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Pharmacological targeting of miR-155 via the NEDD8-activating enzyme inhibitor MLN4924 (Pevonedistat) in FLT3-ITD acute myeloid leukemia.
- Source :
-
Leukemia [Leukemia] 2015 Oct; Vol. 29 (10), pp. 1981-92. Date of Electronic Publication: 2015 May 14. - Publication Year :
- 2015
-
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.
- Subjects :
- Animals
Apoptosis drug effects
Blotting, Western
Cell Differentiation drug effects
Cell Proliferation drug effects
Chromatin Immunoprecipitation
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Leukemic drug effects
Humans
Leukemia, Myeloid, Acute pathology
Mice
Mice, Inbred NOD
Mice, SCID
Monocytes drug effects
Monocytes metabolism
Monocytes pathology
NEDD8 Protein
NF-kappa B genetics
NF-kappa B metabolism
Promoter Regions, Genetic
RNA, Messenger genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction drug effects
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Cyclopentanes pharmacology
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute genetics
MicroRNAs genetics
Pyrimidines pharmacology
Tandem Repeat Sequences genetics
Ubiquitins antagonists & inhibitors
fms-Like Tyrosine Kinase 3 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 29
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 25971362
- Full Text :
- https://doi.org/10.1038/leu.2015.106