RNAi screen for chromatin regulators of differentiation in Acute Myeloid Leukemia

描述(申请人提供)：急性髓系白血病(AML)是最致命的血液系统恶性肿瘤，每年在美国导致10,000多人死亡。AML通常通过化疗治疗，尽管患者经常复发，治疗选择有限。早幼粒细胞亚型AML可通过“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分化和失去增殖。然而，其他AML亚型对ATRA的反应性最低。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细胞无法激活髓系分化基因表达程序。该项目旨在使用RNAi筛选技术来识别负责保持AML细胞处于未分化状态的组蛋白修饰酶。这项研究的主要重点将是确定抑制候选酶是否能在AML细胞组织培养模型中诱导髓系分化，并减轻小鼠AML模型的疾病负担。第二个重点将是在分子和生化水平上了解已识别的酶是如何发挥功能来反对髓系分化的。对这些酶的成功鉴定和分子理解将直接表明它们有可能成为非APL AML的潜在治疗靶点。

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.