Abstract
Myelodysplastic Syndromes (MDS) are clonal neoplasms where stem/progenitor cells endowed with self-renewal and capable of perpetuating the disease have been demonstrated. It is known that oxygen tension plays a key role in driving normal hematopoiesis and that hematopoietic stem cells are maintained in hypoxic areas of the bone marrow (BM). Hypoxia could also regulate leukemic/dysplastic hematopoiesis. We evaluated the stem cell potential of MDS cells derived from the BM of 39 MDS patients and selected under severe hypoxia. MDS cells rescued from hypoxia-incubated cultures were subjected to stem and progenitor cell assays in vitro, as well as to hematopoietic reconstitution assay in NOD-SCID mice. Incubation in severe hypoxia of cells explanted from MDS patients selected a cell subset endowed with stem cell potential, as determined in vitro. This occurred only from the BM of patients classified as IPSS low/INT-1 risk. Transplantation into NOD-SCID mice confirmed using an in vivo model that severe hypoxia selects a cell subset endowed with stem cell potential from bone marrow mononuclear cells (BMMC). derived from patients belonging to the IPSS low/int-1 risk group. Data here reported show that cells endowed with stem cell potential and capable of adapting to hypoxia and escaping hypoxia-induced apoptosis exist within MDS cell populations.
Highlights
Myelodysplastic syndromes (MDS) have been shown to comprise stem/progenitor cells endowed with self-renewal and capable of perpetuating the disease [1]
Transplantation into NOD-SCID mice confirmed using an in vivo model that severe hypoxia selects a cell subset endowed with stem cell potential from bone marrow mononuclear cells (BMMC). derived from patients belonging to the International Prognostic Scoring System (IPSS) low/int-1 risk group
Effects of hypoxia on the maintenance of the stem cell potential of Myelodysplastic Syndromes (MDS) cells The stem cell potential of BMMC obtained from 39 MDS cases and incubated at 0.1% O2 or under standard conditions (“normoxia”) was estimated by the culture repopulation ability (CRA) assay (Figure 1)
Summary
Myelodysplastic syndromes (MDS) have been shown to comprise stem/progenitor cells endowed with self-renewal and capable of perpetuating the disease [1]. How stem cell regulation is altered in MDS and how many residual normal hematopoietic stem cells (HSC) are present in the various stages of these diseases is still not clear [5]. Oxygen tension plays a key role in normal hematopoietic development and stem cells niches, where HSC are hosted, are placed in the most hypoxic areas of BM [6]. The capacity of adaptation of MDS stem/progenitor cells to hypoxia, as well as the majority of human tumor stem cells [11], can be crucial for the maintenance of disease, and its progression, as hypoxia induces genomic instability [12]
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