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Cancer Cell. 2019 Jan 14;35(1):81-94.e7. doi: 10.1016/j.ccell.2018.11.017. Epub 2019 Jan 3.

Hyper-Editing of Cell-Cycle Regulatory and Tumor Suppressor RNA Promotes Malignant Progenitor Propagation.

Author information

1
Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address: q1jiang@ucsd.edu.
2
Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA.
3
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
4
Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
5
Princess Margaret Hospital, Toronto, ON M5T 2M9, Canada.
6
Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA.
7
Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA, USA; Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, and Moores Cancer Center, University of California at San Diego, La Jolla, CA 92093, USA.
8
Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Health Sciences, School of Health and Human Services, National University, San Diego, CA, USA.
9
Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA. Electronic address: cjamieson@ucsd.edu.

Abstract

Adenosine deaminase associated with RNA1 (ADAR1) deregulation contributes to therapeutic resistance in many malignancies. Here we show that ADAR1-induced hyper-editing in normal human hematopoietic progenitors impairs miR-26a maturation, which represses CDKN1A expression indirectly via EZH2, thereby accelerating cell-cycle transit. However, in blast crisis chronic myeloid leukemia progenitors, loss of EZH2 expression and increased CDKN1A oppose cell-cycle transit. Moreover, A-to-I editing of both the MDM2 regulatory microRNA and its binding site within the 3' UTR region stabilizes MDM2 transcripts, thereby enhancing blast crisis progenitor propagation. These data reveal a dual mechanism governing malignant transformation of progenitors that is predicated on hyper-editing of cell-cycle-regulatory miRNAs and the 3' UTR binding site of tumor suppressor miRNAs.

KEYWORDS:

3′ UTR; ADAR1; RNA hyper-editing; cancer stem cell; cell cycle; chronic myeloid leukemia; epitranscriptome; leukemia; microRNAs; progenitors; self-renewal

PMID:
30612940
PMCID:
PMC6333511
[Available on 2020-01-14]
DOI:
10.1016/j.ccell.2018.11.017

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