biostudies-literatureKent AUnited States - Israel Binational Science Foundation (BSF)Cancer Research UKNIAID NIH HHSRobert Wood Johnson Foundation (RWJF)U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)Division of Intramural Research, National Institute of Allergy and Infectious DiseasesDivision of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)Division of Cancer Prevention, National Cancer Institute (NCI Division of Cancer Prevention)United States - Israel Binational Science FoundationNIDDK NIH HHSMedical Research CouncilNCI NIH HHSDivision of Cancer Prevention, National Cancer InstituteWellcome TrustRobert Wood Johnson FoundationU.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases53-67https://www.ebi.ac.uk/biostudies/studies/S-EPMC7618359biostudies-literatureUnknown26(1)The inflammasome plays multifaceted roles in cancer, but less is known about its function during premalignancy upon initial cell transformation. We report a homeostatic function of the inflammasome in suppressing malignant transformation through Ras inhibition. We identified increased hematopoietic stem cell (HSC) proliferation within the bone marrow of inflammasome-deficient mice. HSCs within an inflammasome-deficient stroma expressed a Ras signature associated with increased Ras pathway- and cancer-related transcripts and heightened levels of cytokine, chemokine and growth factor receptors. Stromal inflammasome deficiency established a poised Ras-dependent mitogenic state within HSCs, which fueled progeny B cell lymphomagenesis upon Myc deregulation in a spontaneous model of B cell lymphoma, and shortened its premalignant stage leading to faster onset of malignancy. Thus, the stromal inflammasome preserves tissue balance by restraining Ras to disrupt the most common oncogenic Myc-Ras cooperation and establish a natural defense against transition to malignancy. These findings should inform preventative therapies against hematological malignancies.Nature immunologyA stromal inflammasome Ras safeguard against Myc-driven lymphomagenesis.PMC7618359T32 AI007605T32DK1169702021299A2921074260R21 AI15977229210R01 AI170832R01 AI170897AI159772F30 CA174313AI170897CC2229AI170832AI178327T32 DK116970T32AI007605R21 AI178327Yee Mon KJBarbet GPutzel GGrier AJia BEvan GIKortlever RMZhigarev DBlander JMKent AHutchins ZfalseA stromal inflammasome Ras safeguard against Myc-driven lymphomagenesis.The inflammasome plays multifaceted roles in cancer, but less is known about its function during premalignancy upon initial cell transformation. We report a homeostatic function of the inflammasome in suppressing malignant transformation through Ras inhibition. We identified increased hematopoietic stem cell (HSC) proliferation within the bone marrow of inflammasome-deficient mice. HSCs within an inflammasome-deficient stroma expressed a Ras signature associated with increased Ras pathway- and cancer-related transcripts and heightened levels of cytokine, chemokine and growth factor receptors. Stromal inflammasome deficiency established a poised Ras-dependent mitogenic state within HSCs, which fueled progeny B cell lymphomagenesis upon Myc deregulation in a spontaneous model of B cell lymphoma, and shortened its premalignant stage leading to faster onset of malignancy. Thus, the stromal inflammasome preserves tissue balance by restraining Ras to disrupt the most common oncogenic Myc-Ras cooperation and establish a natural defense against transition to malignancy. These findings should inform preventative therapies against hematological malignancies.2025-01-01T00:00:00Z2025 Jan2026-06-05T16:38:10.664Z2026-06-05T03:06:16.574ZS-EPMC76183593974743310.1038/s41590-024-02028-z