The Role of ATM in Suppression of Lymphomas

描述（由申请人提供）：在本申请中，我们提出阐明ATM在抑制发育中的淋巴细胞的致癌易位中的分子功能，并建立新的人类淋巴细胞恶性肿瘤小鼠模型。淋巴恶性肿瘤的特点是由于淋巴细胞在发育性双链断裂修复过程中发生的错误而引起的反复易位。淋巴细胞恶性肿瘤复发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的发展（如靶向BCR-ABL1的格列卫）。在这里，我们将使用atm缺陷和条件缺陷小鼠作为模型系统来阐明B细胞和T细胞反复易位的机制，包括修复因子可用性、发育阶段和增强因子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（a- t），这是一种通常与免疫缺陷相关的神经系统疾病。ATM缺乏也使患者易患B细胞和T细胞恶性肿瘤，并伴有涉及抗原受体位点的复发易位。在散发性B和T恶性肿瘤中经常报道ATM的体细胞失活和缺失，并且通常与频繁的细胞遗传学改变和侵袭性表型相关。atm缺陷小鼠再现了人类患者的免疫缺陷和易患t细胞淋巴瘤表型。此外，ATM-缺陷小鼠胸腺淋巴瘤的复发性克隆易位与人类患者具有相同的分子起源。然而，产生这种易位的确切机制或其致癌性的潜在机制尚不完全清楚。另一方面，ATM缺陷小鼠的侵袭性T细胞淋巴瘤和早期致死率使得ATM在更普遍的B细胞淋巴瘤病因学中的作用难以研究。因此，我们提出：1)阐明atm缺陷小鼠胸腺淋巴瘤中复发性tcrα / δ基因座易位的分子机制；2)明确并功能性验证人类患者atm缺陷胸腺淋巴瘤及相关未成熟T细胞白血病复发易位的致癌靶点；3)通过生成和表征B细胞特异性条件ATM缺陷淋巴瘤模型，确定ATM在抑制B细胞发育中致癌易位中的作用。本研究的结果将共同探讨发育中的淋巴细胞致癌易位的分子机制以及ATM在淋巴细胞恶性肿瘤病因学中的功能。鉴于我们和其他人记录的atm缺陷小鼠胸腺淋巴瘤与人类未成熟T细胞恶性肿瘤之间的相似性，我们对atm缺陷小鼠淋巴瘤及其人类对应物的分子分析也将导致发现在人类淋巴细胞恶性肿瘤中重要的致癌途径。

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.