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：
10083198
负责人：
Shan Zha
金额：
$ 38万
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：
2011-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083198
关键词：
ATM Gene Mutation ATM deficient ATM function Address Ataxia Telangiectasia Ataxia Telangiectasia Patients B-Lymphocytes Bladder C-terminal Camptothecin Cancer cell line Carcinoma Cell Therapy Cells Chemicals Chromatids Chromosomal translocation Cisplatin Colon Complex Copy Number Polymorphism DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA lesion Defect Development Embryonic Development Event Future Genes Genetic Genomic Instability Hematopoietic stem cells Human Hypersensitivity Lead Lesion Lymphocyte Lymphoma Lymphomagenesis Malignant Neoplasms Malignant lymphoid neoplasm Malignant neoplasm of pancreas Mantle Cell Lymphoma Missense Mutation Molecular Mus Mutate Mutation Neurologic Nonsense Mutation Oncogenic Pancreas Phosphorylation Phosphotransferases Prognosis Prognostic Marker RNA Splicing Recurrence Risk Role Somatic Mutation Structure Surface T-Cell Lymphoma T-Cell Prolymphocytic Leukemia Testing The Cancer Genome Atlas Thymic Lymphoma Topoisomerase-I Inhibitor Tumor Suppressor Genes Tumor Suppressor Proteins Type I DNA Topoisomerases Xenograft procedure alpha helix ataxia telangiectasia mutated protein base cancer cell cancer risk chemotherapeutic agent chemotherapy clinical efficacy congenital immunodeficiency crosslink early onset embryonic stem cell genotoxicity inhibitor/antagonist irinotecan leukemia leukemia/lymphoma malignant breast neoplasm mouse model mutant nervous system disorder new therapeutic target novel nucleotide analog protein expression response targeted agent targeted cancer therapy tumor tumorigenesis

项目摘要

In this application, we propose to elucidate the molecular mechanisms by which ATM suppresses oncogenic translocations in developing lymphocytes. Specifically, we will generate novel mouse models expressing mutated ATM protein (rather than loss ATM), identify and characterize genetic lesions that synergize with ATM mutation in lymphomagenesis, and identify agents that can preferentially target ATM-mutated cancer cells for therapy. Lymphoid malignancies are characterized by recurrent chromosome translocations that result from aberrant repair of DNA double-strand breaks that normally occur during lymphocyte development. The ATM kinase is a master regulator of the DNA damage responses and a tumor suppresser gene. Germline inactivation of ATM causes Ataxia-Telangiectasia (A-T) syndrome, a neurological disorder associated with primary immunodeficiency and greatly increased risk for lymphomas and leukemia. Somatic mutations of ATM have also been identified in a broad spectrum of human cancers including >50% of mantle cell lymphomas and nearly all T-cell prolymphocytic leukemia. Our preliminary study suggests that cancer-associated somatic ATM mutations are functionally distinct from those in A-T patients. While ~89% of A-T patients carry truncating mutations (frameshift, nonsense, splicing) that abrogate ATM protein expression, ~72% of cancer-associated ATM mutations in TCGA are missense mutations clustering around the kinase domain. Expression of catalytically-inactive ATM protein in hematopoietic stem cells is more oncogenic than loss of ATM, resulting in earlier and more frequent B and T cell lymphomas in mice. Based on these findings, we propose to 1) identify the mechanisms by which catalytically-inactive ATM protein promotes lymphomagenesis beyond loss of ATM; 2) evaluate the consequences of other recurrent ATM missense mutation found in human cancers; and 3) identify agents/targets that can preferentially target ATM-mutated cancers. The results from this study will further elucidate the functions of ATM in DNA repair and tumor suppressionand provide the rationale to selectively target ATM mutated human cancers. ATM missense mutations occur in 4-8% of common epithelial cancers (i.g. colon, bladders, pancreas etc.) in additional to lymphomas and are often associated with poor prognosis. The specific DNA repair defects and selective hypersensitivities identified in this study will provide the basis to target ATM-mutated cancer with selective chemotherapy inclinical trials and lead to new strategies to effectively manage cancer with defects in ATM and other DNA repair genes in the future. The similarity between ATM deficient murine thymic lymphomas and human T-ALL also provide the platform to identify and characterize prognostic markers for human T-ALL.

在此应用中，我们打算阐明 ATM 抑制发育中淋巴细胞中致癌易位的分子机制。具体来说，我们将生成表达突变 ATM 蛋白（而不是丢失 ATM）的新型小鼠模型，识别和表征与淋巴瘤发生中的 ATM 突变协同作用的遗传病变，并识别可以优先针对 ATM 突变癌细胞进行治疗的药物。淋巴恶性肿瘤的特征是反复发生的染色体易位，这是由于淋巴细胞发育过程中通常发生的 DNA 双链断裂的异常修复所致。 ATM 激酶是 DNA 损伤反应的主要调节因子和肿瘤抑制基因。 ATM 种系失活会导致共济失调毛细血管扩张 (A-T) 综合征，这是一种与原发性免疫缺陷相关的神经系统疾病，会大大增加患淋巴瘤和白血病的风险。 ATM 的体细胞突变也在多种人类癌症中被发现，包括 > 50% 的套细胞淋巴瘤和几乎所有 T 细胞幼淋巴细胞白血病。我们的初步研究表明，癌症相关的体细胞 ATM 突变在功能上与 A-T 患者的突变不同。虽然约 89% 的 A-T 患者携带消除 ATM 蛋白表达的截短突变（移码、无义、剪接），但 TCGA 中约 72% 的癌症相关 ATM 突变是聚集在激酶结构域周围的错义突变。表达造血干细胞中催化失活的 ATM 蛋白的缺失比 ATM 的缺失更具致癌性，导致小鼠中早期且更常见的 B 和 T 细胞淋巴瘤。基于这些发现，我们建议 1) 确定催化失活 ATM 蛋白促进淋巴瘤发生超越损失的机制自动提款机； 2) 评估人类癌症中发现的其他复发性 ATM 错义突变的后果； 3) 确定可以优先针对 ATM 突变癌症的药物/靶点。这项研究的结果将进一步阐明 ATM 在 DNA 修复和肿瘤抑制中的功能，并为选择性靶向 ATM 突变的人类癌症提供理论依据。除了淋巴瘤之外，ATM 错义突变还发生在 4-8% 的常见上皮癌（例如结肠癌、膀胱癌、胰腺癌等）中，并且通常与不良预后相关。本研究中发现的特定 DNA 修复缺陷和选择性超敏反应将为通过选择性化疗临床试验靶向 ATM 突变癌症提供基础，并导致未来有效管理 ATM 和其他 DNA 修复基因缺陷癌症的新策略。 ATM 缺陷型小鼠胸腺淋巴瘤与人类 T-ALL 之间的相似性也为识别和表征人类 T-ALL 的预后标志物提供了平台。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development.

XLF 修复蛋白和 53BP1 DNA 损伤反应因子在末端连接和淋巴细胞发育中的重叠功能。

DOI：
发表时间：
2012-03-06
期刊：
影响因子：
11.1
作者：
Liu, Xiangyu;Jiang, Wenxia;Dubois, Richard L;Yamamoto, Kenta;Wolner, Zachary;Zha, Shan
通讯作者：
Zha, Shan

ATMIN: a new tumor suppressor in developing B cells.

ATMIN：B 细胞发育过程中的一种新肿瘤抑制因子。

DOI：
发表时间：
2011-05-17
期刊：
影响因子：
50.3
作者：
Liu, Xiangyu;Zha, Shan
通讯作者：
Zha, Shan

Ataxia telangiectasia mutated (ATM) is dispensable for endonuclease I-SceI-induced homologous recombination in mouse embryonic stem cells.

共济失调毛细血管扩张突变 (ATM) 对于内切核酸酶 I-SceI 诱导的小鼠胚胎干细胞中的同源重组来说是可有可无的。

DOI：
发表时间：
2013-03-08
期刊：
影响因子：
0
作者：
Rass, Emilie;Chandramouly, Gurushankar;Zha, Shan;Alt, Frederick W;Xie, Anyong
通讯作者：
Xie, Anyong

Hematopoietic stem cell dysfunction underlies the progressive lymphocytopenia in XLF/Cernunnos deficiency.

造血干细胞功能障碍是 XLF/Cernunnos 缺乏症进行性淋巴细胞减少的基础。

DOI：
发表时间：
2014-09-04
期刊：
影响因子：
20.3
作者：
Avagyan, Serine;Churchill, Michael;Yamamoto, Kenta;Crowe, Jennifer L;Li, Chen;Lee, Brian J;Zheng, Tian;Mukherjee, Siddhartha;Zha, Shan
通讯作者：
Zha, Shan

Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.

不活跃的 Atm 比 Atm 损失更能消除小鼠小脑中的 DSB 修复，且不会引起神经表型。