FIGURE 1.

Cellular and genetic hierarchies and disease progression in MDS. (A) In healthy individuals, hemotopoiesis is charcterzied as a hierarchy in which self-renewing HSCs give rise to non-self-renewal multipotent and commited progintors and eventually mature cells. When aged HSCs acquire somatic mutations and give rise clones with enhanced self-renewal (yellow), thsi is detectable in the peripheral blood as clonal hematopoiesis (CH), which often characterized by mutations in genes such as DMNT3a, TET, and ASXL1. (B) when HSCs harboring CH associated mutations acquire additional mutations in genes such as U2AF1, SRF2, and SF3B1, this leads to the formation of MSD stem cells, MDS-SCs (green). In low-risk MDS, disease stem cells immunophenotypically resemble normal HSCs, while in high-risk disease with excess blasts, resmbles committed myeloid progenitors. (C) It is presumed that acquisitions of lesions such as FLT3 and NRAS mutations in HSCs or committed proginitors drive the formation of leukemia stem cells (LSCs) and non-self-renewing blasts that accumalate in high-risk MDS and sAML. LSCs immunophenotypically resemble committed progenitors. (curved blue arrow = self-renewal).