Interrogating the minor spliceosome to understand and treat leukemia

研究小剪接体以了解和治疗白血病

基本信息

  • 批准号:
    10434705
  • 负责人:
  • 金额:
    $ 64.6万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-03 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

SUMMARY Genes encoding RNA splicing factors are the most common class of mutations in patients with myelodysplastic syndromes (MDS) and are also common across all other forms of myeloid malignancies. These leukemia- associated “spliceosomal mutations” primarily occur in four genes: SF3B1, SRSF2, U2AF1, and ZRSR2. In three of these four genes (SF3B1, SRSF2, and U2AF1), the mutations occur at specific amino acid residues in a heterozygous manner (so-called “mutational hotspots”) and cause gain/alteration of function. In contrast, mutations in ZRSR2 occur throughout the open reading frame and appear to confer loss of function. Moreover, ZRSR2's normal function makes it unique amongst the commonly mutated RNA splicing factors in leukemias: ZRSR2 is the only frequently mutated factor that primarily functions in the recognition of a rare class of introns known as “minor introns.” Thus, ZRSR2 mutations are significantly enriched in leukemia and exhibit a unique genetic spectrum and function amongst recurrent spliceosomal mutations, yet they are comparatively poorly studied and understood compared to mutations in SF3B1, SRSF2, and U2AF1. Here, we propose to determine the mechanistic, functional, and therapeutic consequences of ZRSR2 mutations in leukemia. Our interdisciplinary team consists of a physician-scientist with expertise in leukemia biology and patient care (Abdel-Wahab) and a basic scientist with expertise in RNA splicing and functional genomics (Bradley). As minor introns are far more conserved than are most other introns, we hypothesize that a cross-species comparisons of the effects of ZRSR2 loss will be particularly useful for understanding how molecular alterations in splicing drive malignant transformation. In addition, we hypothesize that aberrant splicing induced by ZRSR2 loss will enable novel therapeutic approaches. In preliminary experiments, we generated a Zrsr2 conditional knockout (cKO) mouse, assembled a relevant patient cohort, characterized the transcriptomes of our Zrsr2 cKO mouse and ZRSR2-mutant MDS, and performed a functional genomic screen to model and prioritize ZRSR2-regulated splicing events. These studies revealed that ZRSR2 mutations cause mis-splicing of a compact set of genes, that Zrsr2 loss promotes aberrant and increased hematopoietic stem cell self-renewal, that simultaneous ZRSR2 and TET2 collaborate to drive malignancy, and that mis-splicing of specific downstream targets of ZRSR2 promotes clonality. We propose to build on these preliminary studies as follows: Aim 1, Determine how ZRSR2 mutations dysregulate the transcriptome and proteome in leukemia; Aim 2, Determine how disruption of ZRSR2-regulated splicing events drives clonal advantage; Aim 3, Identify the functional basis for the frequent co-occurrence of ZRSR2 and TET2 mutations in leukemia. The significance of these studies is that they will elucidate mechanistic and functional connections between ZRSR2 mutations, RNA mis-splicing, and the initiation of myeloid neoplasms. The health relatedness is that the proposed work may reveal new therapies for MDS and leukemia that specifically kill ZRSR2-mutant cells.
总结

项目成果

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Omar Abdel-Wahab其他文献

Omar Abdel-Wahab的其他文献

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{{ truncateString('Omar Abdel-Wahab', 18)}}的其他基金

Synthetic introns for selective targeting of RNA splicing factor-mutant leukemia
用于选择性靶向RNA剪接因子突变型白血病的合成内含子
  • 批准号:
    10722782
  • 财政年份:
    2023
  • 资助金额:
    $ 64.6万
  • 项目类别:
Charting the differentiation topology of SF3B1 mutated clonal hematopoiesis (CH) and myelodysplastic syndromes (MDS) via a multi-omics single-cell toolkit
通过多组学单细胞工具包绘制 SF3B1 突变克隆造血 (CH) 和骨髓增生异常综合征 (MDS) 的分化拓扑图
  • 批准号:
    10570240
  • 财政年份:
    2022
  • 资助金额:
    $ 64.6万
  • 项目类别:
Charting the differentiation topology of SF3B1 mutated clonal hematopoiesis (CH) and myelodysplastic syndromes (MDS) via a multi-omics single-cell toolkit
通过多组学单细胞工具包绘制 SF3B1 突变克隆造血 (CH) 和骨髓增生异常综合征 (MDS) 的分化拓扑图
  • 批准号:
    10366517
  • 财政年份:
    2022
  • 资助金额:
    $ 64.6万
  • 项目类别:
Project 3: Therapeutic inhibition of splicing through inhibition of protein arginine methylation in leukemia
项目3:通过抑制白血病中蛋白质精氨酸甲基化来治疗性抑制剪接
  • 批准号:
    10474285
  • 财政年份:
    2021
  • 资助金额:
    $ 64.6万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10474262
  • 财政年份:
    2021
  • 资助金额:
    $ 64.6万
  • 项目类别:
Career Enhancement Program
职业提升计划
  • 批准号:
    10474318
  • 财政年份:
    2021
  • 资助金额:
    $ 64.6万
  • 项目类别:
The Memorial Sloan Kettering Cancer Center SPORE in Leukemia
纪念斯隆凯特琳癌症中心 SPORE 白血病
  • 批准号:
    10474261
  • 财政年份:
    2021
  • 资助金额:
    $ 64.6万
  • 项目类别:
Targeting an RNA Binding Protein Network in Acute Myeloid Leukemia
靶向急性髓系白血病中的 RNA 结合蛋白网络
  • 批准号:
    10171812
  • 财政年份:
    2020
  • 资助金额:
    $ 64.6万
  • 项目类别:
Interrogating the minor spliceosome to understand and treat leukemia
研究小剪接体以了解和治疗白血病
  • 批准号:
    10210368
  • 财政年份:
    2020
  • 资助金额:
    $ 64.6万
  • 项目类别:
Interrogating the minor spliceosome to understand and treat leukemia
研究小剪接体以了解和治疗白血病
  • 批准号:
    10669013
  • 财政年份:
    2020
  • 资助金额:
    $ 64.6万
  • 项目类别:
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