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RNAi screen for chromatin regulators of differentiation in Acute Myeloid Leukemia

RNAi 筛选急性髓系白血病分化染色质调节因子

基本信息

批准号：
8594586
负责人：
Mario Andres Blanco
金额：
$ 5.22万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2014-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8594586
关键词：
Acute Myelocytic Leukemia Affinity Biochemical Biological Assay Blast Cell Bone Marrow Candidate Disease Gene Cell Line Cells Cessation of life ChIP-seq Characteristics Chromatin Complex Data Detection Differentiation Therapy Enzymes Epigenetic Process Gene Expression Gene Expression Profile Genes Genomics Goals Hematologic Neoplasms Hematopoietic Neoplasms Histones Homologous Gene Human ITGAM gene Image Immunocompetent Lead MLL-AF9 Mass Spectrum Analysis Methods Methylcellulose Methyltransferase Modeling Molecular Mus Mutation Myelogenous Nature Patients Phenotype Physiological Post-Translational Protein Processing Proteins RNA Interference Recruitment Activity Relapse Research Resistance Superoxides Survival Analysis Technology Testing Therapeutic Transplantation Tretinoin Undifferentiated Work Xenograft procedure base burden of illness cellular pathology chemotherapy disorder control functional genomics functional loss human disease in vivo interest mouse model mutant programs public health relevance response screening small hairpin RNA stem therapeutic target tissue/cell culture

项目摘要

DESCRIPTION (provided by applicant): Acute Myeloid Leukemia (AML) is the most lethal hematological malignancy and is the cause of more than 10,000 deaths in the US annually. AML is typically treated by chemotherapy, though patients often relapse and have limited therapeutic options. The promyelocytic subtype of AML is successfully treated by "differentiation therapy" - use of all-trans-retinoic acid (ATRA) to induce cellular differentiation and loss of proliferation in leukemic blasts. Other AML subtypes, however, show minimal ATRA responsiveness. Recent work has suggested that this block to non-APL AML differentiation is epigenetic in nature. Stable - yet reversible - chromatin alterations are thought to render these AML cells unable to activate myeloid differentiation gene expression programs. This project aims to use RNAi screening technology to identify histone-modifying enzymes responsible for keeping AML cells in their undifferentiated state. The main focus of the proposed research will be to determine whether inhibition of candidate enzymes induces myeloid differentiation in AML cell tissue culture models and reduces disease burden in mouse AML models. A secondary focus will be to understand how, on a molecular and biochemical level, the identified enzymes are functioning to oppose myeloid differentiation. Successful identification and molecular understanding of such enzymes would directly suggest their candidacy as potential therapeutic targets for non-APL AML.

描述（由申请人提供）：急性髓性白血病（AML）是最致命的血液恶性肿瘤，每年在美国导致超过10，000例死亡。AML通常通过化疗治疗，尽管患者经常复发并且治疗选择有限。AML的早幼粒细胞亚型通过“分化疗法”成功治疗-使用全反式维甲酸（ATRA）诱导白血病原始细胞中的细胞分化和增殖丧失。然而，其他AML亚型显示出最小的ATRA反应性。最近的研究表明，这种对非APL AML分化的阻断本质上是表观遗传的。稳定但可逆的染色质改变被认为使这些AML细胞不能激活髓样分化基因表达程序。该项目旨在使用RNAi筛选技术来鉴定负责保持AML细胞处于未分化状态的组蛋白修饰酶。拟议研究的主要重点将是确定候选酶的抑制是否会诱导AML细胞组织培养模型中的髓样分化，并减少小鼠AML模型中的疾病负担。第二个重点将是了解如何在分子和生物化学水平上，确定酶的功能，以反对骨髓分化。这些酶的成功鉴定和分子理解将直接表明它们作为非APL AML的潜在治疗靶点的候选资格。