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

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. 1
项目3 /总结

项目成果

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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:
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