Modeling B cell Lymphoma in the Mouse

描述（由申请人提供）：最近B细胞消耗/灭活单克隆抗体的发展彻底改变了B细胞非霍奇金淋巴瘤（B- nhl）的治疗。尽管在国际预后指数评分较低的患者中，B细胞靶向治疗可显著减缓弥漫性大B细胞淋巴瘤（DLBCL）的进展，但高风险患者（疾病更严重/弥散性）的寿命并未显著延长。改进现有的淋巴瘤疗法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对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，该模型在B淋巴细胞中有条件地缺乏PTEN和SHIP肌醇磷酸酶，并在一年内发生100%外显率的致死性淋巴瘤。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。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 -/-小鼠来确定对DLBCL进展重要的体内因子，这些因子可能与最初的淋巴原性损伤无关。我们将确定淋巴瘤形成是否需要自身抗原识别和/或BAFF遭遇。对原发性模型系统淋巴瘤进展的分析将使我们能够比较转移性（肺/肝常驻）和继发性淋巴样淋巴瘤细胞对B细胞靶向治疗的致病性和敏感性。PI3K调控的平行研究将在人类DLBCL和MCL中进行。这里提出的研究是非常新颖的，及时的，对下一代淋巴瘤治疗的发展是必要的。

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.