The transcriptional and epigenetic reprogramming mediated by chronic IL1β exposure drives self-renewal ability and myeloid priming in TET2 deficient stem and progenitor cells

Clonal hematopoiesis (CH) increases risk for the development of hematological malignancy and cardiovascular disease. IL1β is elevated in patients with CH and its inhibition mitigates cardiovascular risk in murine models with Tet2 loss-of-function. How IL1β alters population dynamics of hematopoietic cells upon Tet2 deletion (Tet2-KO) is not well understood. We demonstrated IL1β expands Tet2-KO neutrophils, monocytes/macrophages, and long-term hematopoietic stem cells with reduced lymphopoiesis. IL1β promoted myeloid bias over other lineages of Tet2-KO HSPCs coinciding with failure to demethylate lineage associated enhancer and transcription factor binding sites. IL1β enhanced the self-renewal ability of Tet2-KO HSPCs by upregulating genes associated with self-renewal potential and by resisting demethylation of binding sites of transcription factors promoting terminal differentiation. IL1β-mediated premalignant phenotype is reversed by IL1β antagonist anakinra or deletion of the Il1 receptor, in vivo. Our results demonstrated that targeting IL-1 signaling could be an efficient early intervention strategy in preleukemic disorders.