Mutant p53 in pathogenesis of Myelodysplastic Syndromes

项目摘要 人类衰老与克隆性造血发生的指数增加有关， 不确定的潜力（CHIP），这与血液肿瘤的风险增加有关， 骨髓增生异常综合征（MDS）和急性髓性白血病（AML）。肿瘤中的体细胞突变 抑制基因TP53在CHIP突变基因中居前5位。TP53突变在10至100例患者中发现， 15%的MDS患者与预后不良相关。我们发现，TP53突变在 CHIP和MDS促进HSPC扩增并驱动衰老过程中的MDS发病机制。然而，底层 机制在很大程度上是未知的。前体mRNA剪接失调与人类衰老有关， MDS。剪接因子的突变经常在CHIP和MDS中发现。我们发现突变型p53改变了 前体mRNA剪接在衰老过程中炎症反应的关键调节因子。此外，我们发现突变型p53 在血液恶性肿瘤的发病机制中与剪接因子突变协同作用。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， 祖细胞（HSPCs）在衰老过程中的作用。在这项研究中，我们将利用生物化学，遗传学， 分子和药理学方法以及脊椎动物模型来研究 突变型p53驱动MDS发病机制。我们将确定人MDS细胞对TP53的敏感性， 突变的剪接体抑制剂治疗。描述前体mRNA剪接失调对 老年HSPC将填补关于TP53突变促进细胞增殖的机制的重大知识空白。 CHIP进展和驱动MDS发病机制。这项研究非常重要，因为我们将 探讨剪接体作为TP 53治疗MDS患者的新的潜在靶点的作用 突变。

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.