Inflammation-regulated microRNA in B cell lymphoma

描述（由申请人提供）：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、形态学和遗传学上是一种由大B细胞组成的异质性肿瘤。两个主要的、预后不同的DLBCL亚群通过不同的基因表达谱被鉴定出来，这些基因表达谱要么是正常生发中心b细胞的特征，要么是活化的血记忆b细胞的特征。生发中心b细胞样（GCB-like）亚组与活化b细胞样（ABC-like）亚组相比，预后明显更好。因此，76%的gcb样DLBCL患者在5年后仍然存活，而abc样DLBCL患者只有16%。除了编码基因的差异表达外，abc型淋巴瘤细胞还表达高水平的非编码microRNA miR-155，这是一种肿瘤miR，其异位表达先前已被证明可引起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，同时消融小鼠B细胞中的Ship和Pten （bPten/Ship-/-）可诱导类似DLBCL的致死性淋巴瘤，其外显率为100%，这揭示了Ship作为肿瘤抑制因子的新作用。我们的初步结果进一步表明，miR-155水平的升高，以及随之而来的SHIP表达的消除，是通过TNFa对abc型DLBCL细胞的自分泌刺激介导的，TNFa是一种促炎细胞因子，已知其血清水平在DLBCL患者中升高。因此，我们假设TNFa水平升高通过诱导miR-155导致肿瘤抑制因子SHIP的表达减弱。本提案的目标是：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形成中的作用；3)测试抗TNFa方案（Remicade）的可行性。， Enbrel(r))作为DLBCL的新型辅助治疗。DLBCL是最常见的B细胞非霍奇金淋巴瘤，在美国每年新发病例约为5000例。虽然近年来某些亚组的治疗效果有所改善，但abc型DLBCL的预后仍然很差。本申请中提出的研究将探讨DLBCL的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50万例新发病例。虽然近年来某些亚组的治疗效果有所改善，但abc型DLBCL的预后仍然很差。本申请中提出的研究将探讨DLBCL的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.