Epigenetic mechanisms for oncogene silencing in MLL-rearranged leukemia

MLL重排白血病癌基因沉默的表观遗传机制

基本信息

批准号：
9532338
负责人：
Chun-Wei David Chen
金额：
$ 24.9万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9532338
关键词：
Ablation Achievement Acute Myelocytic Leukemia Acute leukemia Advanced Malignant Neoplasm Award Biochemical Bioinformatics CRISPR library Cancer Biology Chimeric Proteins Chromatin Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Data Deacetylase Deacetylation Defect Development Development Plans Disease Ectopic Expression Environment Enzymes Epigenetic Process Experimental Hematology Faculty Gene Cluster Gene Expression Gene Expression Regulation Gene Rearrangement Gene Targeting Generations Genes Genetic Genetic Models Genetic Transcription Genomics Goals Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells High-Throughput Nucleotide Sequencing Histone Deacetylase Histone H3 Histones Human Individual K-Series Research Career Programs Knockout Mice Knowledge Laboratories Laboratory Research Link Lysine MEIS1 gene MLL gene MLLT3 gene Maintenance Malignant - descriptor Malignant Neoplasms Mediating Medicine Memorial Sloan-Kettering Cancer Center Mentors Mentorship Mixed-Lineage Leukemia Mus Nature Oncogenes Oncogenic Outcome Pathway interactions Patients Pharmacology Phase Pilot Projects Play Positioning Attribute Publishing RNA interference screen Recruitment Activity Repression Research Research Design Resistance Role SIRT1 gene Scientist System Testing Training Treatment Efficacy Treatment Protocols Uncertainty United States National Institutes of Health Work Xenograft procedure base cancer genetics cancer therapy cancer type career career development clinically relevant conventional therapy effective therapy epigenetic profiling epigenetic regulation experience experimental study gene translocation genome-wide histone methyltransferase histone modification in vivo Model inhibitor/antagonist leukemia mouse model novel novel therapeutics pediatric patients pre-clinical programs public health relevance response small hairpin RNA tenure track therapy outcome tool

项目摘要

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.

描述（由申请人提供）：虽然表观遗传失调已被认为在多种癌症的发生和进展中发挥着重要作用，但表观遗传癌症治疗的研究主要集中在针对单一表观遗传调节因子来破坏癌症的维持。由于 DOT1L 抑制剂目前正在针对 MLL-r 白血病患者进行临床试验，因此决定基因表达/沉默的表观遗传途径与治疗结果之间的相互作用才刚刚开始获得认可。单独使用 DOT1L 抑制剂治疗已注意到重要的临床反应，但毫无疑问，联合治疗是必要的，本申请的目的是确定在 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 筛选的初步研究已确定组蛋白脱乙酰酶 Sirtuin 1 (SIRT1) 在沉默 DOT1L 依赖性癌基因中的重要作用MLL-AF9 白血病（发表在《自然医学》上）。这项拟议的研究将进一步利用全基因组遗传和表观遗传学研究工具来剖析 MLL-r 白血病和正常造血过程中癌基因表达和沉默的表观遗传机制。我们认为，因为它引入了一种新的组合靶向概念，可以同时“诱导”和“稳定”表观遗传沉默，从而实现深度癌基因抑制。此外，这项研究具有重要意义，因为它通过同时激活癌基因沉默机制，立即为难以治疗的 MLL-r 白血病提供了新的治疗机会。该提案的具体目标是： 1. 检查 SIRT1 的直接作用。 MLL-r 白血病中 DOT1L 驱动的癌基因沉默的酶活性 2. 评估 SIRT1 和 DOT1L 组合的功效。靶向作为针对 MLL-r 白血病的新型治疗策略 3. 研究 SIRT1 在造血干细胞/祖细胞中 DOT1L 依赖性基因沉默中的作用。 Chun-Wei David Chen 博士目前是癌症系的高级研究科学家。纪念斯隆凯特琳癌症中心的生物学和遗传学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其作用。 SIRT1 和 DOT1L 在 MLL-AF9 白血病和正常造血中的相互作用，他的初步成果最近发表在《自然医学》上，该成果确定了癌症治疗的表观遗传途径之间的交叉抑制机制，他的长期目标是通过了解如何为先进的癌症治疗提供新的机会。表观遗传调控因子在正常和恶性条件下控制基因表达。陈博士将在白血病遗传学领域公认的领导者斯科特·阿姆斯特朗博士的指导下，在一个令人兴奋的学术环境中开展他提出的项目。 Scott A. Armstrong 博士成功帮助两名通过 NIH-K99 职业发展奖获得支持的学员获得终身教授职位，他提出了职业发展计划，以进一步促进陈博士的科学发展和帮助他过渡到独立。