Experimental and preclinical modeling of NUP98-rearranged acute leukemia
NUP98重排急性白血病的实验和临床前模型
基本信息
- 批准号:10230529
- 负责人:
- 金额:$ 2.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-19 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAcute Erythroblastic LeukemiaAcute Myelocytic LeukemiaAcute leukemiaAddressBiochemicalBiological AssayC-terminalCell NucleusCellsChIP-seqChildhood Acute Myeloid LeukemiaChromatinChromatin StructureCoupledCouplingDiseaseDistalEpigenetic ProcessExhibitsExperimental ModelsFluorescenceFluorescence MicroscopyFluorescence Recovery After PhotobleachingFusion Oncogene ProteinsGelGene ExpressionGenesGenetic TranscriptionHOXA9 geneHematologic NeoplasmsHematopoieticIn VitroKnowledgeLengthLiquid substanceMediatingMethodsMolecularMutagenesisN-terminalNUP98 geneNeutronsNuclearNuclear Magnetic ResonanceNuclear Pore Complex ProteinsOncogenesOther GeneticsPhasePre-Clinical ModelPropertyProteinsRNARegulator GenesResolutionRoentgen RaysSiteStructureTestingTreatment outcomebiophysical techniquescell transformationcrosslinkgenetic regulatory proteingenome editinggenomic locusinsightleukemialeukemogenesismetaplastic cell transformationmicroscopic imagingoutcome forecastrecruitsingle moleculesubmicrontherapeutic developmenttranscriptome sequencingviscoelasticity
项目摘要
Project 3/Summary
NUP98 fusion oncogenes (e.g., NUP98-HOXA9, -KDM5A, and -NSD1) are associated with several
hematological malignancies, including pediatric acute myeloid leukemia (AML), characterized by dismal
treatment outcomes. The N-terminal FG-repeat domain that is common to all NUP98 fusion oncogenes
(termed NUP98-N) is known to be intrinsically disordered and, by itself, to undergo phase separation to form
gel-like bodies in vitro and large, spherical puncta in the nuclei of cells. However, these large puncta are not
associated with hematopoietic cell transformation and leukemogenesis. Importantly, NUP98 fusion
oncoproteins (FOs)—in which NUP98-N is fused to a variety of different C-terminal chromatin targeting
domains—form many chromatin-associated, sub-micron-sized puncta that are associated with aberrant gene
transcription, hematopoietic cell transformation and leukemogenesis. Recently, Young, et al., Tjian, et al., and
Rivera, et al., demonstrated that critical transcriptional regulators, i) exhibit disordered regions that undergo
phase separation in vitro and ii) are found within small, liquid-like puncta in cells that are proposed to form
through phase separation. These dynamic puncta are proposed to drive co-localization of distal chromatin sites
and organize the transcriptional machinery for coordinated expression of multiple genes. In the proposed
studies, we will test the hypothesis that phase separation is a unifying mechanism that drives the formation of
aberrant transcription centers by NUP98 FOs at chromatin sites targeted by their various C-terminal fused
domains. These aberrant transcription centers, we propose, recruit components of the transcriptional
machinery to activate expression of HOX and other genes and transform hematopoietic cells.
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项目3 /总结
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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RICHARD W KRIWACKI其他文献
RICHARD W KRIWACKI的其他文献
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{{ truncateString('RICHARD W KRIWACKI', 18)}}的其他基金
Understanding Phase Separation in Biology and Disease
了解生物学和疾病中的相分离
- 批准号:
10612409 - 财政年份:2019
- 资助金额:
$ 2.56万 - 项目类别:
Experimental and preclinical modeling of NUP98-rearranged acute leukemia
NUP98重排急性白血病的实验和临床前模型
- 批准号:
10228888 - 财政年份:2019
- 资助金额:
$ 2.56万 - 项目类别:
Understanding Phase Separation in Biology and Disease
了解生物学和疾病中的相分离
- 批准号:
10392404 - 财政年份:2019
- 资助金额:
$ 2.56万 - 项目类别:
The Molecular Basis of Liquid-like Structure of the Nucleolus
核仁液体状结构的分子基础
- 批准号:
8943482 - 财政年份:2015
- 资助金额:
$ 2.56万 - 项目类别:
The Molecular Basis of Liquid-like Structure of the Nucleolus
核仁液体状结构的分子基础
- 批准号:
9307879 - 财政年份:2015
- 资助金额:
$ 2.56万 - 项目类别:
The Molecular Basis of Liquid-like Structure of the Nucleolus
核仁液体状结构的分子基础
- 批准号:
9696544 - 财政年份:2015
- 资助金额:
$ 2.56万 - 项目类别:
The Molecular Basis of Liquid-like Structure of the Nucleolus
核仁液体状结构的分子基础
- 批准号:
9414888 - 财政年份:2015
- 资助金额:
$ 2.56万 - 项目类别:
Understanding the Structural Mechanism of Puma-induced Apoptosis
了解美洲狮诱导细胞凋亡的结构机制
- 批准号:
8231350 - 财政年份:2009
- 资助金额:
$ 2.56万 - 项目类别:
Understanding the Structural Mechanism of Puma-induced Apoptosis
了解美洲狮诱导细胞凋亡的结构机制
- 批准号:
7787004 - 财政年份:2009
- 资助金额:
$ 2.56万 - 项目类别:
Understanding the Structural Mechanism of Puma-induced Apoptosis
了解美洲狮诱导细胞凋亡的结构机制
- 批准号:
8037225 - 财政年份:2009
- 资助金额:
$ 2.56万 - 项目类别: