Parekh Samir, Polo Jose M, Shaknovich Rita, Juszczynski Przemyslaw, Lev Paola, Ranuncolo Stella M, Yin Yingnan, Klein Ulf, Cattoretti Giorgio, Dalla Favera Riccardo, Shipp Margaret A, Melnick Ari
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Blood. 2007 Sep 15;110(6):2067-74. doi: 10.1182/blood-2007-01-069575. Epub 2007 Jun 1.
The BCL6 transcriptional repressor is the most commonly involved oncogene in diffuse large B-cell lymphomas (DLBCLs). Constitutive expression of BCL6 mediates lymphomagenesis through aberrant proliferation, survival, and differentiation blockade. Binding of BCL6 to the SMRT/N-CoR corepressors mediates the BCL6 survival effect in DLBCL. Although the basis for differentiation blockade is unknown in DLBCL, recent data suggest that BCL6 binding to the MTA3 corepressor might be involved. We report that BCL6 and MTA3 are coexpressed in normal germinal center B cells and DLBCL. Depletion of MTA3 in DLBCL cells induced a differentiation-related BCL6 target gene (PRDM1), but not target genes involved in survival. Accordingly, MTA3 and PRDM1 expression are mutually exclusive in germinal center B cells. We performed chromatin immunoprecipitation (ChIP)-on-chip mapping of the PRDM1 locus, identifying a novel BCL6 binding site on intron 3 of the PRDM1 gene, and show that BCL6 recruits MTA3 to this site. In DLBCL cells, MTA3 depletion induced plasmacytic differentiation but did not decrease viability of DLBCL cells. However, MTA3 depletion synergized with a specific BCL6 inhibitor that blocks SMRT/N-CoR binding to decrease DLBCL viability. Taken together, these results show that BCL6 regulates distinct transcriptional programs through the SMRT/N-CoR and MTA3 corepressors, respectively, and provides a basis for combinatorial therapeutic targeting of BCL6.
BCL6转录抑制因子是弥漫性大B细胞淋巴瘤（DLBCL）中最常涉及的致癌基因。BCL6的组成型表达通过异常增殖、存活和分化阻滞介导淋巴瘤发生。BCL6与SMRT/N-CoR共抑制因子的结合介导了其在DLBCL中的存活效应。尽管DLBCL中分化阻滞的基础尚不清楚，但最近的数据表明可能涉及BCL6与MTA3共抑制因子的结合。我们报告BCL6和MTA3在正常生发中心B细胞和DLBCL中共同表达。在DLBCL细胞中敲除MTA3可诱导一个与分化相关的BCL6靶基因（PRDM1），但不影响与存活相关的靶基因。因此，在生发中心B细胞中，MTA3和PRDM1的表达相互排斥。我们对PRDM1基因座进行了染色质免疫沉淀（ChIP）芯片定位，在PRDM1基因的内含子3上鉴定出一个新的BCL6结合位点，并表明BCL6将MTA3招募到该位点。在DLBCL细胞中，敲除MTA3可诱导浆细胞分化，但不降低DLBCL细胞的活力。然而，敲除MTA3与一种阻断SMRT/N-CoR结合的特异性BCL6抑制剂协同作用，可降低DLBCL的活力。综上所述，这些结果表明BCL6分别通过SMRT/N-CoR和MTA3共抑制因子调节不同的转录程序，并为BCL6的联合治疗靶向提供了依据。
