Molecular Pathogenesis of Acute Myeloid Leukemia
急性髓系白血病的分子发病机制
基本信息
- 批准号:10678908
- 负责人:
- 金额:$ 91.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-13 至 2029-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAcute Myelocytic LeukemiaBackCBFA2T1 geneCBFbeta-MYH11 fusion proteinCell modelCellsChIP-seqClinical Trials DesignCommunitiesCore-Binding FactorDNADNA sequencingDNMT3B geneDNMT3aDNMT3a mutationData AnalysesData SetDatabasesDevelopmentDiseaseEpigenetic ProcessEventFundingGenetically Engineered MouseGenomicsGoalsGrowthHDAC1 geneHematopoieticHematopoietic NeoplasmsHematopoietic stem cellsHistonesHumanMethodsMolecularMutationPML-RARalpha proteinPathogenesisPatientsPharmaceutical PreparationsPrecision therapeuticsPreleukemiaProcessProtein IsoformsProteinsProteomicsRUNX1 geneSamplingSeriesWorkacute myeloid leukemia cellbisulfite sequencingblastomere structureembryo cellengineered stem cellsepigenomicsfitnessgenetic approachgenomic locusinduced pluripotent stem cellinhibitorinsightleukemia initiating cellmouse modelmutantnoveloverexpressionphosphoproteomicsprogramsproteogenomicssingle cell technologytargeted treatmenttherapy designtranscriptome sequencingwhole genome
项目摘要
Project Summary
The long-term goal of this project is to develop effective, precision therapies directed against the
initiating mutations of Acute Myeloid Leukemia (AML). During the current funding period, we performed a
series of genomic and epigenomic studies that have clarified the mechanisms that AML initiating mutations use
to "reprogram" hematopoietic stem progenitor cells (HSPCs), increasing their fitness for transformation. In the
next funding period, we will use primary human AML samples, induced pluripotent stem cells (iPSCs),
and genetically engineered mouse models to further evaluate the molecular mechanisms involved in
preleukemic reprogramming, and progression to AML. Four well characterized events (that initiate more
than half of AML cases) will be studied in detail. We will continue our work with DNMT3A mutations and PML-
RARA, and add the study of Core Binding Factor AML fusions (RUNX1-RUNX1T1 and CBFB-MYH11). The
"toolkit" for these studies will involve the analysis of preleukemic and fully transformed hematopoietic cells from
these models, using bulk DNA and RNA sequencing, whole genome bisulfite sequencing, ATAC-seq, ChIP-
seq and/or CUT&RUN to detect the genomic locations of activating and repressive histone marks (and the
fusions themselves), and single cell technologies for RNA, DNA, and ATAC-seq. We will also be performing
comprehensive proteomic studies to complete "proteogenomic" datasets for these initiating events,
including 1) the identification of the hematopoietic proteins that interact with the initiating proteins
listed above, and 2) the development of quantitative deep-scale proteomic and phosphoproteomic
datasets broadly representative of all AML subtypes. The integrative analysis of these datasets (and their
availability to the AML community) should provide important new insights about AML pathogenesis, and
suggest mechanistically targeted therapies. In this proposal, we provide one representative example of this
process: using novel methods to identify proteins that interact with DNMT3A, we discovered several mutations
that disrupt the normal interaction of DNMT3A with an inactive isoform of DNMT3B (DNMT3B3); these
mutations destabilize DNMT3A and decrease its activity. Remarkably, we found that we can restore the activity
of many mutant DNMT3A proteins by retrovirally overexpressing DNMT3L, a protein that normally interacts
with DNMT3A and 3B in embryonic cells to increase their activity. "Addback" of DNMT3L into hematopoietic
cells with the Dnmt3aR878H mutation remethylates DNA, and decreases the growth of AML cells initiated by this
mutation. Since DNMT3L is epigenetically silenced in nearly all AMLs, a program to identify drugs and genetic
strategies to reactivate DNMT3L in AML cells will be developed. We have already found that Romidepsin, an
HDAC1 inhibitor, potently induces DNMT3L expression, and a clinical trial designed to evaluate the activity of
this drug in DNMT3A mutant AMLs is planned. Additional approaches for developing mechanistically driven
therapies designed to thwart initiating mutations will be developed during the next funding period.
项目总结
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Melanoma in a patient with DNMT3A overgrowth syndrome.
- DOI:10.1101/mcs.a006267
- 发表时间:2023-04
- 期刊:
- 影响因子:1.8
- 作者:Chen, David Y.;Sutton, Leslie A.;Ramakrishnan, Sai Mukund;Duncavage, Eric J.;Heath, Sharon E.;Compton, Leigh A.;Miller, Christopher A.;Ley, Timothy J.
- 通讯作者:Ley, Timothy J.
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{{ truncateString('TIMOTHY J. LEY', 18)}}的其他基金
Molecular Pathogenesis of Acute Myeloid Leukemia
急性髓系白血病的分子发病机制
- 批准号:
10227764 - 财政年份:2015
- 资助金额:
$ 91.43万 - 项目类别:
Molecular Pathogenesis of Acute Myeloid Leukemia
急性髓系白血病的分子发病机制
- 批准号:
9298600 - 财政年份:2015
- 资助金额:
$ 91.43万 - 项目类别:
Molecular Pathogenesis of Acute Myeloid Leukemia
急性髓系白血病的分子发病机制
- 批准号:
10518874 - 财政年份:2015
- 资助金额:
$ 91.43万 - 项目类别:
Molecular Pathogenesis of Acute Myeloid Leukemia
急性髓系白血病的分子发病机制
- 批准号:
9126480 - 财政年份:2015
- 资助金额:
$ 91.43万 - 项目类别:
Project 1 - Molecular Determinants of Decitabine Responses.
项目 1 - 地西他滨反应的分子决定因素。
- 批准号:
10439621 - 财政年份:2013
- 资助金额:
$ 91.43万 - 项目类别:
Project 1 - Molecular Determinants of Decitabine Responses.
项目 1 - 地西他滨反应的分子决定因素。
- 批准号:
10194399 - 财政年份:2013
- 资助金额:
$ 91.43万 - 项目类别:
DNMT3A MUTATIONS IN ACUTE MYELOID LEUKEMIA
急性髓系白血病中的 DNMT3A 突变
- 批准号:
8309966 - 财政年份:2011
- 资助金额:
$ 91.43万 - 项目类别:
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