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Leukemia. 2015 Oct;29(10):1981-92. doi: 10.1038/leu.2015.106. Epub 2015 May 14.

Pharmacological targeting of miR-155 via the NEDD8-activating enzyme inhibitor MLN4924 (Pevonedistat) in FLT3-ITD acute myeloid leukemia.

Author information

1
Program of Molecular, Cellular, and Developmental Biology, The Ohio State University, Columbus, OH, USA.
2
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
3
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
4
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
5
William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.
6
Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.
7
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
8
Department of Molecular Virology, Immunology and Cancer Genetics, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
9
Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
10
James P. Wilmot Cancer Center and Department of Medicine, University of Rochester, Rochester, NY, USA.
11
Division of Hematopoietic Stem Cell & Leukemia Research, Department of Hematology & HCT, Gehr Family Center for Leukemia, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

Abstract

High levels of microRNA-155 (miR-155) are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-κB, the activity of which is, in part, controlled by the NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8-activating enzyme presently being evaluated in clinical trials, decreases binding of NF-κB to the miR-155 promoter and downregulates miR-155 in AML cells. This results in the 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 the 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-κB-dependent regulatory mechanisms. We show the targeting of this oncogenic microRNA with MLN4924, a compound presently being evaluated in clinical trials in AML. As 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.

PMID:
25971362
PMCID:
PMC4868182
DOI:
10.1038/leu.2015.106
[Indexed for MEDLINE]
Free PMC Article

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