Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome- associated non-Hodgkin's lymphoma: association with diffuse large-cell subtype

Abstract

Acquired immunodeficiency syndrome (AIDS)-associated non-Hodgkin's lymphomas (AIDS-NHL), a major source of morbidity and mortality among AIDS patients, are derived from B cells and can be classified into two main histologic categories, small noncleaved cell lymphoma (SNCCL) and diffuse large-cell lymphoma (DLCL). DLCL includes two histologic subsets, ie, large noncleaved cell lymphoma (LNCCL) and large cell- immunoblastic plasmacytoid lymphoma (LC-IBPL). Several studies have shown that AIDS-SNCCL is associated with the clonal accumulation of multiple genetic lesions, including Epstein-Barr virus (EBV) infection, activation of the c-MYC and RAS oncogenes, as well as inactivation of the p53 tumor suppressor gene at variable frequencies. On the contrary, the molecular pathogenesis of AIDS-DLCL is largely obscure, because no genetic lesion other than EBV infection has been specifically identified in this group. In this study, we have tested a panel of 40 AIDS-NHL for structural alterations of BCL-6, a putative proto-oncogene that is frequently altered in DLCL in the immunocompetent host. Our results show that rearrangements of BCL-6 are present in 20% of AIDS- DLCL (5 of 24), including 2 of 8 LNCCL and 3 of 16 LC-IBPL, but in no case of AIDS-SNCCL. BCL-6 rearrangements were detected both in the presence and in the absence of EBV infection of the tumor clone, but in no case were associated with activation of c-MYC or mutations of p53. These data identify a novel genetic lesion in AIDS-DLCL and corroborate the notion that lymphomagenesis in AIDS follows two distinct molecular pathways that are associated with the development of histologically distinct types of AIDS-NHL.

Genetic heterogeneity of AIDS‐related small non‐cleaved cell lymphoma

“…In particular, whereas AIDS-BL was consistently associated with alterations of c-MYC and frequently carried mutations of p53 (this study and Ballerini et al, 1993;, AIDS-BLL was devoid of p53 mutations and carried c-MYC alterations significantly less frequently. Conversely, the distribution of EBV infection appeared to be similar in AIDS-BL and AIDS-BLL, and both tumour types lacked rearrangements of BCL-6 and deletions of 6q, which are detectable in a fraction of AIDS-DLCL (this study and Gaidano et al, 1994;Pastore et al, 1996).…”

“…Whereas gross rearrangements of the gene are restricted to a fraction of AIDS-DLCL, point mutations of BCL-6 5 0 non-coding regions have been shown to occur in the majority of AIDS-BL and AIDS-DLCL (Gaidano et al, , 1997b. Rearrangements of BCL-6 were tested by Southern blot analysis using probes (Sac4.0 and Sac0.8) and restriction enzymes (BamHI and XbaI) that, in combination, explore the region of the gene containing the cluster of chromosomal rearrangements detected among NHL of the immunocompetent host and among AIDS-NHL (Ye et al, 1993a, b;Gaidano et al, 1994). Only cases showing abnormally migrating bands with two restriction enzymes and/or two probes were scored as rearranged.…”

Fluorescence in situ hybridization identifies new chromosomal changes involving 3q27 in non‐Hodgkin's lymphomas with BCL6/LAZ3 rearrangement

“…It is of interest that case 1 developed N H L 6 years after liver transplantation and severe immunosuppressive treatment. Several immunosuppressed patients with lymphoid proliferations characterized by 3q27 translocations have already been reported (Takeuchi et al, 1985;Offit et al, 1989;Bastard et al, 1992;Schlegelberger et al, 1993;Yoshizawa et al, 1993;Gaidano et al, 1994), and a relationship between 3q27 changes and lymphomas arising in this group of patients is clearly emerging from the recent data on BCL6 rearrangements in AIDS patients (Gaidano et al,1 994).…”

“…Rearrangement of the BCL6ILAZ3 locus at 3q27 has been found in 14-20% of lymphoma patients (Bastard et al, 1994;Lo COCO et al, 1994) and is considered to be one of the more common genetic lesions in non-Hodgkin's lymphoma (NHL). A significant correlation between BCL6ILAZ3 abnormalities and diffuse large-B-cell lymphoma subtype was noticed in both of these earlier studies, but BCL6ILAZ rearrangement was detected also in 6-13% of follicular lymphomas.…”

A novel cervical cancer suppressor 3 (CCS‐3) interacts with the BTB domain of PLZF and inhibits the cell growth by inducing apoptosis

“…The BTB/POZ motif, downregulates transcription by interacting with specificity protein 1 (Sp1) zinc finger and by also interfering with DNA binding activity of Sp1 [22]. Another BTB/POZ protein, B-cell lymphoma 6 (Bcl-6), is rearranged in a large diffuse cell known as Hodgkin's lymphoma, as well as in AIDS-associated lymphoma, and is also upregulated during myogenesis [23][24][25]. These reports suggest a critical role played by the BTB/POZ motif.…”