Combinational targeting the feed forward epigenetic circuitry in mixed lineage leukemia

针对混合谱系白血病前馈表观遗传回路的组合

基本信息

批准号：
10059184
负责人：
Chun-Wei David Chen
金额：
$ 39.57万
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：
2018
资助国家：
美国
起止时间：
2018-12-03 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10059184
关键词：
Acetylation Achievement Acute leukemia Affect Binding Biochemical Genetics Biotin Cell Line ChIP-seq Chimeric Proteins Chromatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Complex Elements Epigenetic Process Exhibits Future Gene Cluster Gene Expression Gene Expression Regulation Gene Rearrangement Genes Genetic Screening Genetic Transcription Histone Acetylation Histone Deacetylation Histone H3 Histones Human In Vitro Left Libraries Lysine MEIS1 gene MLL gene MLL-rearranged leukemia Malignant Neoplasms Mediating Methylation Methyltransferase Mixed-Lineage Leukemia Molecular Mutagenesis Oncogenes PHD Finger Patients Peptides Pharmacologic Substance Pharmacology Phase I Clinical Trials Prognosis Proteins Publishing Reader Regimen Research Role SIRT1 gene Scanning Survival Rate Techniques Technology Tertiary Protein Structure Therapeutic Transcriptional Activation Validation Work World Health Organization base cancer type clinically relevant density efficacy evaluation functional genomics genetic approach genome-wide histone acetyltransferase histone modification improved in vivo inhibitor/antagonist innovation leukemia leukemogenesis mutant novel novel therapeutic intervention novel therapeutics patient derived xenograft model pre-clinical programs recruit response small hairpin RNA targeted treatment treatment response

项目摘要

PROJECT SUMMARY/ABSTRACT MLL-rearranged (MLL-r) leukemias account for 5-10% of human acute leukemia and is associated with poor prognosis. The unmet clinical needs and the lack of an effective targeted therapy to the MLL-r leukemias emphasize the need for novel regimens. Recent cancer epigenetics studies discovered a central role for the histone H3 lysine 79 (H3K79) methyltransferase DOT1L in MLL-r leukemogenesis. Important clinical responses have been noted with DOT1L inhibitor treatment as a single agent, however, it is expected that combination treatments will be necessary. Our preliminary studies based on a DOT1L-inhibitor sensitization screen have identified an essential role of the PHF20/KAT8 histone acetyltransferase complex, in supporting the expression of DOT1L-driven oncogenes. The objective of this application is to determine the critical epigenetic mechanisms that collaborate with DOT1L to maintain oncogene expression in MLL-r leukemia. Our central hypothesis is that PHF20 mediates KAT8 recruitment to maintain the locus-specific histone acetylation and transcription of the DOT1L-driven leukemic program. We will investigate the efficacy of DOT1L and PHF20/KAT8 combination therapies (Aim 1), dissect the PHF20/KAT8 chromatin targeting mechanisms (Aim 2), and validate a novel high-density CRISPR protein scan technology for de novo discovery of the functional elements in DOT1L/PHF20/KAT8 (Aim 3). This study is innovative because (1) it introduces a novel concept of simultaneously targeting multiple components of an epigenetic feed-forward loop to efficiently suppress the cancer programs, and (2) it establishes a brand new genetic screen approach for a sub-protein level functional domain discovery. The impact of this research will be of significance because (1) it immediately provides novel therapeutic opportunities against the difficult-to-treat MLL-r leukemias, and (2) it will help identify novel functional elements in epigenetic regulators for future pharmaceutical targeting.

项目概要/摘要 MLL 重排 (MLL-r) 白血病占人类急性白血病的 5-10%，与预后不良。 MLL-r的临床需求未得到满足且缺乏有效的靶向治疗白血病强调需要新的治疗方案。最近的癌症表观遗传学研究发现了一个核心组蛋白 H3 赖氨酸 79 (H3K79) 甲基转移酶 DOT1L 在 MLL-r 白血病发生中的作用。重要的已经注意到 DOT1L 抑制剂作为单一药物治疗的临床反应，但是，预计联合治疗是必要的。我们基于 DOT1L 抑制剂致敏筛选的初步研究已经确定了其重要作用 PHF20/KAT8 组蛋白乙酰转移酶复合物，支持 DOT1L 驱动的表达癌基因。本应用的目的是确定关键的表观遗传机制与 DOT1L 合作维持 MLL-r 白血病中的癌基因表达。我们的中心假设是 PHF20 介导 KAT8 招募以维持位点特异性组蛋白乙酰化和转录 DOT1L 驱动的白血病项目。我们将研究 DOT1L 和 PHF20/KAT8 的功效联合疗法（目标 1），剖析 PHF20/KAT8 染色质靶向机制（目标 2），以及验证一种新型高密度 CRISPR 蛋白扫描技术，用于从头发现功能性蛋白 DOT1L/PHF20/KAT8 中的元素（目标 3）。这项研究具有创新性，因为（1）它引入了同时瞄准多个目标的新概念表观遗传前馈循环的组成部分，可有效抑制癌症程序，以及（2）建立了一种全新的基因筛选方法，用于亚蛋白水平功能域的发现。这这项研究的影响将具有重要意义，因为（1）它立即提供了新的治疗方法对抗难以治疗的 MLL-r 白血病的机会，(2) 它将有助于识别新的功能用于未来药物靶向的表观遗传调节元件。