3137 - IL-1 Drives Clonal Hematopoiesis via Selective Induction of Growth Arrest in Normal HSC

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) results from selective expansion (>0.02% VAF) of hematopoietic clones carrying loss-of-function mutations in key epigenetic and transcriptional regulators such as TET2, ASXL1 and TP53. CHIP is a critical risk factor for myeloid malignancy, coronary heart disease and all-cause mortality. CHIP occurs primarily in settings of chronic inflammation and tissue decline, suggesting that inflammation in the bone marrow (BM) may act as a selective force that favors mutant hematopoietic clones. Interleukin (IL)-1 is a pro-inflammatory cytokine commonly overproduced by senescent and/or damaged cells and may be a candidate driver of CHIP. Here, we show that chronic IL-1 beta stimulation in vivo in mice induces a growth arrest gene program, characterized by broad repression of protein synthesis, cell metabolism and proliferation pathways, and concurrent activation of cell cycle inhibitors, hence leading to LT-HSC quiescence and delayed cell cycle re-entry during chronic IL-1 exposure. Strikingly, this gene program is selectively induced in IL-1-exposed HSC expressing high protein levels of the myeloid transcription factor PU.1. Notably, we find that LT-HSC from chronic IL-1-exposed tamoxifen-inducible, hematopoietic specific SCL-CreERT::Tet2+/- and Tet2-/- (Tet2-deficient) mice incompletely activate the growth arrest program. To test whether IL-1 is required to confer a competitive advantage on Tet2-deficient cells in vivo, we generated WT:Tet2-deficient BM chimeric mice using a low-inflammation conditioning approach. Strikingly, Tet2-deficient cells exhibited preferential expansion in recipient mice exclusively in the presence of chronic IL-1 beta treatment. We are now interrogating the dependence of clonal expansion on PU.1 expression in WT cells, and whether IL-1 blockade and/or depletion of senescent cells reverses Tet2-deficient HSC expansion. Collectively, our study may provide a basis for redefining CHIP as a potentially reversible process of somatic evolution that is driven by chronic IL-1 production and BM inflammation.