The Role of ATM in Suppression of Lymphomas

在这个应用中，我们建议阐明ATM抑制发育中的淋巴细胞的致癌易位的分子机制。具体来说，我们将建立表达突变ATM蛋白（而不是丢失ATM）的新型小鼠模型，识别和表征在淋巴瘤发生中与ATM突变协同作用的遗传病变，并确定可以优先靶向ATM突变癌细胞进行治疗的药物。淋巴细胞恶性肿瘤的特点是由于DNA双链断裂的异常修复，通常发生在淋巴细胞发育过程中染色体易位。ATM激酶是DNA损伤反应的主要调控因子和肿瘤抑制基因。ATM的种系失活导致共济失调-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，大大增加了淋巴瘤和白血病的风险。在广泛的人类癌症中也发现了ATM的体细胞突变，包括50%的套细胞淋巴瘤和几乎所有的t细胞前淋巴细胞白血病。我们的初步研究表明，与癌症相关的体细胞ATM突变在功能上与A-T患者不同。虽然约89%的A-T患者携带截断突变（移码、无义、剪接），从而取消了ATM蛋白的表达，但在TCGA中，约72%的癌症相关ATM突变是围绕激酶结构域聚集的错义突变。表达式

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.