Inflammation-regulated microRNA in B cell lymphoma

描述（由申请方提供）：弥漫性大B细胞淋巴瘤（DLBCL）约占成人非霍奇金淋巴瘤的40%。它在临床上、形态学上和遗传学上是一组由大B细胞组成的异质性肿瘤。通过不同的基因表达谱鉴定了DLBCL的两个主要的、病理学上不同的亚组，所述基因表达谱是正常生发中心B细胞或活化的血液记忆B细胞的特征。与活化B细胞样（ABC样）亚组相比，生发中心B细胞样（GCB样）亚组与显著更好的预后相关。因此，76%的GCB样DLBCL患者在五年后仍然存活，而ABC样DLBCL患者仅为16%。除了编码基因的差异表达之外，ABC型淋巴瘤细胞表达高水平的非编码微小RNA miR-155，其是一种癌性miR，先前已显示其异位表达引起B细胞恶性肿瘤。在我们的初步研究中，我们确定肌醇磷酸酶SHIP是miR-155的第一个真正的靶点。有趣的是，我们最近还发现，在小鼠B细胞（bPten/Ship-/-）中同时消融Ship和Pten诱导类似DLBCL的致死性淋巴瘤，具有100%的转移率，揭示了SHIP作为肿瘤抑制剂的新作用。我们的初步结果进一步证明，miR-155水平的升高和随后SHIP表达的消除是通过经由TNFa（一种促炎细胞因子，其血清水平已知在DLBCL患者中升高）的ABC型DLBCL细胞的自分泌刺激介导的。因此，我们假设升高的TNF α水平通过诱导miR-155导致肿瘤抑制因子SHIP的表达减弱。该提议的目标是1）进一步表征TNFa、miR-155和SHIP之间的分子相互作用，2）研究炎症反应在淋巴瘤发生中的作用，和3）测试抗TNFa方案的可行性（Remicade（r），Enbrel（r）.）作为DLBCL的一种新的支持治疗。DLBCL是最常见的B细胞非霍奇金淋巴瘤，在美国每年有> 25，000例新发病例。虽然近年来某些亚组的治疗疗效有所改善，但ABC型DLBCL的预后仍然很差。本申请中提出的研究将调查DLBCL病因和进展的新理论，并可能为新的治疗策略奠定基础。公共卫生相关性：DLBCL是最常见的B细胞非霍奇金淋巴瘤，在美国每年有> 25，000例新发病例。虽然近年来某些亚组的治疗疗效有所改善，但ABC型DLBCL的预后仍然很差。本申请中提出的研究将调查DLBCL病因和进展的新理论，并可能为新的治疗策略奠定基础。

DESCRIPTION (provided by applicant): Diffuse large B-cell lymphoma (DLBCL) account for approximately 40% of adult non-Hodgkin lymphomas. It is clinically, morphologically and genetically a heterogeneous group of tumors composed of large B cells. Two main, prognostically different subgroups of DLBCL were identified by distinct gene expression profiles either characteristic of normal germinal center B-cells or of activated blood memory B-cells. The germinal center B-cell-like (GCB-like) subgroup was correlated with a significantly better prognosis in comparison to the activated B-cell-like (ABC-like) subgroup. As such, 76% of GCB-like DLBCL patients were still alive after five years, as compared with only 16% of ABC-like DLBCL patients. In addition to differential expression of coding genes, ABC-type lymphoma cells express high levels of the non-coding microRNA miR-155, an onco- miR whose ectopic expression has been previously shown to give rise to B cell malignancies. In our preliminary studies, we identified the inositol-phosphatase SHIP as the first bona-fide target of miR-155. Interestingly, we had also found recently that concomitant ablation of both Ship and Pten in murine B cells (bPten/Ship-/-) induces lethal lymphoma resembling DLBCL with 100% penetrance, revealing a novel role for SHIP as a tumor-suppressor. Our preliminary results further demonstrate that elevated levels of miR-155, and consequent abrogation of SHIP expression, are mediated through autocrine stimulation of ABC-type DLBCL cells via TNFa, a proinflammatory cytokine whose serum levels are known to be elevated in DLBCL patients. We therefore hypothesize that elevated TNFa levels lead to attenuated expression of the tumor suppressor SHIP though induction of miR-155. The goal of this proposal is to 1) further characterize the molecular interplay between TNFa, miR-155 and SHIP, 2) to investigate the role of inflammatory responses in lymphomagenesis, and 3) to test the feasibility of anti-TNFa regimen (Remicade(r)., Enbrel(r).) as a novel supporting treatment for DLBCL. DLBCL is the most common B cell non-Hodgkin's Lymphoma, with > 25,000 new cases in the US every year. While treatment efficacy for certain subgroups has improved over recent years, the prognosis for ABC-type DLBCL is still poor. The studies presented in this application will investigate a novel theory on the etiology and progression of DLBCL, and likely lay the foundation for new treatment strategies. PUBLIC HEALTH RELEVANCE: DLBCL is the most common B cell non-Hodgkin's Lymphoma, with > 25,000 new cases in the US every year. While treatment efficacy for certain subgroups has improved over recent years, the prognosis for ABC-type DLBCL is still poor. The studies presented in this application will investigate a novel theory on the etiology and progression of DLBCL, and likely lay the foundation for new treatment strategies.