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Cancer Cell. 2017 Jan 9;31(1):127-141. doi: 10.1016/j.ccell.2016.11.017. Epub 2016 Dec 22.

FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase.

Author information

1
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
2
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
3
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
4
Departments of Chemistry, Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA; College of Chemistry and Molecular Sciences, Key Laboratory of Biomedical Polymers of Ministry of Education, Wuhan University, Hubei, Wuhan 430072, PR China.
5
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
6
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA; Key Laboratory of Hematopoietic Malignancies, Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
7
Departments of Chemistry, Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
8
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA; Key Laboratory of Hematopoietic Malignancies, Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
9
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
10
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
11
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
12
Key Laboratory of Hematopoietic Malignancies, Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
13
Departments of Chemistry, Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
14
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA. Electronic address: chen3jj@ucmail.uc.edu.

Abstract

N6-Methyladenosine (m6A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m6A in cancer have been limited. Here we show that FTO, as an m6A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m6A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m6A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response.

KEYWORDS:

AML; ASB2; ATRA; FTO; RARA; RNA modification; RNA stability; cell differentiation; leukemogenesis; m6A

PMID:
28017614
PMCID:
PMC5234852
DOI:
10.1016/j.ccell.2016.11.017
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing financial interests.

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