B-cell lymphoma 6 protein (BCL-6) • B-cell lymphoma 5 protein (BCL5, BCL-5) • lymphoma-associated zinc finger gene on chromosome 3 (LAZ3, LAZ-3) • BCL6A • zinc finger protein 51 (ZNF51) • zinc finger and BTB domain-containing protein 27 (ZBTB27) • cys-his2 zinc finger transcription factor • zinc finger transcription factor BCL6S
Gene Location
3q27
Expression Location
intracellular •
nucleus
Marker Description
B-cell CLL/lymphoma 6 (BCL6) is a zinc finger transcription factor containing an N-terminal POZ domain that acts as a sequence-specific repressor of transcription. BCL6 modulates the transcription of START-dependent IL-4 responses of B cells. BCL6 can interact with a variety of POZ-containing proteins that function as transcription corepressors. Alternatively spliced transcript variants encoding different protein isoforms have been discovered for this gene.
BCL6 is a critical regulator of germinal centers (GC), the sites where B cells are selected based on the production of antibodies with high affinity for the antigen. BCL6 is also a frequently activated oncogene in the pathogenesis of human B-cell lymphoma, most of which derive from the GC B cells. BCL6 appears to play a dual role as a safe keeper preventing centroblasts from responding to signals leading to a premature exit from the GC and as a contributor to lymphomagenesis by allowing conditions favorable to malignant transformation (Basso K and Dalla-Favera R, Adv Immunol 2010;105:193-210).
BCL6 is critical for the development of a diverse primary B cell repertoire (Duy C, etal, J Exp Med, 26 May 2010; epub ahead of print).
BCL6 is required for lymphoma cells to survive and multiply. BCL6 is the most commonly involved oncogene in diffuse large B-cell lymphoma (DLBCL), it is frequently translocated and hypermutated in DLBCL, and may be involved in the pathogenesis of DLBCL. BCL6 lymphomagenic activity is dependent on its ability to recruit corepressor proteins to a unique binding site on its N-terminal BTB domain.
A subset of cases involving translocation t(14;18)IgH/BCL2, the molecular hallmark of follicular lymphoma, harbor translocations involving the BCL6-gene locus. Investigators at the University Clinic Schleswig-Holstein (Luebeck, Germany) set out to determine the frequency of BCL2 and BCL6 translocations in follicular lymphoma and to identify morphologic and immunohistochemical features with respect to the presence of BCL2 and BCL6-translocations. Lymphoma cases with BCL6 and BCL2 translocations were very similar to t(14;18)-positive lymphoma without BCL6 translocations. In contrast, t(14;18)-negative lymphoma with BCL6-translocations were of higher grade, less often CD10-positive, involved the bone marrow less frequently and did not infiltrate the lymph node capsule. BCL2 and BCL6-translocations correlate with particular phenotypes of follicular lymphoma. BCL6 translocations seem to affect the phenotype only when they are not accompanied by BCL2 translocations (Gollub W, etal, Anticancer Res, Nov 2009;29(11):4649-55).
Cancer Indication
multiple myeloma
Cancer Indication Description
Investigators at Dana-Farber Cancer Institute (Boston, MA) report that BCL6 is upregulated in the bone marrow microenvironment in multiple myeloma cells. Although constitutive BCL6 expression was undetectable in multiple myeloma cell lines, except U266 cells, it was upregulated by coculture with bone marrow stromal cell-culture supernatant (SCCS). BCL6 expression in patient-derived multiple myeloma cells in the bone marrow was positive. BCL6 expression in multiple myeloma cells is modulated, at least in part, by Janus kinase/STAT3 and canonical nuclear factor-kappaB pathways. Targeting BCL6, either directly or via these cascades, inhibits multiple myeloma cell growth in the bone marrow milieu (Hideshima T, etal, Blood, 6 May 2010;115(18):3772-5).
Cancer Indication
leukemia
Cancer Indication Description
It is suggestedthat BCL6 is important in various forms of leukemia.
Academic Programs
• Investigators Ari Melnick, MD, of Weill Cornell Medical College, Alexander MacKerell, PhD, of the University of Maryland, and Gilbert Privé, PhD, of the University of Toronto, funded by a grant from the Samuel Waxman Cancer Research Foundation, used an integrated biochemical and computational approach to design a small molecule inhibitor of BCL6 as a novel treatment for DLBCL. The BCL6 transcriptional repressor is the most frequently involved oncogene in diffuse large B cell lymphoma (DLBCL). BCL6 lymphomagenic activity is dependent on its ability to recruit corepressor proteins to a unique binding site on its N-terminal BTB domain. The investigators combined computer-aided drug design with functional assays to identify low molecular weight compounds that bind to the corepressor binding groove of the BCL6 BTB domain. One such compound disrupted BCL6/corepressor complexes in vitro and in vivo. This compound induced expression of BCL6 target genes and killed BCL6-positive DLBCL cell lines. The compound was nontoxic and potently suppressed DLBCL tumors in xenografts in vivo and also killed primary DLBCL from patients (Cerchietti LC, etal, Cancer Cell, 13 Apr 2010 ;17(4):400-11; comment: 315-6, and Cerchietti LC, etal, Blood, 9 Apr 2009 9;113(15):3397-405).
