Inflammation-regulated microRNA in B cell lymphoma

B细胞淋巴瘤中炎症调节的microRNA

基本信息

批准号：
7674039
负责人：
ROBERT C RICKERT
金额：
$ 35.85万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-12 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7674039
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Accounting Adult Non-Hodgkin&apos s Lymphoma Affect Animals Attenuated B lymphoid malignancy B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes Blood Burkitt Lymphoma Cell Line Cell Survival Cells Characteristics Classification Code Cyclophosphamide Development Doxorubicin Ectopic Expression Etanercept Etiology Follicular Lymphoma Foundations Functional RNA Gene Expression Genes Goals In Vitro Inflammation Inflammatory Response Lead Lymphoid Lymphoma Lymphomagenesis Malignant - descriptor Mantle Cell Lymphoma Mediating Memory B-Lymphocyte Molecular Molecular Profiling Monoclonal Antibody CD20 Mus PTEN gene Pathway interactions Patients Penetrance Principal Investigator Relapse Role Serum Shipping Ships Structure of germinal center of lymph node Subgroup Testing Tissue Sample Transgenic Mice Treatment Efficacy Treatment Protocols Tumor Suppressor Proteins Vincristine World Health Organization autocrine chemotherapeutic agent chemotherapy cytokine improved in vivo infliximab large cell Diffuse non-Hodgkin&apos s lymphoma myo-inositol-1 (or 4)-monophosphatase novel outcome forecast prednisolone prevent programs public health relevance response restoration rituximab success theories treatment strategy tumor

项目摘要

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.

描述（由申请人提供）：扩散的大B细胞淋巴瘤（DLBCL）约占成年非霍奇金淋巴瘤的40％。它在临床，形态和遗传上是由大型B细胞组成的异质肿瘤。通过正常生发中心B细胞或活化的血液记忆B细胞的特征，通过不同的基因表达谱鉴定了两个主要的DLBCL预后不同亚组。与活化的B细胞样（ABC样）亚组相比，生发中心B细胞样（GCB样子类）与预后相关。因此，五年后，有76％的GCB样DLBCL患者仍然活着，而仅16％的ABC样DLBCL患者。除了编码基因的差异表达外，ABC型淋巴瘤细胞表达了高水平的非编码microRNA miR-155，这是一种先前已证明其异位表达的Onco-miR会引起B细胞恶性肿瘤。在我们的初步研究中，我们确定肌醇 - 磷酸酶船是miR-155的第一个真正的目标。有趣的是，我们最近还发现，在鼠B细胞（BPTEN/SHIP-/ - ）中同时消融船和PTEN会诱导类似于DLBCL的致命淋巴瘤，其渗透率为100％，揭示了船作为肿瘤抑制剂的新作用。我们的初步结果进一步表明，MiR-155的水平升高以及随之而来的船舶表达消除是通过ABC型DLBCL细胞通过TNFA介导的，TNFA是DLBCL患者的血清水平升高的促炎细胞因子。因此，我们假设TNFA水平升高导致肿瘤抑制船的表达减弱，但通过诱导miR-155。该提议的目的是1）进一步描述TNFA，miR-155和船舶之间的分子相互作用，2）研究炎症反应在淋巴细胞内的作用，以及3）测试抗TNFA方案的可行性（Remicade（Remicade）（Remicade（Remicade）（R），ENBREL（R），ENBREL（R）。 DLBCL是最常见的B细胞非霍奇金淋巴瘤，每年在美国> 25,000例新病例。虽然近年来某些亚组的治疗功效有所提高，但ABC型DLBCL的预后仍然很差。本应用程序中介绍的研究将研究关于DLBCL的病因和进展的新理论，并可能为新的治疗策略奠定了基础。公共卫生相关性：DLBCL是最常见的B细胞非霍奇金淋巴瘤，每年在美国> 25,000例新病例。虽然近年来某些亚组的治疗功效有所提高，但ABC型DLBCL的预后仍然很差。本应用程序中介绍的研究将研究关于DLBCL的病因和进展的新理论，并可能为新的治疗策略奠定了基础。