Loss of miR-29s as predictor of response to demethylating agents

描述（由申请人提供）：MicroRNAs通过调节致癌基因和肿瘤抑制基因的表达参与人类癌症的发病。事实上，miR-15a和miR-16-1的缺失导致BCL2和MCL1的过表达和CLL的发展，而miR-155的过表达可能通过抑制SHIP1磷酸酶导致侵袭性B细胞恶性肿瘤的发展。我们发现miR-29s在肺癌、AML和侵袭性CLL中缺失。我们还表明，miR-29s直接靶向新生DNA甲基转移酶（DNMT3A和3B），间接靶向维持性DNA甲基转移酶1 (DNMT1)， miR-29家族成员的缺失导致DNMT3A、3B和1的过表达。这导致肿瘤抑制子通过启动子的CpG岛甲基化而沉默，这可以通过转染miR-29s来逆转。因此，miR-29s的缺失和dnmt的过表达似乎导致了与肿瘤发展相关的表观遗传变化。我们正在提出三个小型临床试验，以验证miR-29的缺失是肺癌、AML和侵袭性CLL中对去甲基化药物（如5-氮杂胞苷（5-Aza）和地西他滨）反应的预测因子。我们还计划在这些疾病的小鼠模型中验证这些试验的结果。因此，该项目将带来重大的研发创新，有效地将其与肿瘤学、公共卫生和医疗保健服务的长期改善和增长联系起来。

DESCRIPTION (provided by applicant): MicroRNAs contribute to the pathogenesis of human cancer by regulating the expression of oncogenes and tumor suppressor genes. In fact, loss of miR-15a and miR-16-1 leads to overexpression of BCL2 and MCL1 and the development of CLL, while overexpression of miR-155 leads to the development of aggressive B cell malignancies, possibly through suppression of SHIP1 phosphatase. We have shown loss of miR-29s in lung cancer, AML and the aggressive form of CLL. We have also shown that miR-29s target directly the de novo DNA methyltransferases (DNMT3A and 3B) and indirectly the maintenance DNA methyltransferase 1 (DNMT1) and that loss of miR-29 family members results in overexpression of DNMT3A, 3B and 1. This leads to silencing of tumor suppressors through methylation of CpG islands of their promoters that can be reversed by transfection with miR-29s. Thus, loss of miR-29s and overexpression of DNMTs seem to cause epigenetic changes associated with tumor development. We are proposing three small clinical trials to validate that loss of miR-29 is a predictor of response to demethylating agents such as 5-azacytidine (5-Aza) and decitabine in lung cancer, AML and the aggressive form of CLL. We are also planning to validate the results of these trials in mouse models of the diseases. Thus, this program will result in major research and development innovations that will effectively be linked to long term improvement and growth in oncology, public health and health care delivery. PUBLIC HEALTH RELEVANCE: We have observed striking responses to demethylating agents in tumors that have lost the expression of microRNAs (miR-29s) that target the DNA methyltransferases. We propose to carry out three small clinical trials to show that patients with lung cancer, AML and the aggressive form of CLL should be stratified on the basis of miR-29 expression, since the tumor cells that have lost mir-29s are killed by demethylating agents. We also intend to validate our hypothesis in mouse models.