title: FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase.
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.
authors.affiliation: 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.
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Hengyou
authors.initials: H
authors.lastname: Weng
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Su
authors.affiliation: 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.
authors.forename: Xiaocheng
authors.initials: X
authors.lastname: Weng
authors.affiliation: 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.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: 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.
authors.forename: Chenying
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
authors.forename: Huilin
authors.initials: H
authors.lastname: Huang
authors.affiliation: Departments of Chemistry, Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Nachtergaele
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: Chao
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lichun
authors.initials: L
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Yungui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Gia-Ming
authors.initials: GM
authors.lastname: Hong
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.affiliation: Departments of Chemistry, Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Shenglai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Strong
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.affiliation: 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.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Pumin
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Hematopoietic Malignancies, Department of Hematology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.affiliation: 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.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: 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.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000502:physiology*; D017209:Apoptosis; D049109:Cell Proliferation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D008745:Methylation; D000090243:Nucleophosmin; D000072482:Retinoic Acid Receptor alpha / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology; D059467:Transcriptome; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C437987:ASB2 protein, human; C000716967:NPM1 protein, human; C000607071:RARA protein, human; D000072482:Retinoic Acid Receptor alpha; D050826:Suppressor of Cytokine Signaling Proteins; D000090243:Nucleophosmin; D014212:Tretinoin; C010223:N-methyladenosine; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D000241:Adenosine
keywords: AML; ASB2; ATRA; FTO; RARA; RNA modification; RNA stability; cell differentiation; leukemogenesis; m6A