Epigenetic Mechanisms and Targeting in MLL Leukemia
MLL 白血病的表观遗传机制和靶向
基本信息
- 批准号:9323316
- 负责人:
- 金额:$ 34.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-08-05 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:ASH1L geneAcute Myelocytic LeukemiaAcute leukemiaAddressBindingBiological ModelsBlood CellsCell modelCellsCharacteristicsChromatinComplexDataDependenceEffectivenessEnzymesEpigenetic ProcessGene ExpressionGene TargetingGeneticGenetic TranscriptionHRX proteinHistone CodeHistone H3HistonesHumanLysineMalignant - descriptorMalignant NeoplasmsMediatingMethylationMolecularMutateMutationNormal CellOncogenesOncogenicOncoproteinsPathogenesisPathologicPathway interactionsPropertyProteinsProteomicsReaderRecruitment ActivityRegulatory PathwayRoleSiteStructureTechniquesTechnologyTherapeuticTranscriptional RegulationWritingbasechromatin immunoprecipitationcurative treatmentsenvironmental enrichment for laboratory animalsepigenomeepigenomicsexperimental studygenetic regulatory proteingenome-widehistone methyltransferasehistone modificationinsightknock-downleukemialeukemogenesismolecular targeted therapiesmouse modelnoveloutcome forecastpre-clinicalpromoterprotein complexsmall hairpin RNAtherapeutic targettumorigenesis
项目摘要
Project Summary/Abstract
MLL is an epigenetic regulatory protein that is mutated in a subset of leukemias with a poor prognosis
and few therapeutic options. The epigenetic pathways and perturbations involved in MLL leukemia
pathogenesis are complex, and the effectiveness of targeted molecular therapies not yet established. The
studies proposed in this renewal application investigate the pathologic contributions of ASH1L, an
epigenetic regulatory factor not previously implicated in MLL leukemia, and will define its role as a
potential therapeutic target.
Substantial preliminary data show that recruitment of MLL at target genes involved in leukemogenesis
is dependent on ASH1L, a histone methyltransferase that specifically di-methylates histone H3 on lysine
36 (H3K36me2) associated with active promoters. Furthermore, ASH1L is required for leukemic
transformation by MLL oncoproteins in mouse models of acute myeloid leukemia. A component of the
MLL complex (LEDGF) specifically binds H3K36me2 suggesting that ASH1L may serve a key upstream
role for recruitment or retention of MLL at its target genes. However, the specific mechanisms involved
and the consequences for human leukemia remain to be determined. The proposed studies will address
the hypothesis that ASH1L serves a crucial role in the MLL oncogenic pathway by establishing a
chromatin environment enriched for H3K36 di-methyl at specific target promoters to facilitate binding of the
MLL protein complex that perturbs gene expression in leukemia cells.
Studies in the first specific aim will establish the functional roles of ASH1L and histone H3K36 di-
methylation in the pathogenesis of MLL leukemia using shRNA technology in pre-clinical and human
leukemia cell model systems. These studies will define which leukemia subtypes are dependent on
ASH1L, and characterize the deleterious consequences of its inhibition to provide the basis for a rational
therapeutic strategy in leukemia.
Studies in the second aim will use chromatin immunoprecipitation techniques to establish the genome-
wide distribution of histone modifications, determine which marks and factors are selectively dependent on
ASH1L, and establish their respective mechanistic roles in defining the epigenomic states required for
aberrant gene expression in MLL leukemia cells.
Studies in the third specific aim will employ structure-function and unbiased proteomics approaches to
characterize ASH1L heterologous interactions that direct its activity to the chromatin of leukemia-
associated target genes. Taken together, the proposed studies will provide significant insights into the
molecular mechanisms of a novel epigenetic regulatory pathway in leukemia cells, and facilitate efforts to
specifically target the pathway to achieve more efficacious therapies.
项目概要/摘要
MLL 是一种表观遗传调节蛋白,在预后不良的白血病亚群中发生突变
和很少的治疗选择。 MLL 白血病涉及的表观遗传途径和扰动
发病机制复杂,靶向分子治疗的有效性尚未确定。这
本次更新申请中提出的研究调查了 ASH1L 的病理贡献,ASH1L 是一种
先前未涉及 MLL 白血病的表观遗传调节因子,并将其作用定义为
潜在的治疗靶点。
大量初步数据表明,MLL 募集到参与白血病发生的靶基因上
依赖于 ASH1L,一种组蛋白甲基转移酶,可特异性地将组蛋白 H3 赖氨酸二甲基化
36 (H3K36me2) 与活性启动子相关。此外,白血病需要 ASH1L
MLL 癌蛋白在急性髓系白血病小鼠模型中的转化。的一个组成部分
MLL 复合物 (LEDGF) 特异性结合 H3K36me2,表明 ASH1L 可能是关键上游
MLL 在其靶基因上的招募或保留的作用。但涉及的具体机制
对人类白血病的后果仍有待确定。拟议的研究将解决
ASH1L 通过建立一个在 MLL 致癌途径中发挥关键作用的假设
在特定目标启动子处富含 H3K36 二甲基的染色质环境,以促进结合
MLL 蛋白复合物扰乱白血病细胞中的基因表达。
第一个具体目标的研究将确定 ASH1L 和组蛋白 H3K36 di 的功能作用
使用 shRNA 技术在临床前和人类中研究 MLL 白血病发病机制中的甲基化
白血病细胞模型系统。这些研究将确定哪些白血病亚型依赖于
ASH1L,并描述其抑制的有害后果,为合理的治疗提供基础
白血病的治疗策略。
第二个目标的研究将使用染色质免疫沉淀技术来建立基因组-
组蛋白修饰的广泛分布,确定选择性依赖于哪些标记和因素
ASH1L,并建立它们各自在定义表观基因组状态所需的机制作用
MLL 白血病细胞中的异常基因表达。
第三个具体目标的研究将采用结构功能和公正的蛋白质组学方法
描述了 ASH1L 异源相互作用,将其活性引导至白血病染色质-
相关的靶基因。总而言之,拟议的研究将为以下方面提供重要的见解:
白血病细胞中新型表观遗传调控途径的分子机制,并促进努力
专门针对实现更有效治疗的途径。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MICHAEL L CLEARY其他文献
MICHAEL L CLEARY的其他文献
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{{ truncateString('MICHAEL L CLEARY', 18)}}的其他基金
Functional and Translational Epigenomics of Acute Lymphoblastic Leukemia
急性淋巴细胞白血病的功能和转化表观基因组学
- 批准号:
10115629 - 财政年份:2018
- 资助金额:
$ 34.5万 - 项目类别:
Functional and Translational Epigenomics of Acute Lymphoblastic Leukemia
急性淋巴细胞白血病的功能和转化表观基因组学
- 批准号:
10356890 - 财政年份:2018
- 资助金额:
$ 34.5万 - 项目类别:
Molecular Targeting of MLL and Associated Factors
MLL 的分子靶向及相关因素
- 批准号:
7624715 - 财政年份:2005
- 资助金额:
$ 34.5万 - 项目类别:
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