Iron Overload Impairs Bone Marrow Mesenchymal Stromal Cells from MDS Patients and Promotes Leukemia Transformation

Abstract

Bone marrow microenvironment plays an important role in the development of myelodysplastic syndrome (MDS). Iron overload (IO) may be related to the prognosis of the MDS patients. The effects of IO damaging mesenchymal stromal cells (MSCs) from MDS patients and promoting leukemia transformation were investigated. In our study, the IO group showed the decreased quantity and weakened abilities on proliferation and differentiation of MSCs. The gene expressions of VEGFA, CXCL12 and TGF-β1 in MSCs regulating hematopoiesis were significantly downregulated in IO group. The levels of reactive oxygen species (ROS) and apoptosis in IO group were significantly higher than those in non-iron overload (NIO) group, with highly expressed caspase3 and β-catenin. Meanwhile, the damages of MSCs caused by IO could be partially reversed by antioxidant or iron chelator. Due to the higher gene mutation frequency in IO group, the effects of IO promoting leukemia transformation were investigated. The IO MDS/AML group had a lower quantity of MSCs compared with IO MDS group, with significantly decreased expression of p-AKT. However, there was no significant differences in apoptosis, gene expressions of VEGF, CXCL12 supporting hematopoiesis, and β-catenin involving leukemia transformation in MSCs between them. In conclusion, IO damages MSCs of MDS patients by inducing ROS related apoptosis and activating caspase3 signals, which could be partially reversed by antioxidant or iron chelator. The increased genetic mutations and activated β-catenin signals in MSCs of MDS patients caused by IO may involve in promoting leukemia transformation. Disclosures No relevant conflicts of interest to declare.