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

2017-03-01   Adriana Zamecnikova 

1.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.

Clinics and Pathology

Disease

B-lineage acute lymphoblastic leukaemia (ALL) mainly.

Phenotype stem cell 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 name
IGH (Immunoglobulin Heavy)
Location
14q32.33
Gene name
BRD4 (bromodomain containing 4)
Location
19p13.12
Protein description
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.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

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).

Highly cited references

Pubmed IDYearTitleCitations
271767952016Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan.23
264048922015Identification of novel kinase fusion transcripts in paediatric B cell precursor acute lymphoblastic leukaemia with IKZF1 deletion.12
240307422014B acute lymphoblastic leukemia with t(14;19)(q32;p13.1) involving IGH/EPOR: a clinically aggressive subset of disease.4
352670032022Pseudo-Chédiak-Higashi inclusions in BCR::ABL1-like B-lymphoblastic leukemia with IGH::EPOR rearrangement.0
341594012021Hematological characteristics, cytogenetic features, and post-induction measurable residual disease in thymic stromal lymphopoietin receptor (TSLPR) overexpressed B-cell acute lymphoblastic leukemia in an Indian cohort.0
323306622020From the archives of MD Anderson Cancer Center: BCR-ABL1-like B acute lymphoblastic leukemia with IGH/EPOR fusion.0
275445112016Development of acute lymphoblastic leukemia with IgH-EPOR in a patient with secondary erythrocytosis.0

Bibliography

Pubmed IDLast YearTitleAuthors
238276912013Chromosomal translocations involving the IGH@ locus in B-cell precursor acute lymphoblastic leukemia: 29 new cases and a review of the literature.Chapiro E et al
200427212010Immunoglobulin heavy chain locus chromosomal translocations in B-cell precursor acute lymphoblastic leukemia: rare clinical curios or potent genetic drivers?Dyer MJ et al
86046881996Karyotype correlates with peripheral blood morphology and immunophenotype in chronic lymphocytic leukemia.Finn WG et al
240307422014B acute lymphoblastic leukemia with t(14;19)(q32;p13.1) involving IGH/EPOR: a clinically aggressive subset of disease.Jaso JM et al
126883152003Genomic abnormalities acquired in the blastic transformation of splenic marginal zone B-cell lymphoma.Martinez-Climent JA et al
188187062009A novel translocation, t(14;19)(q32;p13), involving IGH@ and the cytokine receptor for erythropoietin.Russell LJ et al
218142002011RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.Zuber J et al

Summary

Fusion gene

IGH/EPOR , IGH/BRD4

Citation

Adriana Zamecnikova

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

Atlas Genet Cytogenet Oncol Haematol. 2017-03-01

Online version: http://atlasgeneticsoncology.org/haematological/1681/t(14;19)(q32;p13)

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