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Pharmacological targeting of miR-155 via the NEDD8-activating enzyme inhibitor MLN4924 (Pevonedistat) in FLT3-ITD acute myeloid leukemia. Leukemia Khalife, J. n., Radomska, H. S., Santhanam, R. n., Huang, X. n., Neviani, P. n., Saultz, J. n., Wang, H. n., Wu, Y. Z., Alachkar, H. n., Anghelina, M. n., Dorrance, A. n., Curfman, J. n., Bloomfield, C. D., Medeiros, B. C., Perrotti, D. n., Lee, L. J., Lee, R. J., Caligiuri, M. A., Pichiorri, F. n., Croce, C. M., Garzon, R. n., Guzman, M. L., Mendler, J. H., Marcucci, G. n. 2015

Abstract

High levels of miR-155 are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-?B, the activity of which is in part controlled by NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8 activating enzyme (NAE) presently being evaluated in clinical trials, decreases binding of NF-?B to the miR-155 promoter and downregulates miR-155 in AML cells. This results in upregulation of the miR-155 targets SHIP1, an inhibitor of the PI3K/Akt pathway, and PU.1, a transcription factor important for myeloid differentiation, leading to monocytic differentiation and apoptosis. Consistent with these results, overexpression of miR-155 diminishes MLN4924-induced antileukemic effects. In vivo, MLN4924 reduces miR-155 expression and prolongs survival of mice engrafted with leukemic cells. Our study demonstrates the potential of miR-155 as a novel therapeutic target in AML via pharmacologic interference with NF-?B-dependent regulatory mechanisms. We show the targeting of this oncogenic microRNA with MLN4924, a compound presently being evaluated in clinical trials in AML. Since high miR-155 levels have been consistently associated with aggressive clinical phenotypes, our work opens new avenues for microRNA-targeting therapeutic approaches to leukemia and cancer patients.Leukemia accepted article preview online, 14 May 2015. doi:10.1038/leu.2015.106.

View details for PubMedID 25971362