The CH expansion-inflammation cycle. Age-associated CH is most commonly driven by somatic mutations in HSPCs, involving the epigenetic regulator genes TET2, DNMT3A, and ASXL1 (top). Enhanced fitness imparted by increased self-renewal leads to CH-mutant HSPC expansion and myeloproliferation (right). In turn, and in the context of aging, this leads to increased and chronic expression of proinflammatory cytokines and other mediators that alter the hematopoietic milieu (bottom). While this environment suppresses normal HSPC, gene expression and other adaptations in CH-mutant HPSC lead to a vicious cycle of enhanced CH cell fitness and inflammation (left). This environment may increase the risk of cancer and exacerbate diseases associated with inflammation. The findings of Caiado et al in this issue of Blood (and other recent publications) suggest that targeting inflammatory cytokines, associated receptors, signaling, or other adaptive mechanisms may break this vicious CH cycle and decrease the risk of cancer and comorbid inflammatory diseases. Figure created with BioRender. IFN-γ, interferon gamma; TNF, tumor necrosis factor.