Stem and progenitor cell alterations in myelodysplastic syndromes

Abstract

Recent studies have demonstrated that myelodysplastic syndromes (MDSs) arise from a small population of disease-initiating hematopoietic stem cells (HSCs) that persist and expand through conventional therapies and are major contributors to disease progression and relapse. MDS stem and progenitor cells are characterized by key founder and driver mutations and are enriched for cytogenetic alterations. Quantitative alterations in hematopoietic stem and progenitor cell (HSPC) numbers are also seen in a stage-specific manner in human MDS samples as well as in murine models of the disease. Overexpression of several markers such as interleukin-1 (IL-1) receptor accessory protein (IL1RAP), CD99, T-cell immunoglobulin mucin-3, and CD123 have begun to differentiate MDS HSPCs from healthy counterparts. Overactivation of innate immune components such as Toll-like receptors, IL-1 receptor-associated kinase/tumor necrosis factor receptor-associated factor-6, IL8/CXCR2, and IL1RAP signaling pathways has been demonstrated in MDS HSPCs and is being targeted therapeutically in preclinical and early clinical studies. Other dysregulated pathways such as signal transducer and activator of transcription 3, tyrosine kinase with immunoglobulinlike and EGF-like domains 1/angiopoietin-1, p21-activated kinase, microRNA 21, and transforming growth factor β are also being explored as therapeutic targets against MDS HSPCs. Taken together, these studies have demonstrated that MDS stem cells are functionally critical for the initiation, transformation, and relapse of disease and need to be targeted therapeutically for future curative strategies in MDSs.

Figure 1.

Quantitative stem and progenitor alterations in MDS subgroups. Stem cells and various progenitor populations are shown in normal and myelodysplastic hematopoiesis. Although this is a simplified model of differentiation, recent studies have shown that multipotent progenitors (MPPs) and CMPs can take alternative paths toward differentiation. Expansion of phenotypic HSCs is seen in MDSs and is most pronounced in higher-risk subgroups. Lower-risk MDS samples are characterized by phenotypic CMP expansions and decreased MEPs. Higher-risk samples are associated with GMP expansions.^,, RBC, red blood cell; ST-HSC, short-term hematopoietic stem cell.

Figure 2.

Identification and therapeutic targeting of aberrant stem and progenitor cells in MDSs. Diagram of MDS stem and progenitor cells demonstrates overexpressed markers such as IL1RAP, CD99, and TIM3. Overexpressed pathways include innate immune signaling pathways, Pak1, STAT3, and TGF-β signaling pathways. Various therapeutic approaches in development targeting these pathways are shown. ALK, anaplastic lymphoma kinase; CART123, chimeric antigen receptor T-cell 123; DAMPS: damage associated molecular patterns; TLR2PRR: TLR2-centered pathogen recognition receptor.