Stem cell origin of myelodysplastic syndromes

• Published in: Oncogene Vol. 33; no. 44; pp. 5139 - 5150
• Main Authors: Elias, H K, Schinke, C, Bhattacharyya, S, Will, B, Verma, A, Steidl, U
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.10.2014; Nature Publishing Group
• Subjects: 631/67/1990/1673; 631/67/71; 692/420/755; Analysis; Animal models; Animals; Apoptosis; Blood diseases; Bone marrow; Cell Biology; Cell differentiation; Development and progression; Disease Models, Animal; Epigenetics; Erythrocytes; Genetic aspects; Hematological diseases; Hematology; Hematopoietic stem cells; Hematopoietic Stem Cells - pathology; Hematopoietic Stem Cells - physiology; Human Genetics; Humans; Innovations; Internal Medicine; Leukemia; Leukemia - pathology; Medicine; Medicine & Public Health; Mice; Molecular targeted therapy; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - blood; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Oncology; Patients; Progenitor cells; Properties; Remission; review; Stem cell transplantation; Stem cells; Stem Cells - pathology; HSC; cell-of-origin; stem cell; myelodysplastic syndrome; MDS; progenitor cell
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.520

Myelodysplastic syndromes (MDS) are common hematologic disorders that are characterized by decreased blood counts due to ineffective hematopoiesis. MDS is considered a ‘preleukemic’ disorder linked to a significantly elevated risk of developing an overt acute leukemia. Cytopenias can be observed in all three myeloid lineages suggesting the involvement of multipotent, immature hematopoietic cells in the pathophysiology of this disease. Recent studies using murine models of MDS as well as primary patient-derived bone marrow samples have provided direct evidence that the most immature, self-renewing hematopoietic stem cells (HSC), as well as lineage-committed progenitor cells, are critically altered in patients with MDS. Besides significant changes in the number and distribution of stem as well as immature progenitor cells, genetic and epigenetic aberrations have been identified, which confer functional changes to these aberrant stem cells, impairing their ability to proliferate and differentiate. Most importantly, aberrant stem cells can persist and further expand after treatment, even upon transient achievement of clinical complete remission, pointing to a critical role of these cells in disease relapse. Ongoing preclinical and clinical studies are particularly focusing on the precise molecular and functional characterization of aberrant MDS stem cells in response to therapy, with the goal to develop stem cell-targeted strategies for therapy and disease monitoring that will allow for achievement of longer-lasting remissions in MDS.