Model of innate immune signaling dysregulation in the pathogenesis of MDS. Certain diseases and conditions, such as aging, autoimmune disorders, chronic infections, and/or clonal hematopoiesis of indeterminate potential (CHIP), can induce innate immune signaling dysregulation in HSCs in part by creating an inflammatory BM microenvironment characterized by increased alarmins and/or cytokines. Development of MDS may occur by at least 2 independent mechanisms. (1) CHIP-associated mutations (ie, DNMT3a or TET2) occur in HSCs by innate immune independent mechanisms and drive the expansion of myeloid-biased HSC leading to altered innate immune signaling and development of MDS. (2) Prolonged innate immune signaling caused by clonally expanded myeloid-biased HSCs directly increases the risk of acquiring mutations (ie, CHIP mutations) contributing to MDS. Innate immune signaling dysregulation at the MDS stage occurs through cell-intrinsic (ie, increased cell death via pyroptosis) and cell-extrinsic mechanisms (ie, cytokines and alarmins stimulation from macrophage and myeloid derived suppressor cells [MDSCs]). As a result of altered innate immune signaling, MDSCs also promote regulatory T cell (Treg) activation to limit T-cell surveillance.