Format

Send to

Choose Destination
See comment in PubMed Commons below
Cell Rep. 2013 Oct 31;5(2):471-81. doi: 10.1016/j.celrep.2013.08.050. Epub 2013 Oct 10.

An extensive network of TET2-targeting MicroRNAs regulates malignant hematopoiesis.

Author information

1
Department of Genetics and Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
2
Yale Cancer Center and Center for RNA Science and Medicine, Yale University, New Haven, CT 06520, USA.
3
Department of Cell Biology, Yale University, New Haven, CT 06520, USA.
4
Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
5
Wadsworth Center, New York State Department of Health, 150 New Scotland Avenue, Albany, NY 12201, USA.
6
Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
7
Department of Cell Biology and Genetics, Shantou University Medical College, Guangdong 515041, China.
8
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
#
Contributed equally

Abstract

The Ten-Eleven-Translocation 2 (TET2) gene, which oxidates 5-methylcytosine in DNA to 5-hydroxylmethylcytosine (5hmC), is a key tumor suppressor frequently mutated in hematopoietic malignancies. However, the molecular regulation of TET2 expression is poorly understood. We show that TET2 is under extensive microRNA (miRNA) regulation, and such TET2 targeting is an important pathogenic mechanism in hematopoietic malignancies. Using a high-throughput 3' UTR activity screen, we identify >30 miRNAs that inhibit TET2 expression and cellular 5hmC. Forced expression of TET2-targeting miRNAs in vivo disrupts normal hematopoiesis, leading to hematopoietic expansion and/or myeloid differentiation bias, whereas coexpression of TET2 corrects these phenotypes. Importantly, several TET2-targeting miRNAs, including miR-125b, miR-29b, miR-29c, miR-101, and miR-7, are preferentially overexpressed in TET2-wild-type acute myeloid leukemia. Our results demonstrate the extensive roles of miRNAs in functionally regulating TET2 and cellular 5hmC and reveal miRNAs with previously unrecognized oncogenic potential. Our work suggests that TET2-targeting miRNAs might be exploited in cancer diagnosis.

PMID:
24120864
PMCID:
PMC3834864
DOI:
10.1016/j.celrep.2013.08.050
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for PubMed Central
    Loading ...
    Support Center