The Role of ATM in Suppression of Lymphomas

在这一应用中，我们建议阐明ATM抑制发育中淋巴细胞致癌易位的分子机制。具体地说，我们将建立表达突变ATM蛋白(而不是丢失ATM)的新的小鼠模型，识别和表征在淋巴肿瘤发生中与ATM突变协同的遗传损伤，并识别能够优先针对ATM突变的癌细胞进行治疗的药物。淋巴系恶性肿瘤的特征是反复的染色体易位，这是由于通常发生在淋巴细胞发育过程中的DNA双链断裂的异常修复造成的。ATM激酶是DNA损伤反应的主要调节者，也是肿瘤抑制基因。ATM的种系失活会导致共济失调-毛细血管扩张症(A-T)综合征，这是一种与原发免疫缺陷相关的神经系统疾病，极大地增加了患淋巴瘤和白血病的风险。ATM的体细胞突变也在广泛的人类癌症中被发现，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患者的不同。%的A-T患者携带缺失ATM蛋白表达的截断突变(移码、无义、剪接)，而TCGA中与癌症相关的ATM突变中有72%是聚集在激酶结构域周围的错义突变。表达式 在造血干细胞中失去催化活性的ATM蛋白比失去ATM更容易致癌，结果 在小鼠早期和较常见的B细胞和T细胞淋巴瘤中。基于这些发现，我们建议1) 确定催化失活的ATM蛋白促进淋巴肿大超过丢失的机制 2)评估在人类癌症中发现的其他反复发生的ATM错义突变的后果； 以及3)确定可以优先靶向ATM突变的癌症的试剂/靶点。本研究的结果将进一步阐明ATM在DNA修复和肿瘤抑制中的作用，并为选择性靶向ATM突变的人类癌症提供理论依据。ATM错义突变发生在4%-8%的常见上皮癌(I.G.结肠、膀胱、胰腺等。)除了淋巴瘤外，而且往往与预后不良有关。本研究发现的特异性DNA修复缺陷和选择性超敏反应将为在临床试验中针对ATM突变的肿瘤进行选择性化疗提供依据，并为未来有效地处理ATM和其他DNA修复基因缺陷的癌症提供新的策略。ATM缺陷的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。

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.