Molecular pathogenesis of non-Hodgkin's lymphoma: The role of Bcl-6

被引:105
作者
Pasqualucci, L [1 ]
Bereschenko, O [1 ]
Niu, HF [1 ]
Klein, U [1 ]
Basso, K [1 ]
Guglielmino, R [1 ]
Cattoretti, G [1 ]
Dalla-Favera, R [1 ]
机构
[1] Columbia Univ, Inst Canc Genet, New York, NY 10032 USA
关键词
non-Hodgkin's lymphoma; diffuse large B-cell lymphoma; somatic hypermutation; pathogenesis; Bcl-6; germinal center;
D O I
10.1080/10428190310001621588
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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页码:S5 / S12
页数:8
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