The Role of ATM in Suppression of Lymphomas

描述(申请人提供)：在这项申请中，我们建议阐明ATM在抑制发育中的淋巴细胞致癌易位中的分子功能，并建立新的人类淋巴系统恶性肿瘤的小鼠模型。淋巴系恶性肿瘤的特征是在淋巴细胞发育双链断裂修复过程中发生的错误引起的反复易位。淋巴系统恶性肿瘤中复发易位的分子特征导致了关键癌基因的发现(例如C-MYC)和靶向治疗方法的发展(例如针对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和T细胞反复易位的机制，包括修复因子的可获得性、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者，对于有效和精确修复在淋巴细胞发育过程中抗原受体基因座产生的程序性双链断裂是必不可少的。因此，ATM的失活突变会导致共济失调-毛细血管扩张症(A-T)，这是一种经常与免疫缺陷相关的神经疾病。ATM缺乏也使患者易于患上B和T细胞恶性肿瘤，并伴有涉及抗原受体基因座的反复易位。体细胞ATM的失活和缺失常见于散发性B和T恶性肿瘤，常与频繁的细胞遗传学改变和侵袭性表型有关。ATM缺陷小鼠概括了人类患者的免疫缺陷和易患T细胞淋巴瘤的表型。此外，ATM缺陷的小鼠胸腺淋巴瘤中反复发生的克隆性易位与人类患者的克隆性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潜在机制尚未完全了解。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研究ATM在更为常见的B细胞淋巴瘤的病因学中的作用变得困难。因此，我们建议1)阐明ATM缺陷性小鼠胸腺淋巴瘤中复发的TCRpha/Delta基因相关易位的分子机制；2)确定并从功能上验证ATM缺陷性胸腺淋巴瘤和相关的未成熟T细胞白血病中复发易位的致癌靶点；3)通过建立和鉴定B细胞条件ATM缺陷性淋巴瘤模型，确定ATM在抑制致癌易位发展中的作用。总之，这项研究的结果将解决发育中淋巴细胞致癌易位的分子机制，以及ATM在淋巴系统恶性肿瘤病因学中的作用。鉴于ATM缺陷小鼠胸腺淋巴瘤与我们等人记录的人类未成熟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肿瘤的分子分析也将导致发现在人类淋巴系统恶性肿瘤中重要的致癌途径。 公共卫生相关性：我们建议的研究解决了ATM抑制发育中淋巴细胞致癌易位的分子机制，确定了未成熟T细胞淋巴瘤的新致癌靶点，并建立了新的小鼠模型来研究ATM在发育中B细胞致癌转化中的作用。

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. PUBLIC HEALTH RELEVANCE: Our proposed study addresses the molecular mechanism by which ATM suppresses oncogenic translocations in developing lymphocytes, identifies novel oncogenic targets for immature T cell lymphomas and generates novel mouse models to study the role of ATM in oncogenic transformation of developing B cells.