Molecular pathogenesis of non-Hodgkin's lymphoma: the role of Bcl-6.
Non-Hodgkin's lymphomas (NHL) form a heterogeneous group of diseases, with diffuse large B-cell lymphoma (DLBCL) comprising the largest subgroup. The commonest chromosomal translocations found in DLBCL are those affecting band 3q27. In 35% of DLBCL cases, as well as in a small fraction of follicular lymphomas, the normal transcriptional regulation of Bcl-6 is disrupted by these chromosomal translocations. In addition, about three-quarters of cases of DLBCL display multiple somatic mutations in the 5' non-coding region of Bcl-6, which occur independently of chromosomal translocations and appear to be due to the IgV-associated somatic hypermutation process. Bcl-6 is a 95-kD nuclear phosphoprotein belonging to the BTB/POZ (bric-a-brac, tramtrack, broad complex/Pox virus zinc finger) zinc finger family of transcription factors. It has been suggested that Bcl-6 is important in the repression of genes involved in the control of lymphocyte activation, differentiation, and apoptosis within the germinal center, and that its down-regulation is necessary for normal B-cells to exit the germinal center. Bcl-6 remains constitutively expressed in a substantial proportion of B-cell lymphomas. Recently, acetylation has been identified as a mode for down-regulating Bcl-6 activity by inhibition of the ability of Bcl-6 to recruit complexes containing histone deacetylases (HDAC). The pharmacologic inhibition of two recently identified deacetylation pathways, HDAC- and silent information regulator (SIR)-2-dependent deacetylation, results in the accumulation of inactive acetylated Bcl-6 and thus in cell cycle arrest and apoptosis in B-cell lymphoma cells. These results reveal a new method of regulating Bcl-6, with the potential for therapeutic exploitation. These studies also indicate a novel mechanism by which acetylation promotes transcription, not only by modifying histones and activating transcriptional activators, but also by inhibiting transcriptional repressors.
Pasqualucci
Laura
L
Institute for Cancer Genetics, Columbia University, 1150 St Nicholas Avenue, New York, NY 10032, USA.
Bereshchenko
Oxana
O
Bereschenko
Oxana
O
Niu
Huifeng
H
Klein
Ulf
U
Basso
Katia
K
Guglielmino
Roberta
R
Cattoretti
Giorgio
G
Dalla-Favera
Riccardo
R
D000107:Acetylation; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000209:etiology* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051560:Proto-Oncogene Proteins c-bcl-6; D027041:Somatic Hypermutation, Immunoglobulin; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors