Stem and progenitor cell alterations in myelodysplastic syndromes.
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.
Division of Hemato-Oncology, Department of Oncology, Albert Einstein College of Medicine, Bronx, NY; and.|Montefiore Medical Center, Bronx, NY.
Aditi
A
Shastri
Division of Hemato-Oncology, Department of Oncology, Albert Einstein College of Medicine, Bronx, NY; and.|Montefiore Medical Center, Bronx, NY.
Britta
B
Will
Division of Hemato-Oncology, Department of Oncology, Albert Einstein College of Medicine, Bronx, NY; and.|Montefiore Medical Center, Bronx, NY.
Ulrich
U
Steidl
Division of Hemato-Oncology, Department of Oncology, Albert Einstein College of Medicine, Bronx, NY; and.|Montefiore Medical Center, Bronx, NY.
Amit
A
Verma
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D018450:Disease Progression; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D007113:Immunity, Innate; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology
D014408:Biomarkers, Tumor