PUBLICATION
Ectopic viral integration Site-1 oncogene promotes NRAS pathway through epigenetic silencing of microRNA-124 in acute myeloid leukemia
- Authors
- Lang, W., Han, X., Cai, J., Chen, F., Xu, L., Zhong, H., Zhong, J.
- ID
- ZDB-PUB-220715-13
- Date
- 2022
- Source
- Cellular Signalling 99: 110402 (Journal)
- Registered Authors
- Chen, Fangyuan, Zhong, Ji-Hua
- Keywords
- AML, EVI-1, NRAS/ERK pathway, miR-124
- MeSH Terms
-
- Animals
- Carcinogenesis/genetics
- Cell Proliferation/genetics
- Epigenesis, Genetic
- Leukemia, Myeloid, Acute*/pathology
- MicroRNAs*/genetics
- MicroRNAs*/therapeutic use
- Oncogenes
- RNA, Small Interfering
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Virus Integration
- Zebrafish/metabolism
- PubMed
- 35835333 Full text @ Cell. Signal.
Citation
Lang, W., Han, X., Cai, J., Chen, F., Xu, L., Zhong, H., Zhong, J. (2022) Ectopic viral integration Site-1 oncogene promotes NRAS pathway through epigenetic silencing of microRNA-124 in acute myeloid leukemia. Cellular Signalling. 99:110402.
Abstract
Background Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by genetic mutations that promote proliferation of myeloid progenitors and prevent their differentiation. Over-expression of Ectopic Viral Integration site-1(EVI-1) is related to the poor prognosis in myeloid leukemia, but the underlying mechanism remains unclear.
Methods Using qRT-PCR and western blotting, we quantified expressions of EVI-1, NRAS and ERK/p-ERK in leukemia cell lines and PBMCs. Using WTS-8 and cell cycle analysis, we further investigated whether downregulation of EVI-1 by siRNA can inhibit cell proliferation. Microscopic observation of peripheral blood cells from EVI-1 transgenic zebrafish and WT control were analyzed by Wright Giemsa staining. Using miR-seq, qPCR, dual-luciferase reporter and coimmunoprecipitation assays, we revealed the relationship between EVI-1, miR-124 and NRAS.
Results EVI-1 was highly expressed in both primary AML and leukemia cell lines (THP-1 and K562). In a transgenic zebrafish model, EVI-1 mediated higher mortality and induced immature hematopoietic cells in the blood circulation, suggesting its oncogenic role. Furthermore, our results suggested that EVI-1 upregulated NRAS expression, thereby activating the RAS/ERK pathway through epigenetic silencing of a potent NRAS suppressor, miR-124. In this study, we found that EVI1 physically interacts with Dnmt3a to form a protein complex that targets and binds to regulatory elements of miR-124.
Conclusions Overall, the current findings demonstrate that EVI-1 overexpression converges on the regulation of miR-124 promoter methylation and activation of the RAS/ERK pathway in AML carcinogenesis, and suggest EVI-1 and/or miR-124 as therapeutic targets for this dismal disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping