Mutant p53 promotes clonal hematopoiesis by generating a chronic inflammatory microenvironment

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.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-12-30
DOI
https://doi.org/10.1172/jci184285
Citations
1
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
1.77

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Mutant p53 promotes clonal hematopoiesis by generating a chronic inflammatory microenvironment

M. V. Shumilina, Yasmin Abaza, Sophie Hu, Omar Abdel‐Wahab et al.
1 citations
Journal of Clinical Investigation
Acute Myeloid Leukemia Research
1.77
article

Mutant p53 promotes clonal hematopoiesis by generating a chronic inflammatory microenvironment

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

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.

Journal of Clinical InvestigationVol. 136(3)
Northwestern University (US), University of Southern California (US), Pennsylvania State University (US), Memorial Sloan Kettering Cancer Center (US), Walter and Eliza Hall Institute of Medical Research (AU), Peking University (CN), Yale Cancer Center (US), University of California San Diego (US), Indo-American Center (US), Chongqing Three Gorges Central Hospital (CN), Jesse Brown VA Medical Center (US), National Cancer Institute (US), Shanghai Children's Hospital (CN), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Division of Cancer Epidemiology and Genetics, Indiana University School of Medicine, Chongqing Three Gorges University (CN), Indiana University – Purdue University Indianapolis (US)
Northwestern University, Feinberg School of Medicine, School of Medicine, Indiana University, Robert H. Lurie Comprehensive Cancer Center, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 10%
Acute Myeloid Leukemia Research
1.77
DOIOpen Access PDFOpenAlex
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