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PMID: 28017614 Published · ppublish English Journal Article

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

Cancer cell ·Vol. 31 ·No. 1 ·2017-00-09 ·Pages 127-141

Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, Huang H, Nachtergaele S, Dong L, Hu C, Qin X, Tang L, Wang Y, Hong GM, Huang H, Wang X, Chen P, Gurbuxani S, Arnovitz S, Li Y, Li S, Strong J, Neilly MB, Larson RA, Jiang X, Zhang P, Jin J, He C, Chen J

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
MeSH Terms
Adenosine/analogs & derivatives,metabolism Alpha-Ketoglutarate-Dependent Dioxygenase FTO/physiology Apoptosis Cell Proliferation Humans Leukemia, Myeloid, Acute/drug therapy,enzymology,etiology,pathology Methylation Nucleophosmin Retinoic Acid Receptor alpha/physiology Suppressor of Cytokine Signaling Proteins/physiology Transcriptome Tretinoin/pharmacology
Chemicals
ASB2 protein, human NPM1 protein, human RARA protein, human Retinoic Acid Receptor alpha Suppressor of Cytokine Signaling Proteins Nucleophosmin Tretinoin N-methyladenosine Alpha-Ketoglutarate-Dependent Dioxygenase FTO FTO protein, human Adenosine
Authors & Affiliations
29 authors, click to expand affiliations / ORCID
Li Zejuan
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.
Weng Hengyou
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.
Su Rui
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
Weng Xiaocheng
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.
Zuo Zhixiang
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.
Li Chenying
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.
Huang Huilin
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
Nachtergaele Sigrid
Departments of Chemistry, Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
Dong Lei
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
Hu Chao
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.
Qin Xi
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
Tang Lichun
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Wang Yungui
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.
Hong Gia-Ming
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Huang Hao
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Wang Xiao
Departments of Chemistry, Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
Chen Ping
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Gurbuxani Sandeep
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Arnovitz Stephen
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Li Yuanyuan
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Li Shenglai
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Strong Jennifer
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
Neilly Mary Beth
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Larson Richard A
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Jiang Xi
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.
Zhang Pumin
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Jin Jie
Key Laboratory of Hematopoietic Malignancies, Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
He Chuan
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.
Chen Jianjun
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.
Conflict of Interest

The authors declare no competing financial interests.

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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccell.2016.11.017
Email
chuanhe@uchicago.edu
chen3jj@ucmail.uc.edu
Published
2017-00-09
Epub
2016-00-22
Pages
127-141
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC5234852
Subset
IM
Grants
NCI NIH HHS · R01 CA122623 · United States
NCI NIH HHS · R01 CA182528 · United States
NCI NIH HHS · R01 CA214965 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · R01 CA116097 · United States
NCI NIH HHS · T32 CA009594 · United States
NIGMS NIH HHS · R01 GM071440 · United States
NCI NIH HHS · R01 CA178454 · United States
NCI NIH HHS · R01 CA211614 · United States
Corrections
CommentIn
PMID: 28486104
External Links
PubMed source DOI: 10.1016/j.ccell.2016.11.017 PMC Full Text View journal details
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