Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level

• Published in: Blood 2000-09, Vol.96 (6), p.2012-2021
• Main Authors: Nilsson, Lars, Åstrand-Grundström, Ingbritt, Arvidsson, Ingrid, Jacobsson, Björn, Hellström-Lindberg, Eva, Hast, Robert, Jacobsen, Sten E.W.
• Format: Article
• Language: English
• Subjects: Antigens, CD34; Biological and medical sciences; Cell Lineage; Chromosome Deletion; Chromosomes, Human, Pair 5; Hematologic and hematopoietic diseases; Hematopoiesis; Hematopoietic Stem Cells - pathology; Hematopoietic Stem Cells - physiology; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V96.6.2012

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia. Within MDS, 5q− syndrome constitutes a distinct clinical entity characterized by an isolated deletion of the long arm of chromosome 5 (5q−), a relatively good prognosis, and infrequent transformation to acute leukemia. The cell of origin in 5q− syndrome as well as in other 5q-deleted MDS patients has not been established, but evidence for involvement of multiple myeloid (but not lymphoid) lineages has suggested that a myeloid-restricted progenitor rather than a pluripotent (lympho-myeloid) stem cell might be the primary target in most patients. Although in 9 patients no evidence of peripheral blood T-cell and only 1 case of B-cell involvement was found, the data herein support that 5q deletions occur in hematopoietic stem cells (HSCs) with a combined lympho-myeloid potential. First, in all investigated patients a minimum of 94% of cells in the minor CD34+CD38− HSC compartment were 5q deleted as determined by fluorescence in situ hybridization. Second, in 3 of 5 patients 5q aberrations were detected in a large fraction (25% to 90%) of purified CD34+CD19+ pro-B cells. Furthermore, extensive functional characterization with regard to responsiveness to early-acting cytokines, long-term culture-initiating cells, and nonobese diabetic/severe combined immunodeficiency repopulating cells supported that MDS HSCs in 5q-deleted patients are CD34+CD38−, but inefficient at reconstituting hematopoiesis.