Deficiency of Setd2 in mesenchymal stem cells facilitates the progression of myelodysplastic syndrome to leukemia.
While previous studies have indicated that H3K36me3, which is mediated by Setd2, may regulate the cell fate of mesenchymal stem cells (MSCs) both in vitro and in vivo, the specific role of MSCs in the onset and progression of MDS remains unclear. Thus, the histone methyltransferase Setd2 is implicated in MDS-associated leukemia. This study utilized NUP98-HOXD13 (NHD13) mice with targeted deletion of Setd2 in MSCs. Here, we found that Setd2-deficient mice undergo faster leukemia transformation than control mice do, as evidenced by the abnormal differentiation of hematopoietic stem progenitor cells in the bone marrow, abnormal hematopoiesis, and increased number of blast cells. Compared with that of control mice, the morphology of NHD13 mouse MSCs with Setd2 deficiency was irregular, and the support function of hematopoietic cells was compromised. This study demonstrated that targeted deletion of Setd2 in MSCs facilitates the advancement of MDS. Furthermore, we identified increased expression of coagulation factor XII as a key leukemic transformation mediator in Setd2-deficient MSCs. Moreover, we found that SETD2 expression is significantly lower in high-risk MDS patients than in low-risk MDS patients, further suggesting that the targeted deletion of Setd2 in MSCs is associated with MDS progression. Collectively, our results suggest that Setd2 in MSCs suppresses MDS progression to leukemia through coagulation factor XII-mediated suppression of the stem cell support capacity of MSCs. Overall, this study sheds light on the pathogenesis of MDS and provides a therapeutic strategy for regulating the microenvironment in patients with MDS who cannot be cured by haematopoietic stem cell transplantation.