. Others symbols: TSLPR, CRL2, CRLF2Y.

DNA/RNA

The genomic location of CRLF2 gene in

chromosome X starts at 1,187, 549 bp from Xpter,

and ends at 1, 212, 815 bp from Xpter. The size is

25, 267 bases, with minus strand orientation

NC_018934. CRLF2 has 3 transcripts variant; the

transcript variant 1 has 1606pb mRNA

NM_022148.2, this variant encodes the longer

isoform NM_022148.2(Schmäh et al. 2017); the

transcript variant 2 has 1503pb mRNA

NM_001012288.2, this variant lacks an alternate

exon which results in translation initiation at a

downstream start codon compared to variant 1, the

resulting isoform is shorter at the N-terminus

compared to isoform 1(Russell et al. 2017); the

transcript variant 3, uses an alternative splice

junction at the 5¥end of an exon, and contains

another alternate exon compared to variant 1, this

variant is a non-coding mRNA NR_110830.1.

Protein

The cytokine receptor-like factor 2 has a size of 371

amino acids, with a molecular mass of 42013

Daltons. Cytokine receptor-like factor 2 is a

transmembrane protein with an extracellular domain

of 210 residues, and an intracellular domain of 119

residues (Zhang et al. 2001). CRLF2

heterodimerizes with IL7R constituting a functional

receptor (Figure 5) (Rochman et al. 2010; Bugarin et

al. 2015).

Somatic mutations

The CRLF2 711T>G (Phe232Cys) mutation has

been found in ALL blasts. The CRLF2 Phe232

residue is near to the junction of the extracellular and

transmembrane domains. The Phe232Cys mutation

confers a constitutive dimerization through the

cysteine residues inducing cell growth. This

mutation also promotes the up-regulation of

downstream transcriptional targets of the

Jak2/STAT5 pathway (Figure 5) (Yoda et al. 2010).

Result of the chromosomal anomaly

Hybrid gene

The IGH/CRLF2 rearrangement results from a

cryptic translocation t(X;14)(p22;q32) or

t(Y;14)(p11;q32) involving the PAR1 region, which

is located in the short arm of both sex chromosomes

and the immunoglobulin heavy chain locus located

in the chromosome 14 (Figure 3). Represent the 20-

26% of IGH translocations in B cell precursor ALL

and the principal consequence is a deregulated


Martinez-Anaya D et al.


transcription of CRLF2 by the physical juxtaposition

with the IGH transcriptional enhancers (Figure 4)

(Dyer et al. 2010; Chapiro et al. 2013; Jeffries et al.

2014; Yoda et al. 2010; Tsai et al. 2010).

Description

IGH/CRLF2 translocation can result of an aberrant

D-J or V-DJ recombination that involves the cryptic

recognition signal sequence (RSS) in the

pseudoautosomal region (Figure 4). As a result, the

IGH-J or IGH-DJ regions becomes adjacent to the

CRLF2 entire reading frame and the der(14) carries

the junctions between IGH segments and the

centromeric region of CRLF2 (Dyer et al. 2010;

Chapiro et al. 2013; Yoda et al. 2010; Tsai et al.

2010).

The breakpoints occur approximately 8 to 16 Kb

upstream to the CRLF2 translation start site and,

there is a 311 bp cluster from positions 1,307,403 to

1,307,713 which contains 6 out of 19 described

breakpoints. Tsai et al., 2010 report that 7 of 19

CRLF2 breakpoints are at 5íor 3¥sides of CpG

dinucleotide sequences. Similar to the IGH-BCL2

rearrangement, at least 18 of the 19 IGH breaks in

the IGH/CRLF2 translocation are compatible with

standard V(D)J recombination, the IGH junction is

within 30bp 5¥of an RSS and this junctions contain

non templated nucleotide additions consistent with

the activity of terminal deoxynucleotide transferase

(Dyer et al. 2010; Chapiro et al. 2013; Yoda et al.

2010).

Transcript

There is no a chimeric transcript. Usually the

rearrangement relocates the CRLF2 entire coding

sequence without mutation under transcriptional

control of IGH enhancer and the gene is

overexpressed (Dyer et al. 2010).

Detection

The IGH/CRLF2 translocation involves the

disruption of both loci, based on this FISH technique

using IGH and CRLF2 break-apart probes allows the

detection of the rearrangement (Figure 3).

These probes mark the centromeric region of each

gene of red color and the telomeric region of green

color. A normal cell with intact IGH and CRLF2

shows in each cell two close red (R) and green (G)

fused (F) signals (2F); in a cell with the

translocation, one normal F signal is conserved and

one red and one green are present as a result of the

breakage (1F1R1G pattern). In abnormal

metaphases the hybridization with IGH break-apart

probe shows a der(14) with one centromeric red

signal and one telomeric green signal moved to the

derivative chromosome X or Y (Russell et al. 2009).

Harvey et al. 2010 reported the IGH/CRLF2

detection using a single fusion extra signal probe

consisting of two bacterial artificial chromosomes

(BAC) clones flanking CRLF2 labeled with red

fluorochrome, and a third BAC clone centromeric to

IGH labeled with green fluorochrome. In this assay

an IGH/CRLF2 positive cell shows the 1F2R1G

pattern.

Yoda et al. 2010 amplified the IGH/CRLF2 junction

on der(14) by PCR using a common IGHJ primer and

spaced primers 5` of the CRLF2 coding sequence.

Figure 4. The IGH/CRLF2 translocation. (A) IGH locus. The IGH breakage can occur between the variable (V-H) and diversity (D-H) regions, the orange diamonds represent the transcriptional enhancers. (B) PAR1 region. The breakage can occur 8Kb to

12Kb upstream to CRLF2. (C) The derivative chromosome 14 carries the CRLF2 juxtaposition with IGH transcriptional enhancers and (D) the derivative chromosome X or Y hold the IGH telomeric region.



Figure 5. PATHWAY: IGH/CRLF2 rearrangement increases the expression of CRLF2. CRLF2 signaling pathway involves the activation of Jak2/STAT5 and PI3k/Akt/mTOR that are related with increase in proliferation and survival of leukemic cells. Other cellular mechanism activated by Akt is apoptosis inhibition. Additionally, CRLF2 can activate Src family members which create a

feedback positive loop with Abl, and activate molecules implicated in cellular adhesion and survival (TSLP Signaling Pathway n.d.).

Fusion protein

There is not a fusion protein

Oncogenesis

The overexpression of CRLF2 due to the

IGH/CRLF2 translocation results in its

homodimerization at cellular membrane. This leads

directly to constitutive activation of JAK2/STAT5,

PI3k/ MTOR andSRC signaling pathway, causing

the leukemic blast proliferation and survival (Figures

3 and 5) (Zhong et al. 2014). Nevertheless, the IGH

translocation is not enough for the establishment of

the neoplastic phenotype, concurrent activation of

synergistic oncogenes and loss of tumor suppressor

gene functions are necessary (Moorman et al. 2012).

In the near future, inhibitors for the JAK2 pathway,

Ruxolitinib, and for Src pathway, Dasatinib, could

be used in order to counteract oncogenic effect

caused by IGH/CRLF2 in ALL patients.

References TSLP Signaling Pathway http://www.netpath.org/netslim/TSLP_full.html, accessed December 14, 2017.ñ257.

Arber, Daniel A., Attilio Orazi, Robert Hasserjian, et al.. The 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemia Blood. 2016 May 19;127(20):2391-405. doi: 10.1182/blood-2016-03-643544.

Attarbaschi, Andishe, Maria Morak, Gunnar Cario, et al.. Treatment Outcome of CRLF2-Rearranged Childhood Acute Lymphoblastic Leukaemia: A Comparative Analysis of the AIEOP-BFM and UK NCRI-CCLG Study Groups Br J Haematol. 2012 Sep;158(6):772-7. doi: 10.1111/j.1365-2141.2012.09221.x.

Bugarin, Cristina, Jolanda Sarno, Chiara Palmi, et al.. Fine Tuning of Surface CRLF2 Expression and Its Associated Signaling Profile in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia Haematologica. 2015 Jun;100(6):e229-32. doi: 10.3324/haematol.2014.114447.

Chapiro, Elise, Isabelle Radford-Weiss, Hong-Anh Cung, et al.. Chromosomal Translocations Involving the IGH@ Locus in B-Cell Precursor Acute Lymphoblastic Leukemia: 29 New Cases and a Review of the Literature Cancer Genet. 2013 May;206(5):162-73. doi: 10.1016/j.cancergen.2013.04.004.

Dyer, Martin J. S., Takashi Akasaka, Melania Capasso, et al.. Immunoglobulin Heavy Chain Locus Chromosomal Translocations in B-Cell Precursor Acute Lymphoblastic Leukemia: Rare Clinical Curios or Potent Genetic Drivers? Blood. 2010 Feb 25;115(8):1490-9. doi: 10.1182/blood-2009-09-235986.

Ensor, Hannah M., Claire Schwab, Lisa J. Russell, et al.. Demographic, Clinical, and Outcome Features of Children with Acute Lymphoblastic Leukemia and CRLF2 Deregulation: Results from the MRC ALL97 Clinical Trial Blood. 2011 Feb 17;117(7):2129-36. doi: 10.1182/blood-2010-07-297135.

Harrison, Christine J.. Targeting Signaling Pathways in Acute Lymphoblastic Leukemia: New Insights Hematology Am Soc Hematol Educ Program. 2013;2013:118-25. doi: 10.1182/asheducation-2013.1.118.



Harvey, Richard C., Charles G. Mullighan, I.-Ming Chen, et al.. Rearrangement of CRLF2 Is Associated with Mutation of JAK Kinases, Alteration of IKZF1, Hispanic/Latino Ethnicity, and a Poor Outcome in Pediatric B-Progenitor Acute Lymphoblastic Leukemia Blood. 2010 Jul 1;115(26):5312-21. doi: 10.1182/blood-2009-09-245944.

Herold, Tobias, Stephanie Schneider, Klaus H. Metzeler, et al. Adults with Philadelphia Chromosome-like Acute Lymphoblastic Leukemia Frequently Have IGH-CRLF2 and JAK2 Mutations, Persistence of Minimal Residual Disease and Poor Prognosis Haematologica. 2017 Jan;102(1):130-138. doi: 10.3324/haematol.2015.136366.

Jain, Nitin, Xinyan Lu, Naval Daver, et al.. Co-Occurrence of CRLF2-Rearranged and Ph+ Acute Lymphoblastic Leukemia: A Report of Four Patients Haematologica. 2017 Dec;102(12):e514-e517. doi: 10.3324/haematol.2016.161000.

Jeffries, Sally J., Lisa Jones, Christine J. Harrison, and Lisa J. Russell. IGH@ Translocations Co-Exist with Other Primary Rearrangements in B-Cell Precursor Acute Lymphoblastic Leukemia Haematologica. 2014 Aug;99(8):1334-42. doi: 10.3324/haematol.2014.103820.

Molecular Characterization of Acute Lymphoblastic Leukemia with High CRLF2 Gene Expression in Childhood. Schmh, Juliane, Birthe Fedders, Renate Panzer-Gr¸mayer, et al. Pediatr Blood Cancer. 2017 Oct;64(10). doi: 10.1002/pbc.26539.

Moorman, Anthony V., Claire Schwab, Hannah M. Ensor, et al.. IGH@ Translocations, CRLF2 Deregulation, and Microdeletions in Adolescents and Adults with Acute Lymphoblastic Leukemia J Clin Oncol. 2012 Sep 1;30(25):3100-8. doi: 10.1200/JCO.2011.40.3907.

Roberts, Kathryn G., Zhaohui Gu, Debbie Payne-Turner, et al.. High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults J Clin Oncol. 2017 Feb;35(4):394-401. doi: 10.1200/JCO.2016.69.0073.

Rochman, Yrina, Mohit Kashyap, Gertraud W. Robinson, et al.. Thymic Stromal Lymphopoietin-Mediated STAT5 Phosphorylation via Kinases JAK1 and JAK2 Reveals a Key Difference from IL-7-Induced Signaling Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19455-60. doi: 10.1073/pnas.1008271107.

Russell, Lisa J., Melania Capasso, Inga Vater, et al.. Deregulated Expression of Cytokine Receptor Gene, CRLF2, Is Involved in Lymphoid Transformation in B-Cell Precursor Acute Lymphoblastic Leukemia Blood. 2009 Sep 24;114(13):2688-98. doi: 10.1182/blood-2009-03-208397.

Tsai, Albert G., Akinori Yoda, David M. Weinstock, and Michael R. Lieber. t(X;14)(p22;q32)/t(Y;14)(p11;q32) CRLF2-IGH Translocations from Human B-Lineage ALLs Involve CpG-Type Breaks at CRLF2, but CRLF2/P2RY8 Intrachromosomal Deletions Do Not Blood. 2010 Sep 16;116(11):1993-4. doi: 10.1182/blood-2010-05-286492.

Yoda, Akinori, Yuka Yoda, Sabina Chiaretti, et al.. Functional Screening Identifies CRLF2 in Precursor B-Cell Acute Lymphoblastic Leukemia Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):252-7. doi: 10.1073/pnas.0911726107.

Zhang, W., J. Wang, Q. Wang, et al.. Identification of a Novel Type I Cytokine Receptor CRL2 Preferentially Expressed by Human Dendritic Cells and Activated Monocytes Biochem Biophys Res Commun. 2001 Mar 9;281(4):878-83.

Zhong, Jun, Jyoti Sharma, Rajesh Raju, et al.. TSLP Signaling Pathway Map: A Platform for Analysis of TSLP-Mediated Signaling Database (Oxford). 2014 Feb 25;2014:bau007. doi: 10.1093/database/bau007.


Martinez-Anaya D, Juárez-Velázquez R, Moreno-Lorenzana D, Pérez Vera P. t(X;14)(p22;q32) or t(Y;14)(p11;q32) IGH/CRLF2. Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):194-199.

Case Report Section




Isolated 1q21 rearrangement der(20)t(1;20)(q21;p13) with telomere involvement of 20p in a case of longstanding myelodysplastic syndrome Lubomir Mitev, Liliya Grahlyova, Aselina Asenova, Verginia Uzunova, Julian Raynov

Department of Cytogenetics and Molecular Biology (LM, LG, AA, VU), Clinical of Haematology

(JR), Military Medical Academy, Sofia, Bulgaria, [email protected]

Published in Atlas Database: June 2017

Online updated version : http://AtlasGeneticsOncology.org/Reports/t0120q21p13MitevID100090.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70472/06-2017-t0120q21p13MitevID100090.pdf DOI: 10.4267/2042/70472


Abstract Case report on Isolated 1q21 rearrangement

der(20)t(1;20)(q21;p13) with telomere involvement

of 20p in a case of longstanding myelodysplastic

syndrome.

Clinics

Age and sex

58 years old male patient.

Previous history

No preleukemia; no previous malignancy; no inborn

condition of note

Organomegaly

No hepatomegaly, no splenomegaly, no enlarged

lymph nodes, no central nervous system

involvement

Blood WBC: 4.3X 109/l

HB: 7.8g/dl

Platelets: 232X 109/l

Blasts: 0%

Bone marrow: Bone marrow was hypercellular with

erythroid hyperplasia (68% erythroid precursors)

and erythroblastic and megakaryocytic dysplasia.

The most typical dysplastic features in the erythroid

line were the changes in nuclear morphology

(multinuclearity, nuclear hyperlobulation, irregular

nuclear contours and karyorrhexis). Some of the

erythroblasts resembled the blasts of the pure

erythroid leukemia (large cells with deep

cytoplasmic basophilia and oval nucleus with

prominent nucleolus). The test of ring sideroblasts

was positive (55%). Megakaryocytic dysplasia was

present with hypo- or unilobulated megakaryocytes

of all sizes. Micromegakaryocyte and dysplastic

megakaryocytic fragments were also seen.

Cyto-Pathology Classification

Immunophenotype not done

Rearranged Ig Tcr not done

Pathology

The peripheral blood morphology was characterized

with poikilo anisocytosis and presence of single

oxyphilic erythroblasts. Differential blood count was

1% myelocytes, 2% metamyelocytes, 32% bands,

27% segments, 20% lymphocytes, 17% monocytes

and 1% eosinophils.

Electron microscopy not done

Diagnosis

Refractory cytopenia with multilineage dysplasia

and ring sideroblasts.

Note

Isolated 1q21 rearrangement der(20)t(1;20)(q21;p13) with telomere involvement of 20p in a case of longstanding myelodysplastic syndrome

Mitev L et al.


The patient was hospitalized for the first time in

January 2006 with two years history of mild anemia.

The examinations showed: Hb 104 g/dl, WBC

5x109/l and platelets 327x109/l. Bone marrow was

hypercellular with dysplasia of the erythroid lineage

presented with megaloblastic erythropoiesis.

Conventional cytogenetic analysis revealed a

karyotype of 46, XY,der(20)t(1;20)(q21;p13)[20].

The diagnosis of refractory anemia was made and the

patient was followed-up until 2015. In this period the

patient was in a good clinical condition and good

quality of life maintaining hemoglobin value

between 95 -120 g/dl without blood transfusions. In

October 2015 the patient was hospitalized again.

Conventional and molecular cytogenetic analyses

confirmed the karyotype of

46,XY,der(20)t(1;20)(q21;p13). The diagnosis of

refractory cytopenia with multilineage dysplasia and

ring sideroblasts was made and the patient received

supportive treatment with blood transfusions. In

February 2016 the disease progressed to a refractory

anemia with excess of blasts-2 (14% myeloblasts in

bone marrow) and one course of chemotherapy with

low doses of Cytarabine (80 mg daily) was carried

out. The patient was followed-up in a satisfactory

clinical condition maintaining hemoglobin value

between 75 and 80 mg/ml and myeloblasts in the

bone marrow between 2% and 4%.

Survival

Date of diagnosis 01-2006

Treatment

Blood transfusions and chemotherapy with low

doses of Cytarabine.

Complete remission: no

Treatment related death: no

Relapse: no

Status Alive

Last follow up 03-2017

Survival

138 In March 2017 peripheral blood showed WBC

4.3x109/l, Hb 65 g/dl, platelets 175x109/ l and

differential blood count 1% metamyelocytes, 5%

bands, 52% segments, 31% lymphocytes, 6%

monocytes and 5% eosinophils. Bone marrow

examination revealed normocellular marrow with

trilineage dysplasia and 4% blasts.months

Karyotype

Sample Bone marrow

Culture time 24h

Banding GTG banding.

Results

46,XY,der(20)t(1;20)(q21;p13)[33].

The conventional cytogenetic study revealed

karyotype of 46,XY,der(20)t(1;20)(q21;p13)[33]

(Fig. 1A).

This unbalanced translocation resulted in the

formation of a derivative chromosome, composed of

the recipient chromosome 20 and the additional copy

of 1q21->qter: der(20)(1qter->1q21::20p13-

>20qter). In some metaphases the translocated

segment 1q21qter is as though attached to an intact

chromosome 20, suggesting that the breakpoint in

20p is sub-telomeric or telomeric (Fig.1A).

Figure 1. (A) Partial G- banded karyotypes demonstrating derivative chromosome 20. (B) fluorescence 'in situ'

hybridization of the derivative chromosome 20 with arm specific probe for 1q and 20p compared with the respective

schematic model of its structure.

Other molecular cytogenetics technics

FISH examinations were carried out according to

manufacturer's instructions, using arm specific

probes for 1q (ASP1q) and 20p (ASP20p), sub-

telomere DNA probe for 20p (Kreatech Diagnostic,

Leica, Germany) and telomere probe for 20p

(Vysis/Abbott Molecular, Des Plaines, IL, USA).

Sub-telomere DNA probe was applied

independently and in combination with the arm

specific probes for 1q. Images were captured and

analyzed with epifluorecsent microscope Nicon 80i

(Nikon corporation, Tokyo, Japan) equipped with

CCD camera and DAPI/red/green filter set.

Other molecular cytogenetics results

FISH examination with ASP1q and ASP20p probes

and combination of sub-telomere DNA probe with

ASP for 1q showed normal sub-telomere confirmed

the 1q trisomy and demonstrated that the additional

copy of 1q21qter was translocated to the short arm

of chromosome 20 (Fig 1B and 2A).

In two of the 55 metaphases analyzed der(20) was

not present. One was with trisomy and the other one

with tetrasomy of chromosome 1. FISH examination

with both sub-telomere and telomere DNA probes

for 20p showed normal sub-telomere and telomere

signal patterns - ish

der(20)t(1;20)(q21;p13)(D20S1156x2) and ish

der(20)t(1;20)(q21;p13)(D20S1157x2) (Fig 2B, 2C

and 2D).

Other Molecular Studies


Mitev L et al.


Technics:

Microarray examination of the patient's bone

marrow DNA was performed with CGH+SNP 60K

microarray platform (OGT, Oxford, UK) according

to the manufacturer's protocol. The hybridization of

the reference and patient's DNA was made via

incubation in Mai-Tai hybridization system

(SciGene, USA) for 22-hours at 65oC. Slides were

scanned using scanner GenePix 4400A (Molecular

Devices, USA) and features were extracted by

GenePixPro7 software (Molecular Devices, USA).

The microarray patient's profile was analysed with

CytoSure Interpret software, v 4.4.6. (OGT, Oxford,

UK) using HG 19.

Results:

aCGH study found only the gain of the segment

1q21qter and revealed no 20p losses - arr[hg]

1q21.1q44(142,706,628-248,514,266)x3 (Fig.3 D

and C). Both aCGH and FISH study with sub-

telomere and telomere probes indicated that the

breakpoint in the derivative chromosome 20 is

located in the telomere region.

Figure 2. (A) Metaphase fluorescence "in situ"

hybridization with arm specific probe for 1q (green signal) and 20p (red signal) demonstrating the translocation of the additional copy of 1q21qter to the short arm of chromosome

20. (The derivative chromosome 20 is arrowed). (B) Fluorescence 'in situ' hybridization with arm specific probe

for 1q (green signal) and 20p sub-telomere probe (red signal) showing two normal signals: one in the normal

chromosome 20 and one fitting tightly to the additional copy of 1q21qter (arrowed). (C) Metaphase fluorescence "in situ"

hybridization with 20p sub-telomere probe demonstrating two normal signals - one in the normal and one in the derivative chromosome 20 (arrowed). (D) Metaphase

fluorescence "in situ" hybridization with 20p telomere probe demonstrating two normal signals - one in the normal and

one in the derivative chromosome 20 (arrowed). (E) Ideogram and microarray CGH plot of chromosome 1

showing a gain for the segment 1q21->qter (green shaded area; the breakpoint is arrowed). (F) Ideogram and

microarray CGH plot of chromosome 20 showing no deletion on the p-arm.

Comments Der(20)t(1;20)(q21;p13) belongs to the group of the

unbalanced 1q12-21 translocations observed mostly

as a second genetic event in a large spectrum of

hematological malignances (Zamecnikova A and Al,

Bahar S. 2013). Unbalanced 1q12-21 translocations

affecting 20p have been reported in 10 cases: 6 with

multiple myeloma (Fiedler et al., 1992; Taniwaki et

al., 1994; Keung et al., 1998; Sawyer et al., 1998;

Mohamed et al., 2007; Sawyer et al., 2014), 1 with

acute lymphoblastic leukemia/ lymphoblastic

lymphoma (Wan et al., 2004), 1 with diffuse large B-

cell lymphoma (Levine et al., 1985), 1 with acute

myeloid leukemia (M7) (Yoshida et al., 2013) and 1

with chronic myeloproliferative disorder (L'Abbate

et al., 2015). The molecular pathogenesis of

der(20)t(1;20)(q12-21;p13) is linked to the gain of

1q and the losses of coding DNA from 20p. The

presented case demonstrated that the breakpoint in

20p could occur in telomere region as were reported

in other 1q translocations: 3 with der(2)t(1;2)(q12-

21;q37), 2 with der(16)t(1;16)(q12-21;q24)

(Busson-Le Coniat M et al.,1999) and 1 with

der(12)t(1;12)(q21;p13) (La Starza R et al., 1999).

Because of the telomere involvement of the recipient

chromosomes these 1q12-21 translocations did not

result in losses of coding DNA and theirs molecular

pathogenesis is possibly linked only to the gain of

1q. We supposed that in our case the missing of 20p

losses as well as additional anomalies in the

karyotype are the reasons for the long survival of the

patient.

References Fiedler W, Weh HJ, Hossfeld DK. Comparison of chromosome analysis and BCL-1 rearrangement in a series of patients with multiple myeloma. Br J Haematol. 1992 May;81(1):58-61

Sawyer JR, Tian E, Heuck CJ, Epstein J, Johann DJ, Swanson CM, Lukacs JL, Johnson M, Binz R, Boast A, Sammartino G, Usmani S, Zangari M, Waheed S, van Rhee F, Barlogie B. Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease. Blood. 2014 Apr 17;123(16):2504-12

Wan TS, Ma SK, Chow EY, Li YH, Lin SY, Chan LC. Pathogenesis of jumping translocations: a molecular cytogenetics study. Leuk Res. 2004 Oct;28(10):1075-9

Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, Maarek O, Lafage-Pochitaloff M, Mozziconacci MJ, Baranger L, Brizard F, Radford I, Jeanpierre M, Bernard OA, Berger R. Fluorescence in situ hybridization analysis of chromosome 1 abnormalities in hematopoietic disorders:


Mitev L et al.


rearrangements of DNA satellite II and new recurrent translocations. Leukemia. 1999 Dec;13(12):1975-81

Keung YK, Yung C, Wong JW, Shah F, Cobos E, Tonk V.

Unusual presentation of multiple myeloma with "jumping translocation" involving 1q21. A case report and review of the literature. Cancer Genet Cytogenet. 1998 Oct 15;106(2):135-9

L'Abbate A, Tolomeo D, De Astis F, Lonoce A, Lo Cunsolo C, Mühlematter D, Schoumans J, Vandenberghe P, Van Hoof A, Palumbo O, Carella M, Mazza T, Storlazzi CT. t(15;21) translocations leading to the concurrent downregulation of RUNX1 and its transcription factor partner genes SIN3A and TCF12 in myeloid disorders. Mol Cancer. 2015 Dec 16;14:211

La Starza R, Stella M, Testoni N, Di Bona E, Ciolli S, Marynen P, Martelli MF, Mandelli F, Mecucci C. Characterization of 12p molecular events outside ETV6 in complex karyotypes of acute myeloid malignancies. Br J Haematol. 1999 Nov;107(2):340-6

Levine EG, Arthur DC, Frizzera G, Peterson BA, Hurd DD, Bloomfield CD. There are differences in cytogenetic abnormalities among histologic subtypes of the non-Hodgkin's lymphomas. Blood. 1985 Dec;66(6):1414-22

Mohamed AN, Bentley G, Bonnett ML, Zonder J, Al-Katib A. Chromosome aberrations in a series of 120 multiple myeloma cases with abnormal karyotypes. Am J Hematol. 2007 Dec;82(12):1080-7

Sawyer JR, Lukacs JL, Munshi N, Desikan KR, Singhal S, Mehta J, Siegel D, Shaughnessy J, Barlogie B. Identification

of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping. Blood. 1998 Dec 1;92(11):4269-78

Taniwaki M, Nishida K, Takashima T, Nakagawa H, Fujii H, Tamaki T, Shimazaki C, Horiike S, Misawa S, Abe T. Nonrandom chromosomal rearrangements of 14q32.3 and 19p13.3 and preferential deletion of 1p in 21 patients with multiple myeloma and plasma cell leukemia. Blood. 1994 Oct 1;84(7):2283-90

Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A, Sanada M, Park MJ, Terui K, Suzuki H, Kon A, Nagata Y, Sato Y, Wang R, Shiba N, Chiba K, Tanaka H, Hama A, Muramatsu H, Hasegawa D, Nakamura K, Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Kato K, Nishimura R, Izraeli S, Hayashi Y, Miyano S, Kojima S, Ito E, Ogawa S. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet. 2013 Nov;45(11):1293-9

Zamecnikova, A ; Al, Bahar S. 1q translocations (unbalanced) in myeloid malignancies Atlas Genet Cytogenet Oncol Haematol. 2013;17(12):845-848.


Mitev L, Grahlyova L, Asenova A, Uzunova V, Raynov J. Isolated 1q21 rearrangement der(20)t(1;20)(q21;p13) with telomere involvement of 20p in a case of longstanding myelodysplastic syndrome. Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):200-203.

Case Report Section




A new case of adult Acute Myeloid Leukemia with t(3;3)(p24;q26) Bo Yuan, Janice Smith, April Ewton, Sai Ravi Pingali, Arthur Zieske, Amy Breman

Department of Molecular & Human Genetics, Baylor College of Medicine (BY, JS, AB), Houston,

TX 77030, USA. Baylor Genetics (BY, JS, AB), Houston, TX 77030, USA, [email protected];

[email protected]. Department of Pathology Genomic Medicine, Houston Methodist Hospital (AE,

AZ), Houston, TX 77030, USA. Department of Medicine, Houston Methodist Hospital (SRP),

Houston, TX 77030, USA.

Published in Atlas Database: November 2017

Online updated version : http://AtlasGeneticsOncology.org/Reports/t0303p24q26BremanID100091.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70473/11-2017-t0303p24q26BremanID100091.pdf DOI: 10.4267/2042/70473


Abstract

Case report on a new case of adult Acute Myeloid

Leukemia with t(3;3)(p24;q26).

Clinics

Age and sex

68 years old female patient.

Previous history

No preleukemia; no previous malignancy; no inborn

condition of note

Organomegaly

No hepatomegaly; splenomegaly (acute

splenomegaly); no enlarged lymph nodes; no central

nervous system involvement

Blood WBC: 9.13; RBC: 2.37X 109/l

HB: 6.7g/dl


Blasts: 5%


Phenotype

AML with a translocation or inversion in

chromosome 3; Refractory acute myelogenous

leukemia with poor risk cytogenetics, pancytopenia

secondary to refractory AML, acute Splenomegaly,

fatigue, petechiae, dyspnea on exertion, neutropenic

fever, refractory thrombocytopenia with hematuria

and persistence of disease.

Immunophenotype

CD34: positive in blasts that account for 45% of

cellularity; CD61: positive in megakaryocytes.

MPO: Positive in background myeloid cells.

Negative in blasts. E-Cadherin and glycophorin:

Highlights markedly decreased erythroid precursors

Rearranged Ig Tcr Not performed

Pathology

The marrow cellularity is approximately 90%

(biopsy/clot); Erythroid elements: Markedly

decreased number. Normoblastic; Myeloid

elements: Left shifted with increased blasts. Blasts

account for 18% of cells in the dilute aspirate and

about 45 of cells in the CD34 immunostained biopsy.

Eosinophilia is seen on biopsy specimen;

Megakaryocytes: Markedly increased in number

with clustering and markedly dyspoietic morphology

(small hypolobulated, dysjointed nuclei,

hyperlobed); Reticulin stain shows Grade 1 fibrosis.

Electron microscopy Not performed

Diagnosis

Acute myelogenous leukemia

Survival

Date of diagnosis 02-2017

Treatment

A new case of adult Acute Myeloid Leukemia with t(3;3)(p24;q26)

Yuan B et al.


Reduced dose of anthracycline therapy due to

cardiac function; Cytarabine and idarubicin;

Dacogen; Nivolumab; Decitabine; Hydroxyurea


Treatment related death: no

Relapse: no

Status Alive

Last follow up 05-2017

Survival 3 months

Karyotype

Sample Bone marrow

Culture time 24 and 48 hours unstimulated cultures

Banding GTG banding

Results

45,XX,t(3;3)(p24;q26),-7[20]

Figure 1. Karyotype of the cell line demonstrating the t(3;3)(p24;q26) and loss of a copy of chromosome 7 (red

arrows). The lower panel shows the abnormal chromosomes 3 at increasing band resolution.


Fluorescence in situ Hybridization (FISH)


Confirmatory FISH using the Cytocell EVI1

Breakapart Probe (REF: LPH 036-A / LPH 036-

A50) was performed on cells harvested from 24 hour

bone marrow culture. The FISH probe mixture

consists of a 156 kb probe telomeric to the D3S4415

marker including the LRRC34 gene (red, R), a 179

kb probe including the entire EVI1 (MECOM) gene

plus flanking regions (green, G), and a 559 kb probe

centromeric to the EVI1 gene including the

D3S3364 marker (aqua, A), all within the 3q26.2

region. Interphase cells showed a 1R/1GA/1RGA

signal pattern, corresponding to one split red/green

signal with the aqua signal remaining with the green

signal, confirming the translocation breakpoint

between the EVI1 and LRRC34 genes (Figure 2).

However, the partner of EVI1 resulting from the

translocation remains unknown.

Figure 2. FISH using the Cytocell EVI1 Breakapart Probe demonstrating the breakpoint at 3q26.2 between EVI1 and LRRC34, a gene telomeric to EVI1, in both interphase (A)

and metaphase cells (B).

Comments

Rearrangements involving the 3q26 region have

been described in up to 10% of acute myeloid

leukemias (AML), chronic myeloid leukemias in

blast crisis (CML BC), and myelodysplastic

syndrome (Poppe 2006). The most common

rearrangement is a paracentric inversion of the long

arm, inv(3)(q21q26), although multiple

rearrangements of this region have been described

(Huret 2005, Jancuskova 2014, Lawce 2017). While

the breakpoints are variable and may include

translocations, inversions or other structural

complexities, they unanimously result in EVI1

overexpression. Interphase FISH assays have been

used to detect rearrangements involving the EVI1

locus at 3q26 (Wieser 2003). Monosomy 7 is also

frequently present, and is associated with a poorer

prognosis (Haferlach 2012, Huret 2005, Lugthart

2010). While multiple partners have been identified

for EVI1, the partner of EVI1 in rearrangements

involving 3p24 and 3q26 is unknown. Similar to the

current case, a pericentric inversion involving both

the short and long arms of chromosome 3,

inv(3)(p24q26), has been reported in ten cases

(Haferlach 2012), with elevated EVI1 expression

reported. Therefore, identification of the partner

gene warrants further investigation.

References Haferlach C, Bacher U, Grossmann V, Schindela S, Zenger M, Kohlmann A, Kern W, Haferlach T, Schnittger S. Three novel cytogenetically cryptic EVI1 rearrangements associated with increased EVI1 expression and poor prognosis identified in 27 acute myeloid leukemia cases. Genes Chromosomes Cancer. 2012 Dec;51(12):1079-85

Jancuskova T, Plachy R, Zemankova L, Hardekopf DW, Stika J, Zejskova L, Praulich I, Kreuzer KA, Rothe A, Othman MA, Kosyakova N, Pekova S. Molecular characterization of the rare translocation t(3;10)(q26;q21) in an acute myeloid leukemia patient. Mol Cytogenet. 2014;7:47

Jean-Loup Huret. 3q21q26 rearrangements in treatment

related leukemia Atlas Genet Cytogenet Oncol Haematol. 2005;9(3):234-235. 3q21q26 rearrangements in treatment related leukemia

t A new case of adult Acute Myeloid Leukemia with t(3;3)(p24;q26)

Yuan B et al.


Lawce H, Szabo E, Torimaru Y, Davis C, Osterberg K, Olson S, Moore S. MECOM (EVI1) Rearrangements: A Review and Case Report of Two MDS Patients with Complex 3q Inversion/Deletions J Assoc Genet Technol 2017;43(1):9-14

Lugthart S, Gröschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen-Bhola SL, Jan Ossenkoppele G, Vellenga E, van den Berg-de Ruiter E, Schanz U, Verhoef G, Vandenberghe P, Ferrant A, Köhne CH, Pfreundschuh M, Horst HA, Koller E, von Lilienfeld-Toal M, Bentz M, Ganser A, Schlegelberger B, Jotterand M, Krauter J, Pabst T, Theobald M, Schlenk RF, Delwel R, Döhner K, Löwenberg B, Döhner H. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26 2)/t(3;3)(q21;q26 2) and various other 3q abnormalities in acute myeloidleukemia

Poppe B, Dastugue N, Vandesompele J, Cauwelier B, De Smet B, Yigit N, De Paepe A, Cervera J, Recher C, De Mas V, Hagemeijer A, Speleman F. EVI1 is consistently

expressed as principal transcript in common and rare recurrent 3q26 rearrangements Genes Chromosomes Cancer 2006 Apr;45(4):349-56

Wieser R, Schreiner U, Rieder H, Pirc-Danoewinata H, Grüner H, Loncarevic IF, Fonatsch C. Interphase fluorescence in situ hybridization assay for the detection of rearrangements of the EVI-1 locus in chromosome band 3q26 in myeloid malignancies Haematologica 2003 Jan;88(1):25-30


Yuan B, Smith J, Ewton A, Pingali SR, Zieske A, Breman A. A new case of adult Acute Myeloid Leukemia with t(3;3)(p24;q26). Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):204-206.

Case Report Section




t(4;11)(q23;p15) in paediatric early T cell precursor acute lymphoblastic leukemia Anurag Gupta, Sirisharani Siddaiahgari, Nagaraju Nalla, Mukkanteeswara Rao

Kasaragadda, Manu Goyal

Department of Hematopathology and Genetics, AMPATH, Nallagandla, Serilingampally Hyderabad,

Telangana, India 500019 (AG, NN, MRK, MG); Department of Paediatric Oncology, Rainbow

Children's Hospital, Karvy Lanes, Banjara Hills, Hyderabad, Telangana, India - 500 034 (SS);

[email protected].

Published in Atlas Database: March 2018

Online updated version : http://AtlasGeneticsOncology.org/Reports/t0411q23p15GuptaID100094.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70474/03-2018-t0411q23p15GuptaID100094.pdf DOI: 10.4267/2042/70474


Abstract Case report on t(4;11)(q23;p15) in paediatric early T

cell precursor acute lymphoblastic leukemia.

Clinics

Age and sex


Previous history

No preleukemia, no previous malignancy, no inborn

condition of note

Organomegaly

Hepatomegaly (3 cms below right costal margin),

splenomegaly (3 cms below left costal margin),

enlarged lymph nodes (Cervical lymphadenopathy),

no central nervous system involvement


HB: 6.6g/dl

Platelets: 1.9X 109/l

Blasts: 2%

Bone marrow: 30%; Hypocellular and aparticulate

bone marrow aspirate smears and show presence of

30% blasts.


Phenotype: L1

Immunophenotype

The blast cells were dim CD45 positive and

expressed moderate CD34, CD38, CD7, CD33, dim

CD2, partially CD117 and dim cytoplasmic CD3.

These cells are negative for CD19, CD10, CD20,

HLADR, CD4, CD8, surface CD3, CD5 and CD1a.

Rearranged Ig Tcr

Not done

Pathology

Acute lymphoblastic leukemia

Electron microscopy

Not done

Diagnosis

Early T cell precursor Lymphoblastic leukemia.

Survival

Date of diagnosis

12-2015

Treatment

High risk BFM 95

t(4;11)(q23;p15) in paediatric early T cell precursor acute lymphoblastic leukemia

Gupta A et al.


Complete remission Relapse: no

Status Alive

Last follow up

11-2017

Survival

24+months

Karyotype

Sample Bone marrow aspirate

Culture time 17 overnight with and without

colcemid

Banding GTG

Results

46,XX,t(4?11)(q23?p15)[09]/46,XX[11]


Fluorescence in situ hybridisation was done on bone

marrow culture pellet using NUP98 break apart

probe, Zytovysion, Fischai, Bremerhaven, Germany.


Positive for rearrangement of the NUP98 gene in

34% of the cells.

Figure 1: Karyogram showing t(4;11)(q23?p15) GTG

staining and banding method × 100 oil immersion, Carl Zeiss Axios cope and processed using IKAROS software)

Figure 2: FISH using NUP98 break apart probe,

Zytovysion, Fischai, Bremerhaven, Germany.

Other Findings Negative for BCR/ABL1 fusion, ETV6/RUNX1

fusion, KMT2A gene rearrangement and E2A gene

rearrangement by FISH.

Comments The t(4;11)(q23;p15) is a rare recurrent translocation

in T cell acute lymphoblastic leukemia (T cell ALL)

that has been described in ten cases till date and

leads to the fusion of NUP98 gene and RAP1GDS1

gene (Mohamed AN, In press). The uniqueness of

this translocation is it not involving the T cell

receptor genes. It has previously been associated

with T cell lymphoblastic leukemias arising from

progenitor cells aberrantly expressing myeloid

molecules (Mecucci, C. et.al., 2000). In the present

case this translocation was detected in early

precursor T cell lymphoblastic leukemia (EPT-

ALL), a recently described sub entity of T cell ALLs

associated with inferior outcome that is characterised

by CD1a negative, CD8 negative, CD5 weak,

aberrant expression of myeloid and or stem cell

antigens like CD117 CD13 and CD33 (Coustain S.

et.al., 2009). Although the previous published three

case reports described aberrant myeloid antigen

expression, none were reported with CD117

expression. Nine cases were of adults while a single

case was described in 6 years old female. The

translocation was detected at diagnosis in eight cases

and was associated with additional abnormalities in

three cases. In one case it was cytogenetically cryptic

and was detected by molecular studies (Cimino G.

et.al., 2001). The t(4;11) is associated with

unfavourable outcome (Mohamed AN, In press). All

the described cases died of the disease except a 6

years old female child who remained alive after 25

months of follow up (Pui CH. et.al., 1991). The

present case was of EPTALL with t(4;11) who is

alive and remains in remission 24 months post

diagnosis. It is postulated that t(4;11) may impart

unfavourable prognosis in adults rather than

paediatric population; however, further studies are

warranted.

ACKNOWLEDGEMENTS: The authors wish to

acknowledge Ms. Emily-Jane Rüschendorf and her

scientific team at Zytovysion, Fischai, Bremerhaven,

Germany for their support in performing FISH for

NUP98 on this case.

References Bloomfield CD, Goldman AI, Alimena G, Berger R, Borgström GH, Brandt L, Catovsky D, de la Chapelle A, Dewald GW, Garson OM. Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia. Blood. 1986 Feb;67(2):415-20

Cimino G, Sprovieri T, Rapanotti MC, Foà R, Mecucci C, Mandelli F. Molecular evaluation of the NUP98/RAP1GDS1 gene frequency in adults with T-acute lymphoblastic leukemia. Haematologica. 2001 Apr;86(4):436-7

Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, Cheng C, Su X, Rubnitz JE, Basso G, Biondi A, Pui CH, Downing JR, Campana D. Early T-cell precursor leukaemia: a subtype of very high-risk acute

t(4;11)(q23;p15) in paediatric early T cell precursor acute lymphoblastic leukemia

Gupta A et al.


lymphoblastic leukaemia. Lancet Oncol. 2009 Feb;10(2):147-56

Inoue S, Tyrkus M, Ravindranath Y, Gohle N. A variant translocation between chromosomes 4 and 11, t(4q;11p) in a child with acute leukemia. Am J Pediatr Hematol Oncol. 1985 Summer;7(2):211-4

Mecucci C, La Starza R, Negrini M, Sabbioni S, Crescenzi B, Leoni P, Di Raimondo F, Krampera M, Cimino G, Tafuri A, Cuneo A, Vitale A, Foà R. t(4;11)(q21;p15) translocation involving NUP98 and RAP1GDS1 genes: characterization of a new subset of T acute lymphoblastic leukaemia Br J Haematol 2000 Jun;109(4):788-93

Mohamed AN.. t(4;11)(q23;p15) NUP98/RAP1GDS1 Atlas Genet Cytogenet Oncol Haematol. in press

Pui CH, Frankel LS, Carroll AJ, Raimondi SC, Shuster JJ, Head DR, Crist WM, Land VJ, Pullen DJ, Steuber CP, et al. Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): a collaborative study of 40 cases Blood 1991 Feb 1;77(3):440-7

Stähli BE, Landmesser U. [Optimal Medical Therapy and Secondary Prevention in Patients after an Acute Coronary Syndrome] Dtsch Med Wochenschr 2018 May;143(9):672-679


Gupta A, Siddaiahgari S, Nalla N, Rao Kasaragadda M, Goyal M. t(4;11)(q23;p15) in paediatric early T cell precursor acute lymphoblastic leukemia. Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):207-209.

Case Report Section




t(6;17)(p21;p13) and acquisition of the Philadelphia chromosome translocation with p190 BCR-ABL1 transcript during the course of myelodysplastic syndrome Adriana Zamecnikova

Kuwait Cancer Control Center, Kuwait [email protected]


Online updated version : http://AtlasGeneticsOncology.org/Reports/t0617p21p13AdrianaBCRID100093.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70475/01-2018-t0617p21p13AdrianaBCRID100093.pdf DOI: 10.4267/2042/70475


Abstract

Case report on t(6;17)(p21;p13) and acquisition of

the Philadelphia chromosome translocation with

p190 BCR-ABL1 transcript during the course of

myelodysplastic syndrome.

Clinics

Age and sex

47 years old male patient.

Previous history

Preleukemia The patient had thrombocytopenia for

10 years (platelet counts ranged between 70x106/L

to 130x106/L, for what he had never received any

treatment; no previous malignancy; no inborn

condition of note

Organomegaly

no hepatomegaly , no splenomegaly , no enlarged

lymph nodes , no central nervous system

involvement


HB: 8.6g/dl

Platelets: 6X 109/l

Blasts: 43%

Bone marrow: The bone marrow was hypocellular

with 6.5% blasts at presentation. 7 months later, the

patient MDS transformed to AML and his bone

marrow biopsy showed markedly hypercellular

marrow with 69% blasts (0.4% promyelocytes, 2.7%

myelocytes, 1.1% neutrophils, 1.8% lymphocytes

and 25% erythroblasts).


Phenotype

Acute myeloid leukemia without maturation

Immunophenotype

Myeloid immunophenotype, (positive for CD13,

CD33, CD34, HLDR, CS45 and CD117) with

aberrant expression of CD7.

Diagnosis

AML with myelodysplasia-related changes.

Provisional entity: AML with BCR/ABL1

Survival

Date of diagnosis

08-2011

Treatment

After the patient was diagnosed with MDS, therapy

with decitabine was administrated but the patient

remained cytopenic. At progression chemotherapy

combined with imatinib (400 mg/day) was

administrated that was escalated to 800 mg/day two

weeks later.


t(6;17)(p21;p13) and acquisition of the Philadelphia chromosome translocation with p190 BCR-ABL1 transcript during the course of myelodysplastic syndrome

Zamecknikova A


Status Alive

Last follow up: 04-2012

Survival

7+ The patient had traveled to his native country for

further treatment.months

Karyotype

Sample bone marrow

Culture time 24h

Banding G-banding

Results

47,XY,t(6;17)(p21;p13),+8 [10]/46,XY [10] at

presentation;

47,XY,t(6;17)(p21;p13),+8,t(9;22)(q34;q11)[18]/48

,XY,t(6;17)(p21;p13),+8,t(9;22)(q34;q11),+10

[2]/46,XY [20 ] at transition

Figure 1. Karyotype of the patient from the time of diagnosis showing the 47,XY,t(6;17)(p21;p13),+8.


Fluorescence in situ hybridization studies (FISH)

were performed on slides prepared for cytogenetic

analysis using a t(9;22) specific BCR/ABL dual

color, dual fusion, CEP 8 and LSI P53 probes (Abott

Molecular/Vysis, US).


Breakpoint on 17p13 prompted us to search for

deletion of the p53 gene at presentation; however

fluorescence in situ hybridization with LSI p53

probe revealed only the presence of 2 normal P53

signals in 500 interphase cells. Hybridization with

chromosome 8 centromeric probe showed extra

chromosome +8 in 50 % of cells. FISH studies with

BCR/ABL performed at transition revealed 60%

positive cells while retrospective studies performed

on stored bone marrow cells from MDS phase failed

to detect either the Philadelphia chromosome, either

the BCR/ABL1 rearrangement.

Other Molecular Studies

Technics:

Molecular studies were performed from total RNA

extracted from the bone marrow sample using the

TriZol LS reagent (Invitrogen, US) according to the

manufacturer's recommendations. cDNA was

prepared from 2μg of total RNA with the Superscript

II cDNA Synthesis Kit (Invitrogen, US) according to

manufacturer's instructions.

Results:

Quantitative molecular studies performed with

GeneXpert (Cepheid, US) were negative for the

major BCR/ABL1 transcript. The absence of p210

BCR-ABL1 transcript was confirmed by reverse

transcription-polymerase chain reaction analysis;

however it showed breakpoint cluster region

rearrangement between exons e1 and a2, compatible

with the minor p190 BCR/ABL1 transcript.

Comments We described a rare t(6;17)(p21;p13) (La Starza et

al., 26) in a patient diagnosed with myelodysplastic

syndrome that terminated in AML associated with

acquisition of the Philadelphia chromosome

translocation and the p190 BCR-ABL1 transcript.

The patient initially had thrombocytopenia for 10

years, but developed MDS and at that time

karyotyping revealed the chromosomal translocation

t(6;17)(p21;p13) associated with an extra

chromosome 8.

The initial myelodysplastic syndrome terminated to

acute myeloid leukemia, accompanied by an

appearance of a new clone, characterized by a

Philadelphia chromosome. Reverse transcription-

polymerase chain reaction analysis further revealed

the presence of the minor p190 BCR-ABL1

transcript. Developing a Philadelphia chromosome,

considered a primary anomaly, during the course of

MDS is extremely rare phenomenon, described only

in few patients (Melo et al., 1994; Onozawa et al.,

2003; Advani et al., 2004; Keung et al., 2004). Our

study illustrates that the Ph translocation may

develop from an existing MDS clone, accompanying

or perhaps inducing disease transformation. The

availability of preleukemic MDS phase in our patient

offers an unique opportunity to analyze the role of

BCR-ABL1 in leukemogenesis and the evolution of

leukemia clones in hematological malignancies.

t(6;17)(p21;p13) and acquisition of the Philadelphia chromosome translocation with p190 BCR-ABL1 transcript during the course of myelodysplastic syndrome

Zamecknikova A


Figure 2. (A) Representative metaphase of the patient from the time of transition showing the 47,XY,t(6;17)(p21;p13),+8,t(9;22)(q34;q11) karyotype. (B) Fluorescence in situ hybridization with LSI BCR-ABL1 probe (Vysis, IL, US) showing the fusion BCR-ABL1 signal on der(9) and der(22) chromosomes. (C) Ethidium-bromide-stained agarose gel

showing RT-PCR-amplified BCR-ABL1 chimaeric transcripts1. Lanes M, molecular weight marker; lane 1, e1a2 fusion in a patient; line 2, ABL internal control; line 3, e1a2-positive cell control; line 4, negative control; line 5, negative reaction with

p210BCR/ABL primers in a patient; line 6, p210 CML positive control.

References Advani AS. Philadelphia chromosome positive myelodysplastic syndrome and acute myelogenous leukemia. Leuk Res. 2004 Jun;28(6):545-6

Keung YK, Beaty M, Powell BL, Molnar I, Buss D, Pettenati M. Philadelphia chromosome positive myelodysplastic syndrome and acute myeloid leukemia-retrospective study and review of literature. Leuk Res. 2004 Jun;28(6):579-86

La Starza R, Aventin A, Matteucci C, Crescenzi B, Romoli S, Testoni N, Pierini V, Ciolli S, Sambani C, Locasciulli A, Di Bona E, Lafage-Pochitaloff M, Martelli MF, Marynen P, Mecucci C. Genomic gain at 6p21: a new cryptic molecular rearrangement in secondary myelodysplastic syndrome and acute myeloid leukemia. Leukemia. 2006 Jun;20(6):958-64

Melo JV, Myint H, Galton DA, Goldman JM.. P190BCR-ABL chronic myeloid leukaemia: the missing link with chronic myelomonocytic leukaemia? Leukemia 1994 Jan;8(1):208-11.

Onozawa M, Fukuhara T, Takahata M, Yamamoto Y, Miyake T, Maekawa I.. A case of myelodysplastic syndrome developed blastic crisis of chronic myelogenous leukemia with acquisition of major BCR/ABL. Ann Hematol 2003 Sep;82(9):593-5.


Zamecnikova A. t(6;17)(p21;p13) and acquisition of the Philadelphia chromosome translocation with p190 BCR-ABL1 transcript during the course of myelodysplastic syndrome. Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):210-212.

Case Report Section




t(6;17)(p21;p13) associated with t(3;3)(q21;q26.2) in AML Adriana Zamecnikova

Kuwait Cancer Control Center, Kuwait [email protected]


Online updated version : http://AtlasGeneticsOncology.org/Reports/t0617p21p13AdrianaMECOMID100092.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70476/01-2018-t0617p21p13AdrianaMECOMID100092.pdf DOI: 10.4267/2042/70476


Abstract Case report on t(6;17)(p21;p13) associated with

t(3;3)(q21;q26.2) in AML.

Clinics

Age and sex


Previous history

Preleukemia; no previous malignancy, no inborn

condition of note

Organomegaly

No hepatomegaly , no splenomegaly , no enlarged

lymph nodes , no central nervous system

involvement

Blood WBC: 20X 109/l

HB: 86g/dl


Blasts: 12%

Bone marrow: Hyperplastic bone marrow with

dyserythropoiesis, megaloblastic erythropoiesis,

presence of multinuclear forms, depressed

megakaryocytes and 23% blasts.


Phenotype: Acute myeloid leukemia

Immunophenotype

Positive for CD13, CD33, CD34, HLDR, CS45,

CD11b, MPO and CD64, dim expression of CD14

and CD117.

Diagnosis

AML with t(3;3)(q21;q26.2)

Survival

Date of diagnosis: 12-2017


Last follow up: 12-2017

Karyotype

Sample bone marrow

Culture time 24h

Banding G-banding

Results

45,XX,t(3;3)(q21;q26.2),t(6;17)(p21;p13),-

7[14]/45,XY,t(3;3)(q21;q26.2),-7[4]/ 46,XX [2]

t(6;17)(p21;p13) associated with t(3;3)(q21;q26.2) in AML) Zamecknikova A


Figure 1. Karyotype of the patient with t(3;3)(q21;q26.2) and -7 (A) and with t(6;17)(p21;p13) as an additional anomaly (B) .


Fluorescence in situ hybridization studies (FISH)

were performed using Kreatechô MECOM (EVI1)

t(3;3); inv(3)(3q26) Break FISH probe and

SureFISH 17p13.3 (PAFAH1B1) and RUNX2

(6p21.1) probes.


Hybridization with EVI1 probe confirmed the

rearrangement of the gene as a result of

t(3;3)(q21;q36.2) on 10 metaphases and in 90 % of

interphase cells. Hybridization with Vysis D7S486/

Vysis CEP 7 probe showed monosomy 7 in 90% of

cells. FISH studies with SureFISH PAFAH1B1 and

RUNX2 probes showed normal signals on 2

metaphases without t(6;17) and juxtaposition of

PAFAH1B1 from 17p13.3 to 6p21.1 at the site of

RUNX2 gene in 5 metaphases.

Comments

We described here an AML patient with

t(3;3)(q21;q26.2) associated with monosomy 7 and a

rare translocation t(6;17)(p21;p13) (La Starza et al.,

26). The chromosomal t(6;17)(p21;p13) was found

in a sideline as an additional anomaly to

t(3;3)(q21;q26.2) and monosomy 7, therefore likely

representing a secondary aberration to these primary

anomalies. inv(3)(q21q26.2) or t(3;3)(q21;q26.2) in

AML or MDS result in deregulation of the proto-

oncogene EVI1 (MECOM), which affect the

RAS/receptor tyrosine kinase pathway. The

concomitant monosomy 7 and t(6;17)(p21;p13) are

probably cooperating genetic lesions that developed

during malignant transformation processes in our

patient.

t(6;17)(p21;p13) associated with t(3;3)(q21;q26.2) in AML Zamecknikova A


Figure 2. (A) Fluorescence in situ hybridization with Kreatechô MECOM (EVI1) break apart probe confirmed the rearrangement of the gene as a result of t(3;3)(q21;q36.2). FISH studies with SureFISH PAFAH1B1 located at 17p.13.3 revealed juxtaposition of PAFAH1B1 from 17p13.3 to der(6) chromosome (B). Simultaneous hybridization with SureFISH PAFAH1B1 and RUNX2 probes

showed cohybridization of PAFAH1B1 and RUNX2 genes on 6p21.1 (C).

References La Starza R, Aventin A, Matteucci C, Crescenzi B, Romoli S, Testoni N, Pierini V, Ciolli S, Sambani C, Locasciulli A, Di Bona E, Lafage-Pochitaloff M, Martelli MF, Marynen P, Mecucci C. Genomic gain at 6p21: a new cryptic molecular rearrangement in secondary myelodysplastic syndrome and acute myeloid leukemia. Leukemia. 2006 Jun;20(6):958-64


Zamecnikova A. t(6;17)(p21;p13) associated with t(3;3)(q21;q26.2) in AML. Atlas Genet Cytogenet Oncol Haematol. 2019; 23(7):213-215.




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September 1997 Volume 23 - Number 7 July 2019 - Revues ...

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