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

Zejuan Li; Hengyou Weng; Rui Su; Xiaocheng Weng; Zhixiang Zuo; Chenying Li; Huilin Huang; Sigrid Nachtergaele; Lei Dong; Chao Hu; Xi Qin; Lichun Tang; Yungui Wang; Gia-Ming Hong; Hao Huang; Xiao Wang; Ping Chen; Sandeep Gurbuxani; Stephen Arnovitz; Yuanyuan Li; Shenglai Li; Jennifer Strong; Mary Beth Neilly; Richard A Larson; Xi Jiang; Pumin Zhang; Jie Jin; Chuan He; Jianjun Chen

doi:10.1016/j.ccell.2016.11.017

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

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

Authors

Zejuan Li¹, Hengyou Weng², Rui Su³, Xiaocheng Weng⁴, Zhixiang Zuo⁵, Chenying Li⁶, Huilin Huang³, Sigrid Nachtergaele⁷, Lei Dong³, Chao Hu⁸, Xi Qin³, Lichun Tang⁹, Yungui Wang⁸, Gia-Ming Hong¹⁰, Hao Huang¹⁰, Xiao Wang⁷, Ping Chen¹⁰, Sandeep Gurbuxani¹¹, Stephen Arnovitz¹⁰, Yuanyuan Li¹⁰, Shenglai Li¹⁰, Jennifer Strong³, Mary Beth Neilly¹⁰, Richard A Larson¹⁰, Xi Jiang², Pumin Zhang⁹, Jie Jin¹², Chuan He¹³, Jianjun Chen¹⁴

Affiliations

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.

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / metabolism
Alpha-Ketoglutarate-Dependent Dioxygenase FTO / physiology*
Apoptosis
Cell Proliferation
Humans
Leukemia, Myeloid, Acute / drug therapy
Leukemia, Myeloid, Acute / enzymology
Leukemia, Myeloid, Acute / etiology*
Leukemia, Myeloid, Acute / pathology
Methylation
Nucleophosmin
Retinoic Acid Receptor alpha / physiology
Suppressor of Cytokine Signaling Proteins / physiology
Transcriptome
Tretinoin / pharmacology

Substances

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

Abstract

MeSH terms

Substances

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