A model of mesenchymal niche–facilitated clonal evolution in MDS. NF-κB activation, β-catenin/WNT activation, and/or senescence-associated signaling may induce inflammatory alterations in mesenchymal niche cells that result in secretion of inflammatory ligands, such as S100A8/A9, C-C chemokines, and IL-1β in the HSPC niche. Mesenchymal inflammation may be the result of primary (genetic or epigenetic) alterations in mesenchymal cells or be induced by inflammatory alterations in clonal hematopoietic cells “starting the fire.” The local inflammatory niche induces functional repression of HSCs through direct receptor-mediated genotoxic stress and/or recruitment of proinflammatory innate immune cells, further providing an inflammatory feed-forward loop. The inflammatory stem cell niche may drive the accelerated emergence of mutations in HSPCs through direct genotoxic signaling or the induction of replicative stress. Cells harboring “poising” mutations (ie, mutations that confer resistance to inflammation-induced apoptosis) are selected for in the inflammatory environment by virtue of their relative resistance to inflammation-associated genotoxic stress. The presence of a poising mutation, in an inflammatory environment, accelerates the acquisition of additional genetic events and transformation to frank AML. Thus, inhibition of inflammatory signaling, targeting ligands such as S100A8/A9, C-C chemokines, and IL-1β signaling or related receptors, is anticipated to alleviate the genotoxic stress on normal HSPCs, relieve the selective pressure on preleukemic clones, and attenuate clonal evolution and leukemic progression in MDS.