The Role of ATM in Suppression of Lymphomas

ATM 在抑制淋巴瘤中的作用

基本信息

批准号：
8606350
负责人：
Shan Zha
金额：
$ 32.2万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606350
关键词：
ABL1 gene ATM Gene Mutation ATM deficient ATM function Acute T Cell Leukemia Address Affect Antigen Receptors Ataxia Telangiectasia Ataxia-Telangiectasia-Mutated protein kinase B lymphoid malignancy B-Cell Lymphomas B-Lymphocytes Belief Biological Models Cell Line Chromosomal translocation Chromosomes, Human, Pair 12 Chromosomes, Human, Pair 14 Copy Number Polymorphism Cyclin D1 Cytogenetics DNA Damage DNA Repair DNA Sequence Rearrangement Development Enhancers Etiology Gene Amplification Gene Rearrangement Genetic Enhancer Element Genomics Germ Lines Gleevec Hand Human IGH@ gene cluster Immunologic Deficiency Syndromes In Vitro Knockout Mice Lead Lymphocyte Lymphocyte Function Lymphoid Lymphoma Maintenance Malignant Neoplasms Malignant lymphoid neoplasm Mantle Cell Lymphoma Mediating Modeling Molecular Molecular Profiling Molecular Target Mus Mutation Neoplasms Oncogenes Oncogenic Pathway interactions Patients Pattern Phenotype Premalignant Prevalence Recurrence Reporting Role Staging T-Cell Development T-Cell Leukemia T-Cell Lymphoma T-Lymphocyte Testing Thymic Lymphoma Tumor Suppressor Genes V(D)J Recombination base comparative genomic hybridization in vivo lymphoid neoplasm mouse model nervous system disorder novel programs public health relevance repaired response therapeutic target tumor

项目摘要

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.

描述（由申请人提供）：在本申请中，我们建议阐明ATM在发展淋巴细胞中抑制致癌易位的分子功能，并为人类淋巴恶性肿瘤生成新颖的小鼠模型。淋巴恶性肿瘤的特征是复发易位是由于修复淋巴细胞发育双链断裂时产生的错误。淋巴恶性肿瘤中复发性易位的分子表征导致发现了关键的致癌基因（例如C-MYC）和靶向治疗方法的发展（例如，靶向BCR-ABL1）。在这里，我们将使用ATM缺乏和有条件的缺陷小鼠作为模型系统，以阐明B和T细胞中反复易位的机制，包括修复因子的可用性，发育阶段和增强子元素如何影响易位模式和肿瘤光谱。 ATM激酶是DNA损伤反应的主要调节剂，对于在淋巴细胞发育过程中在抗原受体基因座生成的有效和精确修复的有效修复至关重要。结果，ATM的灭活突变引起的触发性 - 凝血症（A-T），一种通常与免疫缺陷有关的神经系统疾病。 ATM缺乏症还使患者患有B和T细胞恶性肿瘤，并具有涉及抗原受体基因座的复发易位。 ATM的体细胞失活和缺失通常在零星的B和T恶性肿瘤中报道，并且通常与频繁的细胞遗传学改变和侵略性表型有关。 ATM缺陷的小鼠概括了人类患者的免疫缺陷和俯卧的T细胞淋巴瘤表型。此外，ATM缺乏的小鼠胸腺淋巴瘤中的复发性克隆易位与人类患者的分子起源共同。但是，尚未完全了解产生这种易位或致癌性基础机制的确切机制。在手上，ATM缺陷小鼠的侵袭性T细胞淋巴瘤和早期致死性使很难研究ATM在更普遍的B细胞淋巴瘤病因中的作用。因此，在这里，我们建议1）阐明ATM缺乏小鼠胸腺脑淋巴瘤中复发性tcralpha/Delta基因座相关的易位的分子机制； 2）定义并验证了人类患者中ATM缺乏的胸腺淋巴瘤和相关的未成熟T细胞白血病的重复易位靶标的致癌靶标； 3）确定ATM通过产生和表征B细胞特异性有条件ATM缺陷型淋巴瘤模型来抑制发育细胞的致癌易位的作用。总之，这项研究的结果将解决发育中的淋巴细胞中致癌易位的分子机制以及ATM在淋巴结恶性肿瘤病因中的功能。鉴于我们和其他人所记录的ATM缺陷小鼠胸腺淋巴瘤和人类未成熟的T细胞恶性肿瘤，我们对ATM缺乏小鼠淋巴瘤的分子分析及其人类对应物也将导致发现在人类淋巴恶性肿瘤中很重要的致癌途径。