The Role of Mutant P53 in the Pathogenesis of Myelodysplastic Syndromes

Abstract

Human aging is associated with the development of clonal hematopoiesis of indeterminate potential (CHIP), which increases the risk of hematologic neoplasms such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Somatic mutations in the tumor suppressor gene TP53 are found in 10-15% of MDS patients and are associated with poor prognosis and reduced survival. TP53 mutations promote clonal expansion and drive MDS pathogenesis during aging. However, extrinsic factors contributing to the progression of p53 mutant clonal hematopoiesis to MDS remain unknown. We discovered that chronic inflammation provides a competitive growth advantage to p53 mutant hematopoietic stem and progenitor cells (HSPCs) through activating the NLRP1 inflammasome, leading to increased secretion of pro-inflammatory cytokines such as IL-1β and IL-6 from p53 mutant HSPCs, thereby generating a pro-inflammatory microenvironment that negatively affects the fitness of wild-type HSPCs in a paracrine manner. Furthermore, we found that approximately 60% of p53R248W/+ mice develop MDS with age and exhibit elevated levels of IL-1β and IL-6 in their bone marrow (BM). Similarly, increased levels of IL-1β and IL-6 were observed in the BM of MDS or AML patients with TP53 mutations. Mechanistically, mutant p53 dysregulates pre-mRNA splicing in key regulators of the inflammatory response in HSPCs, such as IKBKE and USP15, leading to enhanced NF-κB activation and increased secretion of pro-inflammatory cytokines in the BM of middle-aged p53 mutant mice. Moreover, we discovered that TP53 and SRSF2 mutations cooperate in accelerating the development of hematologic malignancies, possibly through convergent effects on the NF-κB pathway. Thus, we demonstrate that chronic inflammation and aberrant pre-mRNA splicing contribute to the progression of p53 mutant clonal hematopoiesis to MDS. Notably, blocking IL-1β or inhibiting gasdermin D (GSDMD) maturation reduces the fitness of mutant p53 HSPCs, suggesting that IL-1β and GSDMD are potential therapeutic targets for TP53 mutated CHIP and myeloid neoplasms.