Modeling B cell Lymphoma

描述（由申请人提供）：最近开发的B细胞耗竭/灭活单克隆抗体彻底改变了B细胞非霍奇金淋巴瘤（B-NHL）治疗。尽管B细胞靶向显著减缓了具有低国际预后指数评分的患者的弥漫性大B细胞淋巴瘤（DLBCL）进展，但高风险患者（具有更严重/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广泛分析疾病病因。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，而不是用于评价淋巴瘤进展和治疗反应的常见细胞/分子方面。我们已经开发了一种新的小鼠模型，其在B淋巴细胞中条件性地缺乏PTEN和SHIP肌醇磷酸酶，并且在一年内发展为具有100%转移率的致死性淋巴瘤。有趣的是，bPten/Ship-/- B细胞显示对B细胞存活因子BAFF的异常促有丝分裂反应。虽然我们的初步研究将SHIP定义为肿瘤抑制因子具有潜在的诊断/预后效用，但本提案中概述的实验将利用bPten/Ship-/-小鼠来鉴定对DLBCL进展重要且可能独立于初始淋巴瘤性损伤的体内因素。我们将确定淋巴瘤发生是否需要自身抗原识别和/或BAFF遭遇。在原发性模型系统中分析淋巴瘤进展将使我们能够比较转移性（肺/肝驻留）和继发性淋巴瘤细胞的致病性和对B细胞靶向治疗的敏感性。将在人DLBCL和MCL中检查PI 3 K调节的平行研究。这里提出的研究是非常新颖的，及时的，对于下一代淋巴瘤治疗的发展是必要的。 公共卫生相关性：B细胞淋巴瘤是一种流行病，表现为正常B淋巴细胞在发育的确定阶段发生转化。虽然一些B淋巴瘤类型的遗传基础已被确定，淋巴瘤发生和进展的分子基础还没有得到很好的理解。在这项工作中，我们开发了一种新的小鼠模型，以调查的因素驱动B淋巴瘤。

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.