Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations

U2AF1 突变诱导的骨髓增生异常的分子基础

基本信息

  • 批准号:
    10649974
  • 负责人:
  • 金额:
    $ 58.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-15 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

Title: Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations Abstract Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by cytopenia and dysplasia of myeloid linage cells with an increased risk of transformation to acute myeloid leukemia. Current therapies are inadequate to treat MDS. This underscores a need to better understand the molecular mechanism of MDS and identify new therapeutic targets in MDS. Mutations in the genes encoding RNA splicing factors (U2AF1, SRSF2, SF3B1 or ZRSR2) are frequently observed in MDS. U2AF1 is involved in the recognition of the 3’ splice site required for recruitment of the U2 snRNP during pre-mRNA splicing. U2AF1 mutations have been identified in ~11% cases of MDS. However, the functional roles of U2AF1 mutations in MDS and the mechanism by which U2AF1 mutations contribute to MDS pathogenesis remain unclear. To determine the roles of mutant U2AF1 in MDS, we have generated a novel conditional U2AF1-Q157R knock-in mouse. In preliminary studies, we have observed that hematopoietic expression of U2AF1-Q157R mutant results in a macrocytic anemia, erythroid dysplasia and expansion of hematopoietic stem cells (HSC) in the bone marrow. We also have observed that concurrent loss of EZH2 and expression of U2AF1-Q157R mutant promotes rapid progression of MDS. We hypothesize that U2AF1 mutations trigger RNA splicing alterations, gene expression changes, DNA damage and replication stress in HSPC leading to aberrant hematopoiesis, and U2AF1 mutations cooperate with epigenetic regulator mutations in the progression of MDS. To test our hypothesis, we propose three Specific Aims. In Aim 1, we will investigate the consequences of U2AF1-Q157R mutation and underlying molecular mechanisms in myelodysplasia. In Aim 2, we will determine the biological and molecular basis for synergy between U2AF1 mutations and co-occurring epigenetic regulator mutations in the pathogenesis of MDS. In Aim 3, we will identify and test therapeutic strategies for U2AF1 mutant MDS. Results from these studies will provide new insights into the molecular pathogenesis of MDS and may lead to new therapeutic approach for treatment of MDS.
题目:U2AF1突变诱导骨髓发育不良的分子基础

项目成果

期刊论文数量(0)
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Golam Mohi其他文献

Golam Mohi的其他文献

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{{ truncateString('Golam Mohi', 18)}}的其他基金

Targeting of IL-1 Signaling in Myelofibrosis
骨髓纤维化中 IL-1 信号传导的靶向
  • 批准号:
    10657996
  • 财政年份:
    2023
  • 资助金额:
    $ 58.14万
  • 项目类别:
The Role of PTPN11 in Myelofibrosis
PTPN11 在骨髓纤维化中的作用
  • 批准号:
    10077888
  • 财政年份:
    2020
  • 资助金额:
    $ 58.14万
  • 项目类别:
The Role of PTPN11 in Myelofibrosis
PTPN11 在骨髓纤维化中的作用
  • 批准号:
    10324574
  • 财政年份:
    2020
  • 资助金额:
    $ 58.14万
  • 项目类别:
The Role of PTPN11 in Myelofibrosis
PTPN11 在骨髓纤维化中的作用
  • 批准号:
    10545076
  • 财政年份:
    2020
  • 资助金额:
    $ 58.14万
  • 项目类别:
Efficacy of Allosteric SHP2 Inhibitor in RAS Mutant-Driven Myeloid Neoplasms
变构 SHP2 抑制剂在 RAS 突变驱动的骨髓肿瘤中的疗效
  • 批准号:
    9815636
  • 财政年份:
    2019
  • 资助金额:
    $ 58.14万
  • 项目类别:
Targeting of Tyrosine Phosphatase SHP2 in Myeloproliferative Neoplasms
酪氨酸磷酸酶 SHP2 在骨髓增生性肿瘤中的靶向作用
  • 批准号:
    9025334
  • 财政年份:
    2015
  • 资助金额:
    $ 58.14万
  • 项目类别:
Inhibition of Histone Deacetylase in Myeloproliferative Neoplasms
骨髓增殖性肿瘤中组蛋白脱乙酰酶的抑制
  • 批准号:
    8210891
  • 财政年份:
    2011
  • 资助金额:
    $ 58.14万
  • 项目类别:
Efficacy of Histone Deacetylase Inhibitor Vorinostat in Myeloproliferative Neopla
组蛋白脱乙酰酶抑制剂伏立诺他在骨髓增生性肿瘤中的疗效
  • 批准号:
    8049817
  • 财政年份:
    2011
  • 资助金额:
    $ 58.14万
  • 项目类别:
Role of JAK2V617F in the Pathogenesis of Myeloproliferative Neoplasms
JAK2V617F 在骨髓增生性肿瘤发病机制中的作用
  • 批准号:
    9566613
  • 财政年份:
    2009
  • 资助金额:
    $ 58.14万
  • 项目类别:
Role of JAK2V617F in the Pathogenesis of Myeloproliferative Disorders.
JAK2V617F 在骨髓增殖性疾病发病机制中的作用。
  • 批准号:
    8043588
  • 财政年份:
    2009
  • 资助金额:
    $ 58.14万
  • 项目类别:

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  • 批准号:
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    2023
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  • 财政年份:
    2021
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Uncovering Mechanisms of 5' Splice Site Fidelity
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Mechanism of Splice Site Recognition by the U2AF/SF1 Protein Complex
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How do RNA-binding proteins control splice site selection?
RNA 结合蛋白如何控制剪接位点选择?
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Mechanisms of Splice Site Selection in Health and Disease
健康和疾病中剪接位点选择的机制
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  • 财政年份:
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  • 资助金额:
    $ 58.14万
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