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t(14;19)(q32;p13) IGH/EPOR

t(14;19)(q32;p13) IGH/BRD4 ?

Written2017-03Adriana Zamecnikova
Kuwait Cancer control Center, Department of Hematology, Kuwait; annadria@yahoo.com

Abstract Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus at 14q32 are common in mature B-cell neoplasms, but infrequent in B-cell acute lymphoblastic leukemia. Among them, the t(14;19)(q32;p13) is a rare but recurrent anomaly described only in a limited number of patients.

Keywords Chromosome 14; chromosome 19; IGH translocations; B-cell acute lymphoblastic leukemia; t(14;19)(q32;p13); EPOR.

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Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9823/3 Chronic lymphocytic leukaemia /small lymphocytic lymphoma
ICD-Morpho 9689/3
ICD-Morpho 9680/3 Diffuse large B-cell lymphoma (DLBCL), NOS; Primary DLBCL of the CNS; Primary cutaneous DLBCL, leg type; EBV positive DLBCL of the elderly; DLBCL associated with chronic inflammation; B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
Atlas_Id 1681

Clinics and Pathology

Disease B-lineage acute lymphoblastic leukaemia (ALL) mainly.
Phenotype / cell stem origin B-lineage immunophenotype mostly positive for CD10, CD19, CD20, CD22, CD34, CD38, HLA-DR and TdT; may show aberrant expression of myeloid markers, CD13 and/or CD33 (Jaso et al., 2013).
Epidemiology Rare anomaly, with only 16 cases reported to date; found most often in adolescents and young adults (Table 1). Among the reported cases there were 9 males and 7 females aged 11 to 74 years (median age 38 years). 13 patients were diagnosed with B-ALL (Micci et al., 2007; Russell et al., 2009; Chapiro et al., 2013; Jaso et al., 2014) and there were sporadic cases of other B-cell neoplasms: 1 chronic lymphocytic leukemia (Finn et al., 1996), 1 splenic marginal zone B-cell lymphoma (Martinez-Climent et al., 2003) and 1 diffuse B-cell lymphoma (Micci et al., 2007).
Table 1: t(14;19)(q32;p13) cases
 Sex/Age DiagnosisKaryotype FISH
1.M/63  CLL46,XY,t(14;19)(q32;p13)IGH+
2.F SMBCL 48,XX,add(1)(p36),+der(1)t(1;17)(p32;q11)t(1;5)(q31;p12),+3,del(10)(p14),t(11;12)(q23;q12),t(14;18)(q32;q21) 
47,XX,+der(1)t(1;17)t(1;5)(q31;p11),del(10),t(11;12),t(14;18),t(14;19)(q32;p13) 
 
3.16/M  B-ALL 46,XY,t(14;19)(q32;p13)IGH+ BRD4+
4.36/F B-ALL 46,XX,t(14;19)(q32;p13)BRD4-
5.20/20/M DLBCL 50,XY,+X,+add(8)(p11),t(14;19)(q32;p13),+2mar/ 50,idem, t(1;12)(p36;q24)  
6.F/38  B-ALL 46,XX,t(9;15)(q1?;q1?),t(14;19)(q32;p13)/46,XX,add(9)(p1?),t(14;19)IGH+ EPOR+
7.M/11 B-ALL 46,XY,t(14;19)(q32;p13)IGH+ EPOR+ 
8.M/25 B-ALL 46,XY,t(14;19)(q32;p13)  IGH+ EPOR+ 
9.M/38 B-ALL 46,XY,t(14;19)(q32;p13) IGH+ EPOR+ 
10.F/60 B-ALL46,XX,t(14;19)(q32;p13)No material
11.F/41 46,XX,t(14;19)(q32;p13) IGH+ EPOR+
12.F/38 B-ALL 46,XX,t(14;19)(q32;p13) IGH+ EPOR+
13.F/48 B-ALL 39-47,XX,add(5)(q35),del(6)(q23),+add(8)(p23),+11,t(14;19)(q32;p13),-18,-19, +1-4mar  IGH+ EPOR+
14.M/74 B-ALL 44-45,XY,-4,del(6)(q21),t(14;19)(q32;p13),del(17)(p11) IGH+ EPOR+ 
15.M/21 B-ALL 46,XY,del(12)(p12) at diagnosis
46,XY,t(14;19)(q32;p13) at relapse
IGH+ EPOR+ 
16.M/28 B-ALL 46,XY,t(14;19)(q32;p13)IGH+ EPOR+
).
Abreviations: M., male; F., female; CLL., chronic lymphocytic leukemia; SMBCL., splenic marginal zone B-cell lymphoma; B-ALL., B-cell acute lympholastic leukemia; DLBCL., diffuse large B-cell lymphoma. ).
1. Finn et al., 1996; 2. Martinez-Climent et al., 2003; 3-5. Micci et al., 2007; 6-7. Russell et al., 2009; 8-10. Chapiro et al., 2013; 11-16. Jaso et al., 2014.
Clinics Patients presented with severe anemia, thrombocytopenia and circulating blasts in B-ALL patients; markedly elevated serum lactate dehydrogenase and serum beta-2-microglobulin levels may be present. Diagnostic bone marrow samples were hypercellular with high blast percentages with a median blast count of 90% (data from Jaso et al., 2013).
Prognosis Patients with IGH/EPOR fusion descried by Jaso et al., 2013 received aggressive multiagent chemotherapy. Among them, 4 of 6 patients achieved an initial complete response, however all developed multiple relapses (median time to relapse was 6 months) and 5 of them died (median survival 12 months). The 38-year-old patient described by Russell et al, 2007 suffered several relapses after diagnosis followed by bone marrow transplant (BMT) 4 months later; she remains alive at 13 months after diagnosis. The second, 11-year-old boy achieved a complete remission, received a BMT 5 months after diagnosis and was alive at 48 months. The outcome of patients described by Chapiro et al., 2013 is known only for the 38 years old male who died 21 months after diagnosis. These data suggest that t(14;19)(q32;p13) IGH/EPOR is associated with an aggressive clinical course and confers a poor prognosis. The 2 remaining ALL patients described by Micci et al., 2007 achieved complete remission; the 16-years old with BRD4 split (see below) remains in remission 27 months and the 36-years old female relapsed after 1 year and died from progressive leukemia 18 months after diagnosis.

Cytogenetics

Cytogenetics Morphological Cytogenetically subtle rearrangement, involving the telomeric end of 14q while the uncertainty of 19p or 19q breakpoints may lead to misinterpretation of breakpoint positions. May resemble the appearance of t(14;19)(q32;q13) with IGH and BCL3 or CEBPA involvements in suboptimal preparations.
Additional anomalies Described as the sole anomaly in 11 out of 16 cases (Finn et al., 1996; Micci et al., 2007; Russell et al 2009; Chapiro et al., 2013; Jaso et al., 2014) and found in association with del(6q) in 2,+11 in 1, del(17p) in 1 (Jaso et al., 2014) and in 1 patient it was present in two sidelines (Russell et al., 2009). One patient presented with an initial karyotype of 46,XY,del(12)(p12) and acquired the t(14;19)(q32;p13.1) as the sole abnormality at the time of relapse 39 months later (Jaso et al., 2014). The t(14;19)(q32;p13) was found as a part of complex karyotypes in both lymphoma patients (Martinez- Climent et al., 2003; Micci et al., 2007).

Genes involved and Proteins

Note Involvement of EPOR (Erythropoietin Receptor 4) as the IGH (immunoglobulin heavy locus) partner gene in t(14;19)(q32;p13) has been demonstrated by fluorescence in situ hybridization (FISH) in patients with B-ALL (Russel et all., 2007; Chapiro et al., 2013; Jaso et al., 2013). In 1 patient descried by Micci et al., 2007 the IGH was recombined with BRD4 (Bromodomain Containing 4) and in the second case the breakpoint on chromosome 19 was found in a 2.1-Mb region in 19p13.13∼19p13.2.
Gene NameIGH (Immunoglobulin Heavy)
Location 14q32.33
Gene NameEPOR (erythropoietin receptor)
Location 19p13.2
Protein Inherited mutations in the erythropoietin receptor causing premature termination of the receptor cytoplasmic carboxy-terminal region have been described in patients with primary familial and congenital erythrocytosis.
Gene NameBRD4 (bromodomain containing 4)
Location 19p13.12
Protein Bromodomain-containing protein 4 is a member of the BET (bromodomain and extra terminal domain) family containing 2 bromodomains that recognize epigenetic chromatin modifications, such as acetylated lysine residues. BRD4 plays a role in the maintenance of acute myeloid leukaemia stem cells and is often required for MYC expression, therefore it is possible that deregulated BRD4 expression may lead in sustained MYC expression and aberrant self-renewal (Zuber et al., 2011).

Result of the chromosomal anomaly

Fusion Protein
Oncogenesis B-cell acute lymphoblastic leukemia with t(14;19)(q32;p13), in which IGH and EPOR are juxtaposed, has been reported rarely. The translocation was the sole abnormality in the majority of cases, representing an early, possibly initiating event. Translocations involving the immunoglobulin heavy chain locus results in juxtaposition with IGH transcriptional enhancers to the partner gene leading to its deregulated expression. EPOR encodes a type 1 cytokine receptor involved in kinase signaling and is required for normal erythropoiesis. The principal consequence of t(14;19)(q32;p13) is likely over-expression of EPOR, documented by Russel et al., 2007. EPOR is not expressed in normal B-cell precursors and dysregulation of this gene may increase cell survival through activation of the JAK-STAT5. Ectopic expression of EPOR has been identified in B-ALL with t(12;21)(p13;q22) and ETV6 / RUNX1 fusion, indicating that high-level EPOR expression contributes to B-cell precursor transformation by constitutive STAT5 phosphorylation (Dyer et al, 2010; Jasso et al., 2014).
BRD4 split by the t(14;19)(q32;p13) was found only in one of the two examined cases, therefore it is unclear if deregulation of BRD4 or the neighboring NOTCH3 and/or EPHX3 (ABHD9) genes, located distal to BRD4 in 19p13 is implicated in pathogenesis (Micci et al., 2007).
  

Bibliography

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Cancer Genet 2013 May;206(5):162-73.
PMID 23827691
 
Immunoglobulin heavy chain locus chromosomal translocations in B-cell precursor acute lymphoblastic leukemia: rare clinical curios or potent genetic drivers?
Dyer MJ, Akasaka T, Capasso M, Dusanjh P, Lee YF, Karran EL, Nagel I, Vater I, Cario G, Siebert R.
Blood 2010 Feb 25;115(8):1490-9.
PMID 20042721
 
Karyotype correlates with peripheral blood morphology and immunophenotype in chronic lymphocytic leukemia.
Finn WG, Thangavelu M, Yelavarthi KK, Goolsby CL, Tallman MS, Traynor A, Peterson LC.
Am J Clin Pathol 1996 Apr;105(4):458-67.
PMID 8604688
 
B acute lymphoblastic leukemia with t(14;19)(q32;p13.1) involving IGH/EPOR: a clinically aggressive subset of disease.
Jaso JM, Yin CC, Lu VW, Zhao M, Abruzzo LV, You MJ, Yang Y, Luthra R, Medeiros LJ, Lu G.
Mod Pathol 2014 Mar;27(3):382-9.
PMID 24030742
 
Genomic abnormalities acquired in the blastic transformation of splenic marginal zone B-cell lymphoma.
Martinez-Climent JA, Sanchez-Izquierdo D, Sarsotti E, Blesa D, Benet I, Climent J, Vizcarra E, Marugan I, Terol MJ, Sole F, Cigudosad JC, Siebert R, Dyer MJ, Garcèa-Conde J.
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Molecular cytogenetic characterization of t(14;19)(q32;p13), a new recurrent translocation in B cell malignancies.
Micci F, Panagopoulos I, Tjønnfjord GE Kolstad A, Delabie J, Beiske K, Heim S.
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A novel translocation, t(14;19)(q32;p13), involving IGH@ and the cytokine receptor for erythropoietin.
Russell LJ, De Castro DG, Griffiths M, Telford N, Bernard O, Panzer-Grümayer R, Heidenreich O, Moorman AV, Harrison CJ.
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RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.
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Citation

This paper should be referenced as such :
Zamecnikova A
t(14;19)(q32;p13) IGH/EPOR; t(14;19)(q32;p13) IGH/BRD4 ?;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t1419q32p13ID1681.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(14;19)(q32;p13) IGH/EPOR
 t(14;19)(q32;p13) IGH/BRD4

External links

Mitelman databaset(14;19)(q32;p13) [Case List]    t(14;19)(q32;p13) [Association List] Mitelman database (CGAP - NCBI)
Mitelman databaset(14;19)(q32;p13) [Case List]    t(14;19)(q32;p13) [Association List] Mitelman database (CGAP - NCBI)
arrayMapMorph ( 9811/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9823/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9689/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9680/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
Disease databaset(14;19)(q32;p13) IGH/EPOR
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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