Modeling B cell Lymphoma in the Mouse

描述(申请人提供)：B细胞耗尽/灭活的单抗的最新发展已经彻底改变了B细胞非霍奇金淋巴瘤(B-NHL)的治疗方法。尽管B细胞靶向显著减缓国际预后指数评分低的患者的弥漫性大B细胞淋巴瘤(DLBCL)的进展，但高危患者(有更严重/播散性疾病)的寿命并未显著延长。改进现有的淋巴瘤治疗将需要在适当的临床前模型系统中对疾病病因进行广泛的分析。然而，现有的B淋巴瘤模型主要被描述为肿瘤抑制基因或癌基因定义的终点，而不是用于评估淋巴瘤进展和治疗反应的常见细胞/分子方面。我们开发了一种新的小鼠模型，该模型有条件地在B淋巴细胞中缺乏PTEN和运输肌醇磷酸酶，并在一年内发展为100%外显率的致命性淋巴瘤。有趣的是，bPten/Ship-/-B细胞对B细胞存活因子BAFF表现出异常的有丝分裂反应。尽管我们将SHIP定义为肿瘤抑制因子的初步研究具有潜在的诊断/预后作用，但本提案中概述的实验将利用bPten/SHIP-/-小鼠来识别体内对DLBCL进展至关重要的因素，并且可能独立于最初的淋巴瘤性损害。我们将确定淋巴肿大是否需要自身抗原识别和/或BAFF相遇。对初级模型系统中淋巴瘤进展的分析将使我们能够比较转移性(肺/肝居民)和继发性淋巴样淋巴瘤细胞的致病性和对B细胞靶向治疗的敏感性。PI3K调控的平行研究将在人类DLBCL和MCL中进行。这里提出的研究对于下一代淋巴瘤治疗的发展是非常新颖、及时和必要的。 公共卫生相关性：B细胞淋巴瘤是一种流行疾病，表现为正常B淋巴细胞在发育的特定阶段发生转化。虽然一些B淋巴瘤类型的遗传学基础已经确定，但淋巴肿大和进展的分子基础还不是很清楚。在这项工作中，我们开发了一种新的小鼠模型来研究B淋巴瘤的驱动因素。

DESCRIPTION (provided by applicant): The recent development of B cell-depleting/inactivating monoclonal antibodies has revolutionized B cell Non-Hodgkin's Lymphoma (B-NHL) therapy. Although B cell- targeting significantly slows diffuse large B cell lymphoma (DLBCL) progression in patients with low international prognostic index scores, the lifespan of high-risk patients (with more severe/disseminated disease) is not significantly extended. Improving upon existing lymphoma therapies will require extensive analysis of disease etiology in appropriate preclinical model systems. However, existing B lymphoma models have been described predominantly as endpoints in the definition of tumor suppressor genes or oncogenes, and not utilized to evaluate common cellular/molecular aspects of lymphoma progression and response to treatment. We have developed a novel murine model, which conditionally lacks PTEN and SHIP inositol phosphatases in B lymphocytes and develops lethal lymphoma with 100% penetrance within one year. Interestingly, bPten/Ship-/- B cells display abnormal mitogenic responses to the B cell survival factor BAFF. Although our preliminary studies defining SHIP as a tumor suppressor have potential diagnostic/prognostic utility, the experiments outlined in this proposal will utilize bPten/Ship-/- mice to identify in vivo factors that are important for DLBCL progression and likely independent of the initial lymphomagenic insult. We will determine whether lymphomagenesis requires auto-antigen recognition and/or BAFF encounter. Analysis of lymphoma progression in primary model systems will allow us to compare the pathogenicity and sensitivity to B cell targeted therapy of metastatic (lung/liver resident) and secondary lymphoid lymphoma cells. Parallel studies of PI3K regulation will be examined in human DLBCL and MCL. The studies proposed here are highly novel, timely, and necessary for the development of next-generation lymphoma treatments. PUBLIC HEALTH RELEVANCE: B cell lymphoma is a prevalent disease and is represented by the transformation of normal B lymphocytes at definitive stages of development. Although the genetic basis of some B lymphoma types has been identified, the molecular basis of lymphomagenesis and progression is not well understood. In this work, we have developed a novel mouse model to investigate the factors driving B lymphoma.