Concurrent translocation of BCL2 and MYC with a single immunoglobulin locus in high-grade B-cell lymphomas

Abstract

B-cell leukaemia or lymphoma with a combination of t(8;14)(q24;q32) of Burkitt leukaemia/lymphoma and t(14;18)(q32;q21) of follicular lymphoma may present clinically as de novo acute lymphoblastic leukaemia or transformation of follicular lymphoma to aggressive histology diffuse lymphoma. A number of cell lines have been reported with a complex t(8;14;18) with fusion of MYC, IGH and BCL2 on the same derivative 8 chromosome. The objective of this study was to determine the frequency and chromosomal features of this der(8)t(8;14;18) in a series of acute leukaemias and malignant lymphomas. A database of 1350 leukaemia and lymphoma karyotypes was searched for cases with structural alterations affecting both 8q24 and 18q21. A total of 55 cases were identified, of which eight revealed a complex der(8)t(8;14;18) with an MYC-IGH-BCL2 rearrangement resulting from translocation of BCL2 and MYC with a single disrupted IGH allele. Molecular cytogenetic investigation is essential to identify cases of high-grade leukaemia/lymphoma with concurrent translocations affecting the BCL2 and MYC loci.

BCL2 Is a Downstream Effector of MIZ-1 Essential for Blocking c-MYC-induced Apoptosis

“…Establishing the identity of this pro-survival gene should provide a critical advance in our understanding of this previously unknown pathway. A large number of findings from both human tumors and mouse models have established that expression of the pro-survival BCL2 protein cooperates with c-MYC during tumorigenesis (22,(37)(38)(39)(40)(41). Here we link these two previously unrelated sets of observations by demonstrating that MIZ-1 normally activates the transcription of the BCL2 gene, and BCL2 activation blocks c-MYC-induced apoptosis.…”

“…For instance, aggressive germinal center B cell lymphomas with an IGH:BCL2 translocation also contain either an IGH:MYC fusion or a MYC amplification (39). Furthermore, follicular lymphomas, which are defined by a BCL2 translocation, transform to high grade lymphomas upon rearrangement of the c-MYC locus (37,85), reminiscent of the mouse model discussed above. Moreover, the simultaneous overexpression of BCL2 and c-MYC has been reported in supraglottic squamous cell carcinoma (86) and acute lymphoblastic leukemia (87).…”

The cooperating mutation or “second hit” determines the immunologic visibility toward MYC-induced murine lymphomas

“…The available literature on c-MYC-driven lymphoma in people only analyzes the effect of the absence or presence of either BCL-2 or p53 on disease progression: It is clear that patients whose tumor cells have neither incurred a loss of p53 nor acquired high levels of BCL-2 have a better prognosis and, unsurprisingly, respond better to chemotherapy. [42][43][44][45] Unfortunately, these analyses do not provide any accessible information that allow for comparisons of loss of p53 versus BCL-2 overexpression. We therefore initiated a retrospective analysis of clinical data obtained from 59 patients who were admitted to the General Hospital of Vienna during the time period of 1999-2010 and whose condition was diagnosed as either Burkitt lymphoma or DLBCL with MYC translocation.…”

MYC and the Control of Apoptosis

“…In germinal center B-cell lymphomas with an IGH:BCL-2 translocation, IGH:MYC fusions or MYC amplifications have been documented (Martin-Subero et al 2005). Similarly BCL-2 locus translocations in follicular lymphomas are transformed to high-grade lymphomas upon subsequent rearrangement of MYC (Knezevich et al 2005;Mukhopadhyay et al 2005). Numerous other forms of cancer have been documented to carry simultaneous elevation of both BCL-2 and MYC levels (e.g., supraglottic squamous cell carcinoma [Ozdek et al 2004] and acute lymphoblastic leukemia [Berger et al 1996]).…”