Stem Cells in the Myelodysplastic Syndromes

Abstract

The myelodysplastic syndromes (MDS) represent a group of clonal disorders characterized by ineffective hematopoiesis, resulting in peripheral cytopenias and frequent transformation to acute myeloid leukemia (AML). We and others have demonstrated that MDS arises in, and is propagated by malignant stem cells (MDS-SCs), that arise due to the sequential acquisition of genetic and epigenetic alterations in normal hematopoietic stem cells (HSCs). This review focuses on recent advancements in the cellular and molecular characterization of MDS-SCs, as well as their role in mediating MDS clinical outcomes. In addition to discussing the cell surface proteins aberrantly upregulated on MDS-SCs that have allowed the identification and prospective isolation of MDS-SCs, we will discuss the recurrent cytogenetic abnormalities and genetic mutations present in MDS-SCs and their roles in initiating disease, including recent studies demonstrating patterns of clonal evolution and disease progression from pre-malignant HSCs to MDS-SCs. We also will discuss the pathways that have been described as drivers or promoters of disease, including hyperactivated innate immune signaling, and how the identification of these alterations in MDS-SC have led to investigations of novel therapeutic strategies to treat MDS. It is important to note that despite our increasing understanding of the pathogenesis of MDS, the molecular mechanisms that drive responses to therapy remain poorly understood, especially the mechanisms that underlie and distinguish hematologic improvement from reductions in blast burden. Ultimately, such distinctions will be required in order to determine the shared and/or unique molecular mechanisms that drive ineffective hematopoiesis, MDS-SC maintenance, and leukemic transformation.

Keywords: acute myeloid leukemia; clonal hematopoiesis; hematopoietic stem cells; myelodysplastic syndromes; novel therapeutics.

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).