Mutant p53 promotes clonal hematopoiesis by generating a chronic inflammatory microenvironment

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Abstract

Older 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 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 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 CH to myeloid neoplasms.

Authors

Sisi Chen, Sergio Barajas, Sasidhar Vemula, Yuxia Yang, Ed Simpson, Hongyu Gao, Rudong Li, Farzaneh Behzadnia, Sarah C. Nabinger, David A. Schmitz, Hongxia Chen, Wenjie Cai, Shiyu Xiao, Ruyue Luo, Mohammed Abdullahel Amin, Maegan L. Capitano, James P. Ropa, Aidan Fahey, Shuyi Zhou, Tiffany M. Mays, Magdalena Sotelo, Hao Pan, Sophie K. Hu, Sophia Veranga, Moiez Ali, Maria Shumilina, Reuben Kapur, Kehan Ren, Yuzhi Jia, Huiping Liu, Irum Khan, Yasmin Abaza, Jessica K. Altman, Elizabeth A. Eklund, Lucy A. Godley, Christine R. Zhang, Peng Ji, Seth L. Masters, Ben A. Croker, H. Scott Boswell, George E. Sandusky, Zhonghua Gao, Lindsey D. Mayo, Sharon A. Savage, Stephanie Halene, Yali Dou, Leonidas C. Platanias, Madina Sukhanova, Yunlong Liu, Omar Abdel-Wahab, Yan Liu