Epigenetic mechanisms for oncogene silencing in MLL-rearranged leukemia

 描述(申请人提供)：虽然表观遗传失调已经被认为在许多类型癌症的发生和发展中起着重要作用，但表观遗传癌症治疗的研究主要集中在针对单个表观遗传调节因子来扰乱疾病的维持。决定基因表达/沉默和治疗结果的表观遗传途径之间的相互作用才刚刚开始得到承认。这种应用具有直接的临床意义，因为DOT1L抑制剂现在正在对MLL-r白血病患者进行临床试验。DOT1L抑制剂单独治疗已经注意到重要的临床反应，但毫无疑问，联合治疗将是必要的。本应用的目的是确定在DOT1L抑制后在MLL-r白血病中建立癌基因沉默的关键表观遗传效应和机制。基于基因组规模RNAi筛选的初步研究发现，组蛋白脱乙酰酶Sirtuin 1(SIRT1)在沉默MLL-AF9白血病中DOT1L依赖的癌基因方面发挥了重要作用(发表在《自然医学》杂志上)。这项拟议的研究将进一步利用全基因组遗传学和表观遗传学研究工具来剖析MLL-r白血病和正常造血中癌基因表达和沉默的表观遗传学机制。在我们看来，拟议的应用是创新的，因为它引入了一个新的组合靶向的概念，同时“诱导”和“稳定”了深刻的癌基因抑制的表观遗传沉默。此外，这项研究将具有重要意义，因为它通过同时激活癌基因沉默机制，立即为难治性MLL-r白血病提供了新的治疗机会。该建议的具体目的是：1.检测SIRT1酶活性在沉默MLL-r白血病中DOT1L驱动的癌基因方面的直接作用。2.评价SIRT1和DOT1L联合靶向治疗MLL-r白血病的疗效。3.研究SIRT1在抑制造血干/祖细胞DOT1L依赖基因表达中的作用。陈春伟博士目前是纪念斯隆-凯特琳癌症中心癌症生物学和遗传部的高级研究科学家。基于他在表观遗传调控和实验血液学方面的科学训练，陈博士发现并正在研究SIRT1和DOT1L相互作用在MLL-AF9白血病和正常造血中的作用。他的初步成果确定了癌症治疗表观遗传途径之间的交叉抑制机制，最近发表在《自然医学》杂志上。他的长期目标是通过了解表观遗传调节器如何在正常和恶性条件下控制基因表达，为先进的癌症治疗提供新的机会。陈博士将在斯科特·阿姆斯特朗博士的指导下，在一个激动人心的学术环境中实施他提出的项目。阿姆斯特朗博士是白血病遗传学和表观遗传学领域公认的领导者。斯科特·A·阿姆斯特朗博士已经成功地帮助两名通过NIH-K99职业发展奖获得支持的实习生获得终身教职。他提出了一项职业发展计划，以促进陈博士的科学发展，并帮助他过渡到独立。

 DESCRIPTION (provided by applicant): Although epigenetic dysregulation is already recognized to play an important role in the initiation and progression of many types of cancers, studies on epigenetic cancer therapy have been primarily focused on targeting a single epigenetic regulator to disrupt the maintenance of the disease. The cross-talks between epigenetic pathways that dictate gene expression/silencing and therapeutic outcome are just beginning to gain recognition. This application has immediate clinical relevance since DOT1L inhibitors are now in clinical trials for individuals with MLL-r leukemia. Important clinical responses have been noted with DOT1L inhibitor treatment alone, but there is no doubt that combination approaches will be necessary. The objective in this application is to determine the critical epigenetic effectors and mechanisms that establish oncogene silencing in MLL-r leukemia upon DOT1L inhibition. Preliminary studies based on a genome-scale RNAi screen have identified an essential role of histone deacetylase Sirtuin 1 (SIRT1) in silencing DOT1L-dependent oncogenes in MLL-AF9 leukemia (published in Nature Medicine). This proposed study will further utilize genome-wide genetic and epigenetic research tools to dissect the epigenetic mechanisms underlying the expression and silencing of oncogenes in both MLL-r leukemia and normal hematopoiesis. The proposed application is INNOVATIVE, in our opinion, because it introduces a novel concept of combinational targeting that simultaneously "induces" and "stabilizes" epigenetic silencing for profound oncogene suppression. In addition, this research will be of SIGNIFICANCE because it immediately provides novel therapeutic opportunities against the difficult-to-treat MLL-r leukemias by simultaneously activating the oncogene silencing mechanisms. The Specific Aims of this proposal are: 1. Examine the direct effect of SIRT1 enzymatic activity on silencing DOT1L-driven oncogenes in MLL-r leukemia. 2. Evaluate the efficacy of SIRT1 and DOT1L combinational targeting as a novel therapeutic strategy against MLL-r leukemia. 3. Investigate the role of SIRT1 in silencing DOT1L-dependent genes in hematopoietic stem/progenitor cells. Dr. Chun-Wei David Chen is currently a Senior Research Scientist in the Department of Cancer Biology and Genetics at Memorial Sloan Kettering Cancer Center. Building on his scientific training in epigenetic regulation and experimental hematology, Dr. Chen uncovered and is now investigating the role of SIRT1 and DOT1L interactions in MLL-AF9 leukemia and normal hematopoiesis. His initial achievement identifies cross-inhibitory mechanisms between epigenetic pathways for cancer therapy was recently published in Nature Medicine. His long term goal is to provide novel opportunities for advanced cancer therapies by understanding how epigenetic regulators control gene expression under normal and malignant conditions. Dr. Chen will carry out his proposed project in a stimulating academic environment under the mentorship of Dr. Scott Armstrong, a recognized leader in the fields of leukemia genetics and epigenetics. Dr. Scott A. Armstrong has successfully helped two trainees who have obtained support through the NIH-K99 Career Development Award to obtain tenure-track faculty positions. He has proposed a career development plan to further Dr. Chen's scientific development and to help his transition to independence.