The Role of ATM in Suppression of Lymphomas

描述（由申请人提供）：在本申请中，我们拟阐明ATM在抑制发育中淋巴细胞中致癌易位中的分子功能，并建立新型人类淋巴恶性肿瘤小鼠模型。恶性淋巴瘤的特征是淋巴细胞发育性双链断裂修复过程中发生的错误引起的复发性易位。淋巴恶性肿瘤复发性易位的分子特征导致了关键癌基因（如C-MYC）的发现和靶向治疗方法（如靶向BCR-ABL 1的Gleevec）的开发。在这里，我们将使用ATM缺陷型和条件缺陷型小鼠作为模型系统，以阐明B和T细胞中复发性易位的机制，包括修复因子的可用性，发育阶段和增强子元件如何影响易位模式和肿瘤谱。 ATM激酶是DNA损伤反应的主要调节因子，对于淋巴细胞发育过程中抗原受体位点产生的程序性双链断裂的有效和精确修复至关重要。因此，ATM的失活突变导致共济失调-毛细血管扩张症（A-T），这是一种通常与免疫缺陷相关的神经系统疾病。ATM缺陷也使患者易患B细胞和T细胞恶性肿瘤，并伴有涉及抗原受体基因座的复发性易位。ATM的体细胞失活和缺失常在散发性B和T恶性肿瘤中报告，并且常与频繁的细胞遗传学改变和侵袭性表型相关。ATM缺陷小鼠概括了人类患者的免疫缺陷和倾向性T细胞淋巴瘤表型。此外，ATM缺陷型小鼠胸腺淋巴瘤的复发性克隆易位与人类患者的克隆易位具有共同的分子起源。然而，产生这种易位的确切机制或其致癌性的机制尚未完全了解。另一方面，ATM缺陷小鼠的侵袭性T细胞淋巴瘤和早期致死性使得难以研究ATM在更普遍的B细胞淋巴瘤的病因中的作用。因此，我们在此提出：1）阐明ATM缺陷型小鼠胸腺淋巴瘤中复发性TCR α/δ位点相关易位的分子机制; 2）确定并功能性验证ATM缺陷型胸腺淋巴瘤和相关的人类未成熟T细胞白血病患者中复发性易位的致癌靶点;和3）通过产生和表征B细胞特异性条件ATM缺陷型淋巴瘤模型，确定ATM在抑制发育中的B细胞中致癌易位中的作用。 本研究的结果将共同阐明淋巴细胞发育中致癌易位的分子机制以及ATM在淋巴恶性肿瘤病因学中的作用。鉴于ATM缺陷小鼠胸腺淋巴瘤和人类未成熟T细胞恶性肿瘤之间的相似性，我们和其他人记录，我们的ATM缺陷小鼠淋巴瘤及其人类同行的分子分析也将导致致癌途径的发现，是重要的人类淋巴恶性肿瘤。

DESCRIPTION (provided by applicant): In this application, we propose to elucidate the molecular function of ATM in suppression of oncogenic translocations in developing lymphocytes and generate novel mouse models for human lymphoid malignancies. Lymphoid malignancies are characterized by recurrent translocations arise from errors incurred during the repair of developmental double strand breaks in lymphocytes. Molecular characterizations of recurrent translocations in lymphoid malignancies have led to the discovery of key oncogenes (e.g. C-MYC) and the development of targeted therapeutic approaches (e.g. Gleevec targeting BCR-ABL1). Here we will use ATM-deficient and conditional deficient mice as the model system to elucidate the mechanisms that underlie recurrent translocations in both B and T cells, including the how repair factor availability, developmental stage and enhancer elements affect translocation pattern and tumor spectrum. ATM kinase is a master regulator of DNA damage responses and is essential for efficient and precise repair of programmed double strand breaks generated at the antigen receptor loci during lymphocyte development. As a result, inactivation mutations of ATM cause Ataxia-Telangiectasia (A-T), a neurological disorder that is often associated with immunodeficiency. ATM deficiency also predisposes patients to both B and T cell malignancies with recurrent translocations involving antigen receptor loci. Somatic inactivation and deletion of ATM are often reported in sporadic B and T malignancies and is often associated with frequent cytogenetic alterations and aggressive phenotypes. ATM-deficient mice recapitulate the immunodeficiency and prone T-cell lymphoma phenotype of human patients. Moreover the recurrent clonal translocations in ATM- deficient mouse thymic lymphomas share molecular origins with those from human patients. However the precise mechanisms that generate such translocations or the mechanisms underlying their oncogenicity are not yet fully understood. On the hand, the aggressive T cell lymphoma and early lethality of ATM-deficient mice render it difficult to study the role of ATM in the etiology of the more prevalent B cell lymphomas. Therefore here we propose to 1) elucidate the molecular mechanism of the recurrent TCRalpha/delta locus related translocations in ATM-deficient mouse thymic lymphomas; 2) define and functionally validate the oncogenic targets for the recurrent translocations in ATM-deficient thymic lymphomas and the related immature T cell leukemias in human patients; and 3) determine the role of ATM in suppressing oncogenic translocations in developing B cells by generating and characterizing B cell specific conditional ATM-deficient lymphoma models. Together the results from this study will address the molecular mechanism of oncogenic translocations in developing lymphocytes and the functions of ATM in the etiology of lymphoid malignancies. Given the similarity between ATM-deficient mice thymic lymphomas and human immature T cell malignancies documented by us and others, our molecular analyses of ATM-deficient mouse lymphomas and their human counterparts will also lead to the discovery of oncogenic pathways that are important in human lymphoid malignancies.