Dysregulated genome architecture in acute myeloid leukemia
急性髓系白血病基因组结构失调
基本信息
- 批准号:10555303
- 负责人:
- 金额:$ 35.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAcute Myelocytic LeukemiaAffectArchitectureBiological AssayCRISPR/Cas technologyCell LineCellsChromatinDNADNA IntegrationDNA MethylationDataDevelopmentETV6 geneEnhancersEpigenetic ProcessEvolutionExhibitsGene ClusterGene ExpressionGene Expression ProfileGene Expression RegulationGenesGenetic Enhancer ElementGenetic TranscriptionGenomeGenomic SegmentGoalsHematopoieticHematopoietic stem cellsHomeobox GenesHypermethylationImpairmentIn SituIn VitroIndividualLinkMalignant NeoplasmsMediatingMethylationModelingModificationMusMutationPathogenesisPathway interactionsPatternPhenotypePreleukemiaRegulatory ElementReporterRoleSamplingSomatic MutationTestingTherapeuticXenograft ModelXenograft procedureacute myeloid leukemia celldata integrationdefined contributiongenome editinggenome-widegenome-wide analysisgenomic locusimprovedin vivoinsightleukemiamethylation patternmutantnew therapeutic targetnovel strategiespreventpromoterself-renewaltranscription factor
项目摘要
The long-term goal of this proposal is to define the contribution of altered epigenetic patterns and
genome organization to the pathogenesis of acute myeloid leukemia. Acute myeloid leukemia (AML) is a
devastating cancer that is initiated by somatic mutations in hematopoietic stem/progenitor cells. AML cells are
also characterized by DNA methylation changes and altered gene expression patterns, but the relationships
between AML mutations, DNA methylation, and transcriptional activity in AML are poorly understood. We have
performed comprehensive epigenetic analysis to investigate the regulatory mechanisms that control expression
of the HOX gene loci in AML cells, which encode transcription factors that maintain normal hematopoietic stem
cell identity and promote self-renewal in AML. These studies have identified specific long-range three-
dimensional (3D) genome interactions at the HOXA locus that are increased in AML vs. normal hematopoietic
stem cells. Further analysis has showed that the loci involved in these interactions have AML-specific epigenetic
changes suggesting they may be enhancers. We have extended these studies by performing a genome-wide
analysis of DNA methylation and 3D genome architecture in primary AML samples. This demonstrated that AMLs
with canonical mutations in either IDH1 or IDH2 have focal hypermethylation at enhancers that form direct
interactions with genes relevant for AML pathogenesis, including MYC and ETV6. Based on these findings,
we hypothesize that epigenetic changes at specific regulatory enhancers in AML cells can cause the
dysregulation of genes that contribute to AML pathogenesis. Here we propose to test this hypothesis by
performing detailed, mechanistic studies of enhancers and gene regulation in primary AML samples and AML
cell line models. In Aim 1, we will use capture-HiC to perform in-depth studies of the HOXA locus in primary AML
samples and AML cell lines that will define the relationships between AML mutations, enhancer interactions, and
HOXA gene expression. We will then use massively parallel reporter assays, CRISPR/Cas9 mediated genome
editing, and functional studies in vitro and in vivo to identify the specific enhancers and epigenetic pathways that
regulate expression of HOXA genes. In Aim 2, we will use in situ HiC to define the 3D genome organization of
primary AML samples with mutations in IDH1 and IDH2 that have focal DNA hypermethylation at enhancers. We
will integrate these data with DNA methylation, chromatin profiling, and gene expression to determine how DNA
methylation influences enhancer-promoter interactions and gene regulation in AML cells. Together, these
studies will provide mechanistic insights into HOX gene regulation that may guide therapeutic
approaches that target the HOX self-renewal pathway in AML cells, and determine the extent to which
DNA methylation contributes to the leukemia phenotype by altering the function of regulatory enhancers.
这项建议的长期目标是确定改变的表观遗传模式和
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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David H Spencer其他文献
Clearance of Leukemia Associated Mutations (LAMs) after Induction Therapy Is Associated with Favorable Outcomes in Intermediate Risk Acute Myeloid Leukemia: Interim Results of a Multicenter, Prospective Phase II Trial
- DOI:
10.1182/blood-2024-201694 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Meagan Jacoby;David H Spencer;Geoffrey L. Uy;Feng Gao;Tasha Burton;Sharon E Heath;Feiyu Du;Shelly O'Laughlin;Robert Fulton;Zeina A. Al-Mansour;Christopher R. Cogle;Eric J Huselton;John F. DiPersio;Peter Westervelt;Mark A. Schroeder;Armin Ghobadi;Iskra Pusic;Keith Stockerl-Goldstein;Brad S. Kahl;Amanda F. Cashen - 通讯作者:
Amanda F. Cashen
Prospective Evaluation of the Impact of Measurable Residual Disease (MRD) By Error Corrected Next-Generation Sequencing (NGS) with CPX-351 in Acute Myeloid Leukemia (AML)
- DOI:
10.1182/blood-2024-205211 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
David Sallman;Amy F McLemore;Onyee Chan;Andrew T. Kuykendall;Eric Padron;Zhuoer Xie;Alison R. Walker;David H Spencer;Rami S. Komrokji;Jeffrey E Lancet;Meagan Jacoby - 通讯作者:
Meagan Jacoby
Assessment of T-Cell Receptor (TCR) Mediated T-Cell Activation in Acute Myeloid Leukemia at Diagnosis Has Implications for Risk Stratification and Response to Immune Checkpoint Inhibitors
- DOI:
10.1182/blood-2023-189573 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Nancy BJ Arthur;Agata Gruszczynska;Ma Xenia G Illagan;Michael Prinsen;Sharon E Heath;Tasha Burton;Victoria Donaldson;Cara Lunn Shirai;Eric J. Duncavage;Amanda F Cashen;Geoffrey L Uy;David H Spencer;Stephen M Sykes;Timothy J Ley;Francesca Ferraro - 通讯作者:
Francesca Ferraro
Clonal Myeloid Heterogeneity in Older Autopsy Patients Determined By Multiple Bone Marrow Site Sequencing
- DOI:
10.1182/blood-2022-162624 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Rohan Kodgule;Joshua Robinson;Sridhar Nonavinkere Srivatsan;Cara Lunn Shirai;Feiyu Du;Tianjiao Wang;Ajay Khanna;Catrina Fronick;Robert Fulton;David H Spencer;Matthew J Walter;Eric Duncavage - 通讯作者:
Eric Duncavage
Spatial Organization of Hematopoietic Clones in the Bone Marrow of a Patient with Polycythemia Vera
- DOI:
10.1182/blood-2022-167351 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Andrew L Young;Hannah C Davis;David H Spencer;Timothy J Ley;Stephen T Oh;Matthew J Walter;Grant A Challen - 通讯作者:
Grant A Challen
David H Spencer的其他文献
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{{ truncateString('David H Spencer', 18)}}的其他基金
Dysregulated genome architecture in acute myeloid leukemia
急性髓系白血病基因组结构失调
- 批准号:
10366725 - 财政年份:2022
- 资助金额:
$ 35.23万 - 项目类别:
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