SPOP promotes acute myeloid leukemia initiation and development through miR-183-mediated METAP2 inhibition

Abstract Recent studies have highlighted the potential of miRNAs as diagnostic and prognostic indicators in acute myeloid leukemia (AML), which are reportedly associated in the interplay with certain mRNAs. Our main objective in this study was to characterize the functional relevance of the SPOP/miR-183/METAP2 axis in AML in vivo and in vitro. Differentially expressed mRNAs and downstream regulatory miRNA were predicted by analysis in silico. We induced SPOP/miR-183/METAP2 overexpression or inhibition to examine their effects on AML cell proliferation and apoptosis in vitro and tumor growth in vivo, along with their interaction with β-catenin. Peripheral blood samples and cell lines obtained from AML patients showed high expression of SPOP and miR-183, and downregulated METAP2. SPOP accelerated the proliferation of AML cells and suppressed apoptosis, and also enhanced β-catenin protein stability and its nuclear translocation, leading to upregulated miR-183 expression. The overexpression of miR-183 facilitated proliferation and inhibited apoptosis of AML cells by targeting METAP2. Furthermore, miR-183 inhibition and METAP2 overexpression reversed SPOP-induced AML cell malignancy. All the findings in vitro were matched in analogous settings in vivo. Overall, SPOP stimulated malignant progression of AML by inducing β-catenin protein stability and miR-183/METAP2 axis activation, thus highlighting a potential therapeutic action against AML.