Epigenetic Mechanisms and Targeting in MLL Leukemia
Epigenetic Mechanisms and Targeting in MLL Leukemia
批准号:
9323316
负责人:
MICHAEL L CLEARY
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
项目状态:
已结题
起止时间:
2005-08-05 至 2021-06-30
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
中文摘要
项目总结/文摘
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Functional and Translational Epigenomics of Acute Lymphoblastic Leukemia
-
批准号:10356890
-
项目类别:
-
资助金额:$36.0万
-
财政年份:2018
-
负责人:MICHAEL L CLEARY
-
依托单位:
Functional and Translational Epigenomics of Acute Lymphoblastic Leukemia
-
批准号:10115629
-
项目类别:
-
资助金额:$36.72万
-
财政年份:2018
-
负责人:MICHAEL L CLEARY
-
依托单位:
Cancer Biology
-
批准号:8709571
-
项目类别:
-
资助金额:$7.5万
-
财政年份:2013
-
负责人:MICHAEL L CLEARY
-
依托单位:
Role of PGDH in leukemia pathogenesis
-
批准号:8373391
-
项目类别:
-
资助金额:$33.28万
-
财政年份:2012
-
负责人:MICHAEL L CLEARY
-
依托单位:
Role of PGDH in leukemia pathogenesis
-
批准号:8658403
-
项目类别:
-
资助金额:$32.34万
-
财政年份:2012
-
负责人:MICHAEL L CLEARY
-
依托单位:
Role of PGDH in leukemia pathogenesis
-
批准号:8873970
-
项目类别:
-
资助金额:$33.37万
-
财政年份:2012
-
负责人:MICHAEL L CLEARY
-
依托单位:
Role of PGDH in leukemia pathogenesis
-
批准号:8508203
-
项目类别:
-
资助金额:$31.31万
-
财政年份:2012
-
负责人:MICHAEL L CLEARY
-
依托单位:
Cancer Biology
-
批准号:8180967
-
项目类别:
-
资助金额:$1.74万
-
财政年份:2010
-
负责人:MICHAEL L CLEARY
-
依托单位:
Inhibitors of MLL-Menin Interaction
-
批准号:7290277
-
项目类别:
-
资助金额:$19.69万
-
财政年份:2007
-
负责人:MICHAEL L CLEARY
-
依托单位:
Molecular Targeting of MLL and Associated Factors
-
批准号:6963168
-
项目类别:
-
资助金额:$31.14万
-
财政年份:2005
-
负责人:MICHAEL L CLEARY
-
依托单位:
Molecular Targeting of MLL and Associated Factors
-
批准号:8081772
-
项目类别:
-
资助金额:$30.42万
-
财政年份:2005
-
负责人:MICHAEL L CLEARY
-
依托单位:
Molecular Targeting of MLL and Associated Factors
-
批准号:7888617
-
项目类别:
-
资助金额:$31.33万
-
财政年份:2005
-
负责人:MICHAEL L CLEARY
-
依托单位:
Molecular Targeting of MLL and Associated Factors
-
批准号:7624715
-
项目类别:
-
资助金额:$29.57万
-
财政年份:2005
-
负责人:MICHAEL L CLEARY
-
依托单位:
Molecular Targeting of MLL and Associated Factors
-
批准号:7237921
-
项目类别:
-
资助金额:$26.67万
-
财政年份:2005
-
负责人:MICHAEL L CLEARY
-
依托单位:
Epigenetic Mechanisms and Targeting in MLL Leukemia
-
批准号:9174817
-
项目类别:
-
资助金额:$34.47万
-
财政年份:2005
-
负责人:MICHAEL L CLEARY
-
依托单位:
Molecular Targeting of MLL and Associated Factors
-
批准号:8449721
-
项目类别:
-
资助金额:$28.65万
-
财政年份:2005
-
负责人:MICHAEL L CLEARY
-
依托单位:
Molecular Targeting of MLL and Associated Factors
-
批准号:7105645
-
项目类别:
-
资助金额:$33.28万
-
财政年份:2005
-
负责人:MICHAEL L CLEARY
-
依托单位:
Molecular Targeting of MLL and Associated Factors
-
批准号:7434034
-
项目类别:
-
资助金额:$29.55万
-
财政年份:2005
-
负责人:MICHAEL L CLEARY
-
依托单位:
Molecular Targeting of MLL and Associated Factors
-
批准号:8252210
-
项目类别:
-
资助金额:$30.45万
-
财政年份:2005
-
负责人:MICHAEL L CLEARY
-
依托单位:
Hematologic Malignancies
-
批准号:6672512
-
项目类别:
-
资助金额:$0.3万
-
财政年份:2003
-
负责人:MICHAEL L CLEARY
-
依托单位:
海外基金