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

• 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
• 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

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.

项目摘要 人类衰老与克隆造血的发生指数增加有关 不确定的电位（芯片），这与血液学肿瘤的风险增加有关 骨髓增生综合征（MDS）和急性髓样白血病（AML）。肿瘤中的体细胞突变 抑制剂基因TP53在芯片突变的基因中排名前五。 TP53突变在10至 15％的MDS患者与预后不良有关。我们发现TP53突变在 CHIP和MDS促进HSPC的扩展，并在衰老期间驱动MDS发病机理。但是，基础 机制在很大程度上未知。失调的前MRNA剪接与人类衰老有关 MDS。剪接因子中的突变经常在芯片和MD中发现。我们发现突变体p53改变了 衰老过程中炎症反应的关键调节剂中的mRNA剪接。此外，我们发现突变体p53 与剪接因子突变合作在血液系统恶性肿瘤的发病机理中。我们假设这一点 突变体p53通过改变造血茎中的MDS剪接来驱动MD的发病机理 衰老期间的祖细胞（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，以研究通过 突变p53驱动MDS发病机理。我们将确定人类MDS细胞对TP53的敏感性 剪接抑制剂治疗的突变。描述了失调的前MRNA剪接对的影响 老化的HSPC将填补有关TP53突变促进的机制的显着知识差距 芯片进展并驱动MDS发病机理。拟议的研究非常重要，因为我们将 询问剪接体作为治疗TP53患者的新型潜在靶标的作用 突变。