Inflammation-regulated microRNA in B cell lymphoma

描述(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%。它在临床上、形态上和遗传学上都是由大B细胞组成的异质性肿瘤群。根据正常生发中心B细胞或激活的血液记忆B细胞的不同基因表达谱，DLBCL有两个主要的、预后不同的亚群。生发中心B细胞样亚组(GCB样亚组)预后明显好于激活的B细胞样亚组(ABC样亚组)。因此，76%的GCB样DLBCL患者在五年后仍然活着，而ABC样DLBCL患者中只有16%存活。除了编码基因的差异表达外，ABC类型的淋巴瘤细胞还表达高水平的非编码microRNA miR-155，这是一种癌-miR，其异位表达已被证明会导致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，同时去除小鼠B细胞中的SHIP和Pten(bPten/SHIP-/-)可以诱导出类似于DLBCL的致命性淋巴瘤，具有100%的外显率，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证明，miR-155水平的升高以及随之而来的SHIP表达的降低是通过TNFa自分泌刺激ABC型DLBCL细胞所介导的，TNFa是一种促炎症细胞因子，其血清水平在DLBCL患者中升高。因此，我们假设，升高的TNFa水平通过诱导miR-155导致肿瘤抑制因子SHIP的表达减弱。这项建议的目标是1)进一步表征TNFa、miR-155和SHIP之间的分子相互作用，2)研究炎性反应在淋巴肿大中的作用，3)测试抗TNFa方案(Remicade(R)，Enbrel(R))的可行性。作为治疗DLBCL的一种新的支持疗法。DLBCL是最常见的B细胞性非霍奇金淋巴瘤，在美国每年有25000例新病例。虽然近年来某些亚型DLBCL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索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。与公共卫生相关：DLBCL是最常见的B细胞性非霍奇金淋巴瘤，在美国每年有25,000例新病例。虽然近年来某些亚型DLBCL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索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.