Exportin 1 Inhibitor Combined With Venetoclax Induces Apoptosis in Myelodysplastic Syndrome by Mitochondria‐Induced Apoptosis Pathway

BACKGROUND: Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies that pose a serious health threat. Current therapies include symptomatic treatments for low-risk and hypomethylating agents for high-risk MDS. However, many patients develop resistance to hypomethylating drugs. (Exportin 1) XPO1 inhibition has shown efficacy in inducing tumor cell death by blocking the nuclear export of oncogenes; nevertheless, the role of XPO1 inhibition in MDS remains unexplored. METHODS: We investigated the role of XPO1 in the pathogenesis of MDS by analyzing XPO1 expression in MDS patients with different risk stratification and healthy controls in the GEO database, and evaluated the effects of the XPO1 inhibitor Selinexor on the proliferation and apoptosis of MDS cells and its mechanism by CCK-8, EdU, flow cytometry, and immunofluorescence. The effects of Selinexor on the proliferation and apoptosis of MDS cells, its mechanism, and its synergistic effect with Bcl-2 inhibitor Venetoclax were evaluated. RESULTS: We found that XPO1 may have an important role in the development of MDS, and Selinexor induced apoptosis and inhibited the proliferation of MDS cells by inhibiting the nuclear export of p53. Drug combination index assays showed that Selinexor was able to synergize with Venetoclax. The combination of the two resulted in the inhibition of XPO1, which could increase ROS levels in MDS cells and activate mitochondria-mediated apoptotic pathways in cells after inducing elevated MOMP. CONCLUSION: Our study found that inhibition of XPO1 is a promising modality in the treatment of MDS, especially when combined with Venetoclax, which could be a potential target for MDS therapy.