The transcriptional and epigenetic reprogramming associated with chronic IL1β-mediated expansion and myeloid priming in TET2 deficient stem and progenitor cells

Clonal hematopoiesis (CH) increases the 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 monocytes/macrophages, and long-term hematopoietic stem cells. IL1β promoted myeloid bias over other lineages of Tet2 -KO HSPCs coinciding with the 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 and by resisting the demethylation of binding sites of transcription factors promoting terminal differentiation. The IL1β-mediated premalignant phenotype is suppressed by the IL1β antagonist or deletion of the IL1 receptor-1, in vivo in aged mice. Our results demonstrate that targeting IL1 signaling could be an efficient early intervention strategy in preleukemic disorders. STATEMENT OF SIGNIFICANCE IL1β promoted myeloid expansion and self-renewal capacity of TET2-null pre-leukemic cells. Lineage bias occurred early within progenitors towards pro-inflammatory macrophages. Genes specific to aging and with roles in promoting self-renewal capacity, and myeloid bias were upregulated. Hypermethylation occurred within lymphoid and erythroid lineage-specific regulatory elements. Targeting IL1R1 reduced aberrant myeloid bias and premalignant phenotype. ### Competing Interest Statement The authors have declared no competing interest.