Epigenetic Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B Cell Lymphomas A Potential Role of the MicroRNA Let-7
Epigenetic Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B Cell Lymphomas A Potential Role of the MicroRNA Let-7
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DOI：
10.2353/ajpath.2010.091291
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发表时间：
2010-09-01
影响因子：
6
通讯作者：
Tam, Wayne
中科院分区：
文献类型：
--
作者：
Nie, Kui;Zhang, Taotao;Tam, Wayne
PRDM 1/Blimp-1是B细胞终末分化的主要调节因子，是弥漫性大B细胞淋巴瘤（DLBCL）中的假定肿瘤抑制因子。先前已在非免疫中心B细胞样（GCB）DLBCL的子集中鉴定出PRDM 1的失活突变。我们研究了在25个原发性DLBCL和6个DLBCL细胞系的队列中下调PRDM 1的替代机制的存在。虽然一些DLBCL，主要是GCB型，显示低水平的PRDM 1 α mRNA和蛋白质，推测是由于直接转录抑制，两者之间的不一致表达被确定在一个子集的DLBCL没有PRDM 1突变，主要是非GCB型，与翻译下调一致。DLBCL的这个子集。表现出相对高的PRDM 1 α mRNA水平，但PRDM 1水平低。从表达分析、荧光素酶报告基因测定和转染实验获得的数据支持通过microRNA let-7家族靶向PRDM 1在介导这种下调中的作用。Let-7，特别是let-7 b，在DLBCL中相对于正常GCB细胞过表达，表明其被去调控。因此，let-7和其他microRNA对PRDM 1的异常表观遗传下调可能代表了在具有相对高的PRDM 1 α mRNA表达和未突变的PRDM 1的DLBCL亚组中降低正常PRDM 1功能的替代机制。这些发现为终末B细胞分化障碍在DLBCL发病机制中的重要作用提供了进一步的证据。(Am J Pathol 2010，177：1470-1479：DOI：10.2353/ajpath.2010.091291）
PRDM1/Blimp-1, a master regulator for B cell terminal differentiation, is a putative tumor suppressor in diffuse large B cell lymphomas (DLBCL). Inactivating mutations of PRDM1 have been previously identified in a subset of nongerminal center B cell like (GCB) DLBCL. We investigated the presence of alternative mechanisms of down-regulating PRDM1 in a cohort of 25 primary DLBCL and six DLBCL cell lines. While some DLBCL, predominantly the GCB-type, showed low levels of both PRDM1 a mRNA and protein, presumably as a result of direct transcription repression, discordant expressions between the two were identified in a subset of DLBCL without PRDM1 mutations, the primarily non-GCB type, consistent with translational down-regulation. This subset of DLBCL. exhibits relatively high PRDM1 a mRNA levels but low levels of PRDM1. Data obtained from expression analysis, luciferase reporter assays, and transfection experiments support a role of targeting of PRDM1 by microRNA let-7 family in mediating this down-regulation. Let-7, in particular let-7b, is overexpressed in DLBCL relative to normal GCB cells, suggesting that it is deregulated. Thus, abnormal epigenetic down-regulation of PRDM1 by let-7 and other microRNAs may represent an alternative mechanism of reducing normal PRDM1 function in a subset of DLBCL with relatively high PRDM1 a mRNA expression and unmutated PRDM1. These findings provide further evidence for an important role of impairment of terminal B cell differentiation in DLBCL pathogenesis. (Am J Pathol 2010, 177:1470-1479: DOI: 10.2353/ajpath.2010.091291)