Letter | Published:

Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia

Nature volume 545, pages 500504 (25 May 2017) | Download Citation

Abstract

Reprogrammed cellular metabolism is a common characteristic observed in various cancers1,2. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2–BCAT1 axis drives cancer progression in myeloid leukaemia.

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Acknowledgements

We thank W. Pear, D. Baltimore and S. Lowe for plasmids, and S. Dalton, C. Jordan, B. Zimdahl, J. Ninomiya-Tsuji, K. Sai, K. Matsumoto, H. Hanafusa, T. Mizuno, Y. Kuwatsuka, Y. Minami and M. Merritt for discussions and comments on the manuscript. We also thank J. Nelson at the CTEGD Cytometry Shared Resource Laboratory, University of Georgia, for assistance in cell sorting, K. Sekimizu, C. West, M. Mandalasi and H. van der Wel for advice on radioisotope use, and K. MacKeil, J. Nist and K. Ogata for technical help. This work was supported by grants from the University of Georgia Research Foundation and the Heather Wright Cancer Research Fund (T.I.); by the Japan Society for the Promotion of Science Bilateral Open Partnership Joint Research Projects Program (M.T.); A.S.E. and the Complex Carbohydrate Research Center NMR facility were partly supported by the Southeast Center for Integrated Metabolomics, National Institutes of Health U24DK097209 and the Georgia Research Alliance.

Author information

Affiliations

  1. Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, The University of Georgia, Athens, Georgia 30602, USA

    • Ayuna Hattori
    • , Fariba Tayyari
    • , Daniel McSkimming
    • , Natarajan Kannan
    • , Arthur S. Edison
    •  & Takahiro Ito
  2. The University of Georgia Cancer Center, The University of Georgia, Athens, Georgia 30602, USA

    • Ayuna Hattori
    • , Natarajan Kannan
    •  & Takahiro Ito
  3. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo 113-0033, Japan

    • Makoto Tsunoda
  4. Department of Hematology and Oncology, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan

    • Takaaki Konuma
    • , Masayuki Kobayashi
    •  & Arinobu Tojo
  5. Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602, USA

    • Tamas Nagy
  6. Complex Carbohydrate Research Center, The University of Georgia, Athens, Georgia 30602, USA

    • John Glushka
    • , Fariba Tayyari
    •  & Arthur S. Edison
  7. Institute of Bioinformatics, The University of Georgia, Athens, Georgia 30602, USA

    • Daniel McSkimming
    • , Natarajan Kannan
    •  & Arthur S. Edison
  8. Department of Genetics, Franklin College of Arts and Sciences, The University of Georgia, Athens, Georgia 30602, USA

    • Arthur S. Edison

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Contributions

A.H. designed the studies, performed all experiments, analysed the data and wrote the manuscript. M.T. designed and performed experiments related to quantitative analysis of amino and keto acids. T.K., M.K. and A.T. provided and performed experiments with human primary samples. T.N. performed histological and cytological analysis. J.G., F.T. and A.S.E. designed and conducted NMR-based metabolic analysis. D.M. and N.K. performed bioinformatics analysis of gene expression datasets. T.I. conceived and supervised the project and wrote the manuscript.

Competing interests

T.I. and A.H. are named inventors of a provisional patent application number 62/413,028.

Corresponding author

Correspondence to Takahiro Ito.

Reviewer Information Nature thanks B. Huntly, D. Sabatini and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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DOI

https://doi.org/10.1038/nature22314

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