Macrophage migration inhibitory factor (MIF) has been confirmed as an oncogene in solid tumor development, and its overexpression causes cell proliferation in T acute lymphoblastic leukemia (T‑ALL); however, the underlying mechanisms remain unclear. The overexpression of MIF promotes cellular transformation and proliferation, in part, through interaction with UHRF1. Nevertheless, overexpression of UHRF1 cannot upregulate MIF expression in T‑ALL. New insights into MIF regulation in T‑ALL are imperative to offer the opportunity for therapeutic intervention. In the present study, using RT‑qPCR, western blot analysis, confocal microscopy and RNA sequence, we report the identification and validation of UHRF1 as a negative regulator of MIF, which functions to downregulate MIF expression by binding to the CATT repeat sequence of the MIF promoter. By contrast, HMG‑box protein 1 (HBP1) functions as a positive regulator of MIF. Moreover, we demonstrated that HBP1 suppressive signaling is reduced by UHRF1 through promotion of the interaction between MIF and HBP1. MIF deficiency caused by UHRF1 knockdown resulted in enhanced apoptosis in T‑ALL as compared with that caused by decreased MIF or increased HBP1 expression alone. These results identify UHRF1 as a key regulator of MIF transcription in T‑ALL, although these transcription factors possess opposite regulatory functions. Thus, this mechanism may provide insight into how to effectively prevent MIF‑dependent oncogenic activity. Finally, T‑ALL mice possessing high HBP1 or low UHRF1 expression levels are associated with longer survival as compared with control mice, with UHRF1‑knockdown mice living the longest. Taken together, these findings indicate that MIF and its regulators are potential treatment targets and biomarkers for the prediction of prognosis in T‑ALL.
Keywords: HMG‑box protein 1; acute lymphoblastic leukemia; inverted CCAAT box binding protein 90 kDa; macrophage migration inhibitory factor; regulation.