Mutant p53 promotes clonal hematopoiesis through generating a chronic inflammatory microenvironment
- Author(s)
- Chen, S; Barajas, S; Vemula, S; Yang, Y; Simpson, E; Gao, H; Li, R; Behzadnia, F; Nabinger, SC; Schmitz, DA; Chen, H; Cai, W; Xiao, S; Luo, R; Amin, MA; Capitano, ML; Ropa, JP; Fahey, A; Zhou, S; Mays, TM; Sotelo, M; Pan, H; Hu, SK; Veranga, S; Ali, M; Shumilina, M; Kapur, R; Ren, K; Jia, Y; Liu, H; Khan, I; Abaza, Y; Altman, JK; Eklund, EA; Godley, LA; Zhang, CR; Ji, P; Masters, SL; Croker, BA; Boswell, HS; Sandusky, GE; Gao, Z; Mayo, LD; Savage, SA; Halene, S; Dou, Y; Platanias, LC; Sukhanova, M; Liu, Y; Abdel-Wahab, O; Liu, Y;
- Journal Title
- Journal of Clinical Investigation
- Publication Type
- Dec 30
- Abstract
- Aged individuals with somatic TP53 mutations manifest clonal hematopoiesis (CH) and are at high risk of developing myeloid neoplasms. However, the underlying mechanisms are not fully understood. Here we show that inflammatory stress confers a competitive advantage to p53 mutant hematopoietic stem and progenitor cells (HSPCs) by activating the NLRP1 inflammasome and increasing the secretion of pro-inflammatory cytokines such as IL-1β, inhibiting wild type (WT) HSPC fitness in a paracrine fashion. During aging, mutant p53 dysregulates pre-mRNA splicing in HSPCs, leading to enhanced NF-κB activation and increased secretion of IL-1β and IL-6, thereby generating a chronic inflammatory bone marrow microenvironment. Furthermore, blocking IL-1β with IL-1β neutralizing antibody or inhibiting IL-1β secretion using gasdermin D (GSDMD) inhibitor decreases the fitness of p53 mutant HSPCs. Thus, our findings uncover an important role for mutant p53 in regulating inflammatory signaling in CH and suggest that curbing inflammation may prevent the progression of TP53-mutant clonal hematopoiesis to myeloid neoplasms.
- Publisher
- ASCi
- Keywords
- Cytokines; Hematology; Hematopoietic stem cells; Inflammation; NF-kappaB
- Research Division(s)
- Inflammation
- PubMed ID
- 41468163
- Publisher's Version
- https://doi.org/10.1172/jci184285
- Open Access at Publisher's Site
https://doi.org/10.1172/JCI184285- Terms of Use/Rights Notice
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Creation Date: 2026-01-22 09:59:55
Last Modified: 2026-01-22 10:03:26