The mechanisms by which hematopoietic stem and progenitor cells (HSC and HPC) from myelodysplastic syndromes (MDS) undergo ineffective production of blood cells and disease transformation into acute myeloid leukemia remain to be investigated. It has been confirmed that increased production of reactive oxygen species (ROS) under various pathological conditions impairs HSC self-renewal and causes HSC premature exhaustion and BM suppression primarily via induction of HSC senescence, and oncogene induces accumulation of ROS and DNA damage and subsequently cellular senescence, which functions as an important barrier to prevent the growth of transformed cells to form a neoplasia. Here we investigated whether MDS CD34(+) cells enriched with HSC and HPC undergo senescence through accumulation of ROS and DNA damage and their action mechanisms. In this study, the percentages of SA-β-gal positive senescent CD34(+) cells increased in lower-risk MDS patients, but not in higher-risk MDS and AML patients, compared to that of healthy controls. The increases were associated with an elevated expression of p21 but not the activation of p38. Further study found that there were increased ROS and DNA damage in CD34(+)CD38(-) cells enriched with HSC progression from lower-risk MDS, higher-risk MDS to AML. Therefore, these data suggest that CD34(+) cells from patients with lower-risk MDS present p21 dependent premature senescence, increased accumulation of ROS and DNA damage in CD34(+)CD38(-) cells could contribute to this process; however, CD34(+) cells from patients with higher-risk MDS could develop some mechanisms to uncouple ROS and DNA damage induced senescence.
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