Friday, May 9, 2025
5/9/2025
Mutant p53 in pathogenesis of Myelodysplastic Syndromes - 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.
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