Activating and sustaining c-Myc by depletion of miR-144/451 gene locus contributes to B-lymphomagenesis

Oncogene
Lan DingDuonan Yu

Abstract

Hyper activity of protooncogene c-Myc is one of the hallmarks of highly aggressive lymphomas. However, the mechanism of how c-Myc is subjected to activation and amplification is still not well defined. In this study, we use gene knockout strategy to show that targeted depletion of a well-conserved microRNA gene locus miR-144/451 initiates tumorigenesis including B-lymphoma development in aged mice. This is due, at least in part, to the direct activation of the c-Myc gene by loss of miR-144/451 expression in hematopoietic cells. Moreover, oncoprotein c-Myc inversely regulates miR-144/451 expression by directly binding to the miR-144/451 promoter region, forming a miRNA-Myc positive feedback loop to safeguard the high level of c-Myc in B-lymphocytes. We also demonstrate that this miRNA-Myc crosstalk is disrupted in human diffuse large B-cell lymphomas with aberrant c-Myc expression. Therefore, our findings provide strong evidence, for the first time, that deficiency of miR-144/451 expression may play a bona fide role in derepression of silenced c-Myc, which contributes to tumor development including B-lymphomagenesis.

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Citations

Nov 20, 2018·Molecular Oncology·Lotteke J Y M SwierJoost Kluiver
Feb 28, 2019·American Journal of Respiratory Cell and Molecular Biology·M Rizwan SiddiquiThomas P Shanley
Aug 23, 2019·Wiley Interdisciplinary Reviews. RNA·Shama Prasada KabekkoduKapaettu Satyamoorthy
Jun 19, 2020·International Journal of Molecular Sciences·Eleonora VecchioIleana Quinto
Nov 17, 2020·Frontiers in Oncology·Jingwen LiYu Hu
Dec 16, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Lei XuDuonan Yu
Feb 19, 2021·The American Journal of the Medical Sciences·Fangfang WangDuonan Yu
Sep 6, 2020·Trends in Immunology·Teresa FuertesVirginia G de Yebenes
Nov 8, 2020·Seminars in Cancer Biology·Rongfu TuGuoliang Qing
Mar 24, 2018·Cell·David P Bartel
Aug 2, 2021·Oral Diseases·Vidyadharan Geetha ManasaSankarareddiar Kannan

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Methods Mentioned

BETA
gene knockout
PCR
ChIP
immunoprecipitation
nuclear translocation
genotyping
GeneScreen
Transfection
Assay

Software Mentioned

MirTarbase
Vista
TargetScan

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