Mutant p53 promotes clonal hematopoiesis by generating a chronic inflammatory microenvironment
Sisi Chen, et al.
Sisi Chen, et al.
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Research Article Hematology Inflammation

Mutant p53 promotes clonal hematopoiesis by generating a chronic inflammatory microenvironment

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

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Figure 2

p53 mutant HSPCs show increased NLRP1 activation.

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p53 mutant HSPCs show increased NLRP1 activation. (A) LSK cells were sub...
(A) LSK cells were subjected to ATAC-seq assays to identify differential regions of chromatin accessibility. Heatmap shows differential active regions in p53+/+ and p53R248W/+ LSKs. (B) Enriched biological processes of genes associated with significantly upregulated ATAC-seq peaks in p53R248W/+ LSKs analyzed by DAVID Functional Annotation Tool. (C) Enrichment of transcription factor (TF) motifs in peaks that gain open accessibility in p53R248W/+ LSKs compared with p53+/+ LSKs determined by HOMER de novo Known Motif Analysis. (D) Nlrp1a and Nlrp1b acquired significant open chromatin peaks in p53R248W/+ LSKs. (E) Nlrp1a and Nlrp1b were significantly upregulated in p53R248W/+ LSKs compared with p53+/+ LSKs; n = 3 biological replicates. (F) The level of Nlrp1b was increased in p53R248W/+ Lin− cells. (G) The levels of Nlrp1b and Nlrp3 in BM-derived macrophages following LPS stimulation were determined by immunoblotting. (H) GFP or p53R248W was introduced into Nlrp1+/+ and Nlrp1−/− Lin− BM cells using retrovirus. Transduced cells (GFP+) were differentiated into macrophages. Macrophages were stimulated with LPS (100 ng/mL) for 12 hours, and the levels of secreted cytokines and chemokines were assayed using a Cytokine/Chemokine array; n = 4 biological replicates. The comparison among multiple groups was evaluated with 1-way ANOVA (E and H). Statistical significance: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.