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


 Background: Recent miRNA profiling studies have implicated the potential use of miRNAs as as diagnostic and prognostic indicators in acute myeloid leukemia (AML), which has been reportedly implicated in the interplay with certain mRNAs. Herein this study, we intend to characterize the functional relevance of SPOP/miR-183/METAP2 axis in AML in vivo and in vitro. Methods: Differentially expressed mRNAs and downstream regulatory miRNA were predicted by in silico analysis. 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. Results: SPOP and miR-183 were highly expressed, while METAP2 was poorly expressed in patient peripheral blood samples and cell lines of AML. SPOP accelerated the proliferation of AML cells and repressed apoptosis. Mechanistically, SPOP enhanced β-catenin protein stability and nuclear translocation leading to upregulated expression of miR-183. 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. Besides, in vitro findings were reproduced by in vivo findings. Conclusion: SPOP stimulated AML malignant progression by inducing β-catenin stability and miR-183/METAP2 axis activation, highlighting a potential therapeutic target against AML recurrence and metastasis.