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Erroneous class switching and false VDJ recombination: molecular dissection of t(8;14)/MYC-IGH translocations in Burkitt-type lymphoblastic leukemia/B-cell lymphoma.

ABSTRACT: The chromosomal translocation t(8;14)(q24;q32) with juxtaposition of MYC to enhancer elements in the immunoglobulin heavy chain (IGH) gene locus is the genetic hallmark of the majority of Burkitt lymphoma and a subset of Diffuse large B-cell lymphoma patients. Around 3% of adult B-lineage acute lymphoblastic leukemia (ALL) patients show this aberration. Flow cytometry mostly reveals a "mature B-ALL" or "Burkitt-type" ALL immunophenotype. Using long-distance PCR for t(8;14)/MYC-IGH fusion, we investigated bone marrow, peripheral blood and a few other samples with suspected Burkitt-ALL or mature B-ALL and identified 133 MYC-IGH-positive cases. The location of the chromosomal breaks in the IGH joining and the 8 different switch regions was determined using a set of long-distance PCRs. The chromosomal breakpoints with the adjacent MYC regions on 8q24 were characterized by direct sequencing in 49 cases. The distribution of chromosomal breaks among the IGH joining and switch regions was the following: JH 23.3%, M 21.8%, G1 15.0%, G2 7.5%, G3 3.8%, G4 4.5%, A1 12.8%, A2 3.8%, E 7.5%. Two breakpoint clusters near MYC were delineated. There was no clear correlation between the degree of somatic hypermutation and the chromosomal break locations. Epstein Barr virus was detected in 5 cases (4%). This detailed and extensive molecular analysis illustrates the molecular complexity of the MYC-IGH translocations and the detected distribution of breakpoints provides additional evidence that this translocation results from failed switch and VDJ recombinations. This study may serve as a model for the analysis of other IGH translocations in B-cell lymphoma.

SUBMITTER: Burmeister T

PROVIDER: S-EPMC5528421 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Erroneous class switching and false VDJ recombination: molecular dissection of t(8;14)/MYC-IGH translocations in Burkitt-type lymphoblastic leukemia/B-cell lymphoma.

Burmeister Thomas T Molkentin Mara M Schwartz Stefan S Gökbuget Nicola N Hoelzer Dieter D Thiel Eckhard E Reinhardt Richard R

Molecular oncology 20130425 4

The chromosomal translocation t(8;14)(q24;q32) with juxtaposition of MYC to enhancer elements in the immunoglobulin heavy chain (IGH) gene locus is the genetic hallmark of the majority of Burkitt lymphoma and a subset of Diffuse large B-cell lymphoma patients. Around 3% of adult B-lineage acute lymphoblastic leukemia (ALL) patients show this aberration. Flow cytometry mostly reveals a "mature B-ALL" or "Burkitt-type" ALL immunophenotype. Using long-distance PCR for t(8;14)/MYC-IGH fusion, we inv ...[more]

PMID: 23673335

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Project description:B-cell malignancies, such as human Burkitt's lymphoma, often contain translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH, encoded by Igh). The nature of elements that activate oncogenes within such translocations has been a long-standing question. Translocations within Igh involve DNA double-strand breaks initiated either by the RAG1/2 endonuclease during variable, diversity and joining gene segment (V(D)J) recombination, or by activation-induced cytidine deaminase (AID, also known as AICDA) during class switch recombination (CSR). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (Cmu) exons, which are the first of several sets of C(H) exons ('C(H) genes') within a C(H) locus that span several hundred kilobases (kb). In mature B cells, CSR deletes Cmu and replaces it with a downstream C(H) gene. An intronic enhancer (iEmu) between the variable region exons and Cmu promotes V(D)J recombination in developing B cells. Furthermore, the Igh 3' regulatory region (Igh3'RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes. Transgenic mice bearing iEmu or Igh3'RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression. However, in many B-cell lymphomas, Igh-c-myc translocations delete iEmu and place c-myc up to 200 kb upstream of the Igh3'RR. Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations. We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations. As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes.

Project description:The t(8;14)(q24.1;q32), the cytogenetic hallmark of Burkitt's lymphoma, is also found, but rarely, in cases of chronic lymphocytic leukemia (CLL). Such translocation typically results in a MYC-IGH@ fusion subsequently deregulating and overexpressing MYC on der 14q32. In CLL, atypical rearrangements resulting in its gain or loss, within or outside of IGH@ or MYC locus, have been reported, but their clinical significance remains uncertain. Herein, we report a 67 year-old male with complex cytogenetic findings of apparently balanced t(8;14) and unreported complex rearrangements of IGH@ and MYC loci. His clinical, morphological and immunophenotypic features were consistent with the diagnosis of CLL.Interphase FISH studies revealed deletions of 11q22.3 and 13q14.3, and an extra copy of IGH@, indicative of rearrangement. Karyotype analysis showed an apparently balanced t(8;14)(q24.1;q32). Sequential GPG-metaphase FISH studies revealed abnormal signal patterns: rearrangement of IGH break apart probe with the 5'-IGH@ on derivative 8q24.1 and the 3'-IGH@ retained on der 14q; absence of MYC break apart-specific signal on der 8q; and, the presence of unsplit 5'-MYC-3' break apart probe signals on der 14q. The breakpoint on 8q24.1 was found to be at least 400 Kb upstream of 5' of MYC. In addition, FISH studies revealed two abnormal clones; one with 13q14.3 deletion, and the other, with concurrent 11q deletion and atypical rearrangements. Chromosome microarray analysis (CMA) detected a 7.1 Mb deletion on 11q22.3-q23.3 including ATM, a finding consistent with FISH results. While no significant copy number gain or loss observed on chromosomes 8, 12 and 13, a 455 Kb microdeletion of uncertain clinical significance was detected on 14q32.33. Immunohistochemistry showed co-expression of CD19, CD5, and CD23, positive ZAP-70 expression and absence of MYC expression. Overall findings reveal an apparently balanced t(8;14) and atypical complex rearrangements involving 3'-IGH@ and a breakpoint at least 400 Kb upstream of MYC, resulting in the relocation of the intact 5'-MYC-3' from der 8q, and apposition to 3'-IGH@ at der 14q. This case report provides unique and additional cytogenetic data that may be of clinical significance in such a rare finding in CLL. It also highlights the utility of conventional and sequential metaphase FISH in understanding complex chromosome anomalies and their association with other clinical findings in patients with CLL. To the best of our knowledge, this is the first CLL reported case with such an atypical rearrangement in a patient with a negative MYC expression.

Dataset Information

Erroneous class switching and false VDJ recombination: molecular dissection of t(8;14)/MYC-IGH translocations in Burkitt-type lymphoblastic leukemia/B-cell lymphoma.

Publications

Erroneous class switching and false VDJ recombination: molecular dissection of t(8;14)/MYC-IGH translocations in Burkitt-type lymphoblastic leukemia/B-cell lymphoma.

Similar Datasets

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