BCL2 and MYC Dual-Hit Lymphoma/Leukemia

Abstract

Translocation of the BCL2 gene on the chromosome band 18q21.3 results in consistent expression of the Bcl2 protein, an apoptosis inhibitor. BCL2 usually translocates to the immunoglobulin (IG) heavy chain (IGH) gene as t(14;18)(q32;q21.3) and rarely to IG light chain (IGK, IGL) loci as t(2;18)(p11;q21.3) or t(18;22)(q21.3;q11). The t(14;18) translocation is observed in 70-95% of follicular lymphoma cases and 20-30% of diffuse large B-cell lymphoma (DLBCL) cases. The MYC gene on chromosome band 8q24 acts as an accelerator of cell proliferation. MYC translocates to 14q32/IGH as t(8;14)(q24;q32) or less commonly to 2p11/IGK as t(2;8)(p11;q24) or 22q11/IGL as t(8;22)(q24;q11). The 8q24/MYC translocation is detected in nearly all Burkitt lymphoma (BL) and up to 10% of DLBCL cases. Both translocations rarely occur in an identical cell and this lymphoid malignancy is termed BCL2 and MYC dual-hit lymphoma/ leukemia (DHL). The pathological diagnosis in most cases of DHL with BCL2-IG and MYC-IG translocation is B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, although DLBCL is most common in DHL with BCL2-IG and MYC-nonIG translocation. The frequency of DHL with BCL2 and MYC translocation is estimated at around 2% of all B-cell malignancies. The condition is characterized by elevated serum lactate dehydrogenase levels, the presence of B symptoms, bone marrow involvement, advanced disease stage, extranodal involvement, and central nervous system (CNS) involvement at presentation or disease progression. Despite treatment strategies including CNS-targeted therapy, the prognosis for DHL is extremely poor. In this review, the current knowledge of the clinicopathological status of DHL is summarized and discussed. 〔J Clin Exp Hematopathol 51 (1) : 7-12, 2011〕

B-lymphopoiesis is stopped by mobilizing doses of G-CSF and is rescued by overexpression of the anti-apoptotic protein Bcl2

“…Bcl2 is an anti-apoptotic protein necessary to early B-cell development 32 and mutations in Bcl2 gene are frequent in B-cell neoplasms. [33][34] Overexpression of Bcl2 in hematopoietic cells causes a pan-leukophilia, Bcell accumulation in the spleen, evolving to follicular lymphoma after 40-week latency. 18,35 We conducted experiments in 8-week old mice that did not shown any sign of malignancy despite a pronounced leukophilia in steadystate (data not shown).…”

Case report. A rare case of triple-hit diffuse large B-cell lymphoma of the parotid gland in a patient with Sjogren’s syndrome

“…Their rarity and the fact that clinical evolution is unfavourable have made establishing a precise incidence virtually impossible 6 . A few published studies that shared the same genetic BCL2/MYC translocations in DLBCLs provided a range of 3-11% in incidence, but further data collection and analysis are necessary 23,24 .…”

Molecular Mechanisms Underlying Genomic Instability in Brca-Deficient Cells

“…Importantly, greater than 50% of common amplifications and deletions observed in human diffuse large B cell lymphoma map to ERFSs , suggesting that ERFSs may be a significant source of genomic instability that act together with AID-induced DNA damage to promote lymphomagenesis. One ERFS identified using this approach was Bcl-2 (Barlow et al, 2013), an apoptotic regulator located within the so-called major breakpoint region (mbr) that contains clusters of CpG dinucleotides, adopts a single-stranded non-B DNA structure, and is translocated to Igh in 70%-95% of follicular lymphomas and 20%-30% of diffuse large B cell lymphomas (Raghavan et al, 2004;Tomita, 2011). The observation that CpG dinucleotides can be found within 40%-70% of breakpoints at chromosomal translocations in immature human B cell lymphomas recently led to a proposal that DSBs at Bcl-2 and other genes may arise from sequential action of AID and the structurespecific nicking activity of the RAG1/RAG2 complex during early B lymphocyte development (Tsai et al, 2008).…”