Mutant p53 promotes clonal hematopoiesis by generating a chronic inflammatory microenvironment

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Somatic TP53 mutations are linked to clonal hematopoiesis (CH) and increased risk of myeloid neoplasms in aging individuals.
• The precise mechanisms driving this progression remain incompletely understood.

Purpose of the Study:

• To elucidate the role of inflammatory stress and mutant TP53 in the pathogenesis of CH.
• To investigate the potential of targeting inflammatory pathways to prevent the development of myeloid neoplasms.

Main Methods:

• Analysis of hematopoietic stem and progenitor cells (HSPCs) from aged individuals with TP53 mutations.
• Assessment of NLRP1 inflammasome activation, cytokine secretion (IL-1β, IL-6), and NF-κB signaling.
• Inhibition of IL-1β signaling using neutralizing antibodies and gasdermin D (GSDMD) inhibitors.

Main Results:

• Inflammatory stress provides a competitive advantage to p53 mutant HSPCs.
• Mutant p53 dysregulates pre-mRNA splicing, leading to chronic inflammation via enhanced IL-1β and IL-6 secretion.
• Paracrine inhibition of wild-type (WT) HSPC fitness by pro-inflammatory cytokines.
• Blocking IL-1β or inhibiting IL-1β secretion reduced the fitness of p53 mutant HSPCs.

Conclusions:

• Mutant TP53 plays a critical role in orchestrating inflammatory signaling within the bone marrow microenvironment during CH.
• Targeting inflammation, specifically IL-1β, presents a potential therapeutic strategy to mitigate the progression of TP53-mutant CH to myeloid neoplasms.