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Abstract

LI and COLLEAGUES, 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 studied how FTO [Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase] plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase.

Background

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 [Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase] FTO, as an m6A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML).

Methodology

FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.

Results

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.

Conclusion

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.

References

Li Z1, Weng H2, Su R3, Weng X4, Zuo Z5, Li C6, Huang H3, Nachtergaele S7, Dong L3, Hu C8, Qin X3, Tang L9, Wang Y8, Hong GM10, Huang H10, Wang X7, Chen P10, Gurbuxani S11, Arnovitz S10, Li Y10, Li S10, Strong J3, Neilly MB10, Larson RA10, Jiang X2, Zhang P9, Jin J12, He C13, Chen J14. FTO [Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase] Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase. Cancer Cell. 31(1):127-141. Jan 9 2017. doi: 10.1016/j.ccell.2016.11.017. Epub Dec 22 2016. Comment in
 IDH Mutation, Competitive Inhibition of FTO, and RNA Methylation. [Cancer Cell. 2017]

Comment

The above research at the molecular level with its considerable international collaboration of researchers, demonstrates how FTO [Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase] as an m6A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML).