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.
摘要 编码RNA剪接因子的基因是骨髓增生异常患者中最常见的一类突变 综合征(MDS)和在所有其他形式的髓系恶性肿瘤中也很常见。这些白血病- 相关的“剪接体突变”主要发生在四个基因中:SF3B1、SRSF2、U2AF1和ZRSR2。在……里面 这四个基因中的三个(SF3B1、SRSF2和U2AF1),突变发生在 一种杂合的方式(所谓的“突变热点”),并导致功能的增加/改变。相比之下, ZRSR2的突变发生在整个开放阅读框架中,并似乎导致功能丧失。此外, ZRSR2的S正常功能使其在白血病常见的突变核糖核酸剪接因子中独一无二: ZRSR2是唯一一个主要在识别一类罕见内含子中起作用的频繁突变因子 被称为“小内含子”。因此,ZRSR2突变在白血病中显著丰富,并表现出独特的 反复发生的剪接体突变的遗传谱和功能,但它们相对较差 与SF3B1、SRSF2和U2AF1的突变相比,学习和理解。 在这里,我们建议确定ZRSR2的机制、功能和治疗后果 白血病的突变。我们的跨学科团队由一位在白血病方面有专长的内科科学家组成。 生物学和病人护理(Abdel-Wahab)和一名在RNA剪接和功能方面有专长的基础科学家 基因组学(布拉德利)。由于较小的内含子比大多数其他内含子保守得多,我们假设 对ZRSR2缺失的影响进行跨物种比较将特别有助于理解 剪接过程中的分子变化会导致恶性转化。此外,我们假设这一反常现象 ZRSR2缺失引起的剪接将使新的治疗方法成为可能。在初步实验中,我们 产生了一只Zrsr2条件基因敲除(CKO)小鼠,组装了相关的患者队列,表征了 我们的ZRSR2 CKO小鼠和ZRSR2突变的MDS的转录本,并进行了功能基因组筛选 对ZRSR2调控的剪接事件进行建模和优先排序。这些研究表明,ZRSR2突变会导致 一组紧凑基因的错误拼接,即Zrr2缺失促进了造血干细胞的异常和增加 细胞自我更新,同时ZRSR2和TET2协同推动恶性肿瘤,以及错接 ZRSR2的特定下游目标促进克隆性。我们建议在这些初步研究的基础上, 目的:1、研究ZRSR2基因突变对白血病转录组和蛋白质组的影响; 目标2,确定ZRSR2调控的剪接事件的中断如何推动克隆优势;目标3,确定 白血病中ZRSR2和TET2突变频繁并存的功能基础这个 这些研究的意义在于,它们将阐明 ZRSR2突变、RNA错误剪接和髓系肿瘤的发生。与健康相关的是 这项拟议的工作可能会揭示治疗MDS和白血病的新疗法,这种疗法可以特异性地杀死ZRSR2突变细胞。

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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