No abstract

Bone marrow-derived mesenchymal stem cells (BMMSCs) have the ability to differentiate into osteoblasts and adipocytes, and have been found to promote disease progression of myeloid malignancies like myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). MDS/AML patient-derived BMMSCs often show a shift in the balance between osteoblastogenesis and adipogenesis, indicating that BMMSCs may be reprogrammed or educated. However, the results of reprogrammed differentiation have been inconclusive. In this study, we found that clonal MDS/AML cells promote adipogenic differentiation and inhibit osteogenic differentiation of BMMSCs, which in turn promotes MDS expansion. Mechanistically, highly expressed transcription factor TWIST1 in clonal MDS/AML cells plays a vital role in the MDS/AML cell-mediated BMMSCs reprogramming differentiation. Enhanced TWIST1 expression induces MDS/AML cells to secrete more IFN-γ, which can induce oxidative stress through STAT1-depenent manner, ultimately causing enhanced adipogenic differentiation and inhibited osteogenic differentiation in BMMSCs. Overall, our findings suggest that targeting the driving oncogenes in malignant clonal cells, such as TWIST1, may offer new therapeutic strategies by remodeling the surrounding bone marrow microenvironment in the treatment of MDS/AML and other hematopoietic malignancies.