Aging drives Tet2(+/−) clonal hematopoiesis via IL-1 signaling

Clonal hematopoiesis of indeterminate potential (CHIP), also referred to as aging-related clonal hematopoiesis, is defined as an asymptomatic clonal expansion of mutant mature hematopoietic cells in ≥4% of blood leukocytes. CHIP associates with advanced age and increased risk for hematological malignancy, cardiovascular disease, and all-cause mortality. Loss-of-function somatic mutations in TET2 are frequent drivers of CHIP. However, the contribution of aging-associated cooperating cell-extrinsic drivers, like inflammation, remains underexplored. Using bone marrow (BM) transplantation and newly developed genetic mosaicism (HSC-SCL-Cre-ER(T); Tet2(+/flox); R26(+/tm6[CAG-ZsGreen1]Hze)) mouse models of Tet2(+/−)driven CHIP, we observed an association between increased Tet2(+/−) clonal expansion and higher BM levels of the inflammatory cytokine interleukin-1 (IL-1) upon aging. Administration of IL-1 to mice carrying CHIP led to an IL-1 receptor 1 (IL-1R1)–dependent expansion of Tet2(+/−) hematopoietic stem and progenitor cells (HSPCs) and mature blood cells. This expansion was caused by increased Tet2(+/−) HSPC cell cycle progression, increased multilineage differentiation, and higher repopulation capacity compared with their wild-type counterparts. In agreement, IL-1α–treated Tet2(+/−) hematopoietic stem cells showed increased DNA replication and repair transcriptomic signatures and reduced susceptibility to IL-1α–mediated downregulation of self-renewal genes. More important, genetic deletion of IL-1R1 in Tet2(+/−) HPSCs or pharmacologic inhibition of IL-1 signaling impaired Tet2(+/−) clonal expansion, establishing the IL-1 pathway as a relevant and therapeutically targetable driver of Tet2(+/−) CHIP progression during aging.