Mutant p53 in pathogenesis of Myelodysplastic Syndromes

突变型 p53 在骨髓增生异常综合征发病机制中的作用

基本信息

批准号：
10592239
负责人：
Sergio Barajas
金额：
$ 4.33万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10592239
关键词：
Acute Myelocytic Leukemia Aging Alleles Apoptosis Biochemical Biological Biological Assay Cell Aging Cells Clonal Expansion Disease Dysmyelopoietic Syndromes EZH2 gene Elderly Epigenetic Process Exhibits Gene Expression Gene Mutation Genes Genetic Health Benefit Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Neoplasms Hematopoietic stem cells Histones Human Individual Inflammation Inflammatory Response Interleukin-1 beta Interleukin-6 Knowledge Life Literature Malignant Neoplasms Messenger RNA Modeling Molecular Mutant Strains Mice Mutate Mutation Outcome Pathogenesis Patients Prognosis Proliferating Protein Isoforms Publishing RNA Splicing Research Risk Role SRSF2 gene Somatic Mutation Spliceosomes TP53 gene Tumor Suppressor Genes aged cytokine in vivo inhibitor mRNA Precursor mutant novel novel therapeutic intervention pharmacologic prevent progression risk stem cells transcriptome sequencing

项目摘要

PROJECT SUMMARY Human aging is associated with an exponential increase in the occurrence of clonal hematopoiesis of indeterminate potential (CHIP), which is associated with an increased risk of hematologic neoplasms such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Somatic mutations in the tumor suppressor gene TP53 rank in the top five among genes mutated in CHIP. TP53 mutations are found in 10 to 15% of MDS patients and are associated with poor prognosis. We found that TP53 mutations identified in CHIP and MDS promote HSPC expansion and drive MDS pathogenesis during aging. However, the underlying mechanisms are largely unknown. Dysregulated pre-mRNA splicing has been implicated in human aging and MDS. Mutations in splicing factors are frequently found in CHIP and MDS. We found that mutant p53 alters pre-mRNA splicing in key regulators of inflammatory response during aging. Further, we found that mutant p53 cooperates with splicing factor mutations in pathogenesis of hematological malignancies. We hypothesize that mutant p53 drives the pathogenesis of MDS through altering pre-mRNA splicing in hematopoietic stem and progenitor cells (HSPCs) during aging. In this proposed research, we will utilize biochemical, genetic, molecular, and pharmacological approaches as well as vertebrate models to investigate the mechanisms by which mutant p53 drives MDS pathogenesis. We will determine the sensitivity of human MDS cells with TP53 mutations to spliceosome inhibitor treatment. Delineating the impact of dysregulated pre-mRNA splicing on aged HSPCs will fill a significant knowledge gap regarding the mechanisms by which TP53 mutations promote CHIP progression and drive MDS pathogenesis. The proposed research is highly significant because we will interrogate the role of the spliceosome as a novel potential target for treating MDS patients with TP53 mutations.

项目概要人类衰老与克隆造血发生率呈指数增加有关不确定电位（CHIP），与血液肿瘤风险增加相关，例如骨髓增生异常综合征（MDS）和急性髓系白血病（AML）。肿瘤中的体细胞突变抑制基因TP53在CHIP突变基因中排名前五。 TP53 突变存在于 10 至 15%的MDS患者与不良预后相关。我们发现 TP53 突变在 CHIP 和 MDS 在衰老过程中促进 HSPC 扩增并驱动 MDS 发病机制。然而，底层机制很大程度上是未知的。前 mRNA 剪接失调与人类衰老和 MDS。剪接因子突变常见于 CHIP 和 MDS。我们发现突变的p53改变了衰老过程中炎症反应关键调节因子中的前 mRNA 剪接。此外，我们发现突变体p53 与剪接因子突变共同参与血液恶性肿瘤的发病机制。我们假设突变型 p53 通过改变造血干细胞中的前体 mRNA 剪接驱动 MDS 的发病机制衰老过程中的祖细胞（HSPC）。在这项拟议的研究中，我们将利用生化、遗传、分子和药理学方法以及脊椎动物模型来研究其机制 p53 突变体驱动 MDS 发病机制。我们将用 TP53 测定人类 MDS 细胞的敏感性剪接体抑制剂治疗的突变。描述失调的前 mRNA 剪接对老化的 HSPC 将填补关于 TP53 突变促进机制的重大知识空白 CHIP 进展并驱动 MDS 发病机制。拟议的研究非常重要，因为我们将探讨剪接体作为治疗 TP53 MDS 患者的新潜在靶点的作用突变。