Transcriptional and epigenetic reprogramming mediated by chronic IL1ß exposure drives self-renewal ability and myeloid priming in TET2 deficient stem and progenitor cells [10x_scRNAseq]

Clonal hematopoiesis (CH) increases risk for the development of hematological malignancy and cardiovascular disease. IL1ß is elevated in patients with CH and its inhibition mitigates cardiovascular risk in murine models with Tet2 loss-of-function. How IL1ß alters population dynamics of hematopoietic cells upon Tet2 deletion (Tet2-KO) is not well understood. We demonstrated IL1ß expands Tet2-KO neutrophils, monocytes/macrophages, and long-term hematopoietic stem cells with reduced lymphopoiesis. IL1ß promotes myeloid bias over other lineages coinciding with failure to demethylate lineage associated enhancer and transcription factor binding sites in Tet2-KO HSPCs. IL1ß enhanced self-renewal ability of Tet2-KO HSPCs by upregulating genes associated with self-renewal potential and by failure to demethylate binding sites of transcription factors promoting differentiation. IL1ß-mediated premalignant phenotype is reversed by IL1ß 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. Overall design: High throughput single cell RNA sequencing (10x scRNA-seq) was performed for lineage depleted bone marrow cells (Lin-ve BM) isolated from Tet2 wild type (WT) or knockout (KO) animals that were treated with either recombinant IL-1ß or vehicle for five weeks prior to collection. In total four biological replicates were performed for each genotype/ treatment condition (16 Lin- BM samples from 16 animals).