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

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP), also referred to as aging-related clonal hematopoiesis (ARCH), is defined as an asymptomatic clonal expansion of mutant mature hematopoietic cells over 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 under-explored. Using bone marrow (BM) transplantation and newly developed genetic mosaicism (HSC-SCL-Cre-ERT; 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 IL-1 upon aging. Administration of IL-1 to mice carrying CHIP led to an 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 to their WT counterparts. In agreement, IL-1α-treated Tet2+/- HSCs showed increased DNA replication and repair transcriptomic signatures and reduced susceptibility to IL-1α-mediated downregulation of self-renewal genes. Importantly, genetic deletion of IL-1R1 in Tet2+/- HPSC or pharmacological 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.

Biomarkers of aging

“…The age-dependent elevation of secretory factors, such as IFN-γ and TNFα, promote DNMT3a-mutant HSC expansion and leads to CH (Hormaechea-Agulla et al, 2021;Liao et al, 2022). Consistent with this finding, another study reveals that aging drives Tet2 +/− CH via IL-1 signaling in aged mice (Caiado et al, 2023). Together, these observations point out the translational value of targeting secretory factors to treat age-dependent myeloid malignancies.…”

“…Increase in chronic inflammation is a driving force accelerating HSC and hematopoietic system aging (Caiado et al, 2023;Caiado et al, 2021). Recent studies have highlighted the emerging role of inflammation signals, particularly the secretory factors in both bone marrow microenvironment and the systemic circumstance on shaping the hematopoietic system.…”

Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging

“…Prior murine studies show that Tet2 -/- , 38,49,50 Dnmt3a -/- , and Dnmt3a R878H/+ HSPCs 47,48 exhibit clonal advantage in inflammatory environments. Various studies have implicated exposure to different cytokines in the clonal advantage of mutant HSPCs: IL-1 through the IL-1 receptor, 50 IL-6 through Shp/Stat3 signaling, 49 TNFα through the TNFR1, 48 and IFN-γ. 47 Intestinal bacterial translocation 38 and chronic mycobacterial infection 47 can act as triggers for this inflammatory state.…”

Hematopoietic Stem Cells and the Immune System in Development and Aging

“…As mentioned above, clonal haematopoiesis is associated with mutations in the Tet2 gene. However, successful propagation of mutant clones is dependent on IL-1 signaling, highlighting the role of inflammation in the development of clonal haematopoiesis [ 200 ]. Moreover, HSCs bearing Tet2 gene mutation are sensitive to inflammatory stimuli.…”