Relationship of HIF­1α expression with apoptosis and cell cycle in bone marrow mesenchymal stem cells from patients with myelodysplastic syndrome.

ABSTRACT

Myelodysplastic syndrome (MDS) is a group of abnormal clonal disorders with ineffective hematopoiesis, which are incurable with conventional therapy. Of note, MDS features an abnormal bone marrow microenvironment, which is related to its incidence. The hypoxia­inducible factor­1α (HIF­1α) transcriptional signature is generally activated in bone marrow stem/progenitor cells of patients with MDS. To analyze the expression of HIF­1α in bone marrow mesenchymal stem cells (BM­MSCs) and the apoptosis and cell cycle features associated with the disease, BM­MSCs were obtained from 40 patients with a definitive diagnosis of MDS and 20 subjects with hemocytopenia but a negative diagnosis of MDS as a control group. Reverse transcription­quantitative PCR and western blot analyses were used to measure HIF­1α expression in cells from the two groups and apoptosis and cell cycle were also analyzed and compared between the groups using flow cytometry assays. BM­MSCs from both the control group and the MDS group exhibited a fibroblast­like morphology, had similar growth cycles and were difficult to passage stably. It was observed that BM­MSCs from the MDS group had significantly higher HIF­1α expression levels than the control group (P<0.05). Furthermore, the BM­MSCs from the MDS group had a higher proportion of cells in early apoptosis (5.22±1.34 vs. 2.04±0.08%; P<0.0001) and late apoptosis (3.38±0.43 vs. 1.23±0.11%; P<0.01) and exhibited cell cycle arrest. This may be a noteworthy aspect of the pathogenesis of MDS and may be related to high HIF­1α expression under a hypoxic state in the bone marrow microenvironment. Furthermore, the expression of HIF­1α in bone marrow tissue sections from patients with MDS in the International Prognostic Scoring System (IPSS) lower­risk group was higher than that from patients with MDS in the IPSS high­risk group. These results revealed the role of HIF­1α as a central pathobiology mediator of MDS and an effective therapeutic target for a broad spectrum of patients with MDS, particularly for patients in the lower­risk group.