Letter | Published:

Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia

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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Targeting cancer metabolism: a therapeutic window opens. Nat. Rev. Drug Discov. 10, 671–684 (2011)

  2. 2.

    & Cellular metabolism and disease: what do metabolic outliers teach us? Cell 148, 1132–1144 (2012)

  3. 3.

    , & Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990)

  4. 4.

    et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc. Natl Acad. Sci. USA 99, 7622–7627 (2002)

  5. 5.

    & Branched-chain amino acids: enzyme and substrate regulation. J. Nutr. 136 (Suppl.), 207S–211S (2006)

  6. 6.

    , & Branched-chain amino acid metabolism: implications for establishing safe intakes. J. Nutr. 135 (Suppl), 1557S–1564S (2005)

  7. 7.

    et al. Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism. J. Neurochem. 71, 863–874 (1998)

  8. 8.

    et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc. Natl Acad. Sci. USA 103, 2794–2799 (2006)

  9. 9.

    et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351, 43–48 (2016)

  10. 10.

    et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149, 410–424 (2012)

  11. 11.

    & Regulation of mTORC1 by amino acids. Trends Cell Biol. 24, 400–406 (2014)

  12. 12.

    , & Amino acid signalling upstream of mTOR. Nat. Rev. Mol. Cell Biol. 14, 133–139 (2013)

  13. 13.

    , & Musashi: a translational regulator of cell fate. J. Cell Sci. 115, 1355–1359 (2002)

  14. 14.

    , , & The Musashi family of RNA binding proteins: master regulators of multiple stem cell populations. Adv. Exp. Med. Biol. 786, 233–245 (2013)

  15. 15.

    et al. Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells. Nature 532, 508–511 (2016)

  16. 16.

    et al. The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Mol. Cell. Biol. 21, 3888–3900 (2001)

  17. 17.

    & Musashi protein-directed translational activation of target mRNAs is mediated by the poly(A) polymerase, germ line development defective-2. J. Biol. Chem. 289, 14239–14251 (2014)

  18. 18.

    et al. Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival. Mol. Cancer 9, 221 (2010)

  19. 19.

    et al. RNA-binding protein Musashi1 modulates glioma cell growth through the post-transcriptional regulation of Notch and PI3 kinase/Akt signaling pathways. PLoS ONE 7, e33431 (2012)

  20. 20.

    et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 466, 765–768 (2010)

  21. 21.

    et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat. Med. 16, 903–908 (2010)

  22. 22.

    et al. ECA39 is a novel distant metastasis-related biomarker in colorectal cancer. World J. Gastroenterol. 12, 5884–5889 (2006)

  23. 23.

    et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat. Med. 19, 901–908 (2013)

  24. 24.

    et al. The RNA-binding protein Musashi-1 regulates proteasome subunit expression in breast cancer- and glioma-initiating cells. Stem Cells 32, 135–144 (2014)

  25. 25.

    et al. The Msi family of RNA-binding proteins function redundantly as intestinal oncoproteins. Cell Rep. 13, 2440–2455 (2015)

  26. 26.

    et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016)

  27. 27.

    , & The role of apoptosis in the regulation of hematopoietic stem cells: overexpression of Bcl-2 increases both their number and repopulation potential. J. Exp. Med. 191, 253–264 (2000)

  28. 28.

    , , & Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc. Natl Acad. Sci. USA 100, 183–188 (2003)

  29. 29.

    , , , & Oncogenic interaction between BCR-ABL and NUP98-HOXA9 demonstrated by the use of an in vitro purging culture system. Blood 100, 4177–4184 (2002)

  30. 30.

    et al. Leukemia stem cells in a genetically defined murine model of blast-crisis CML. Blood 110, 2578–2585 (2007)

  31. 31.

    et al. Gene sets identified with oncogene cooperativity analysis regulate in vivo growth and survival of leukemia stem cells. Cell Stem Cell 11, 359–372 (2012)

  32. 32.

    , & Amino acids analysis using a monolithic silica column after derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F). J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 879, 335–340 (2011)

  33. 33.

    , & Rapid determination of amino acids in biological samples using a monolithic silica column. Amino Acids 42, 1897–1902 (2012)

  34. 34.

    , , , & Branched-chain keto-acids and pyruvate in blood: measurement by HPLC with fluorimetric detection and changes in older subjects. Clin. Chem. 46, 848–853 (2000)

  35. 35.

    et al. Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity. J. Biol. Chem. 274, 19745–19751 (1999)

  36. 36.

    et al. Establishment and characterization of mammalian cell lines stably expressing human L-type amino acid transporters. J. Pharmacol. Sci. 108, 505–516 (2008)

  37. 37.

    et al. Metabolomics Workbench: an international repository for metabolomics data and metadata, metabolite standards, protocols, tutorials and training, and analysis tools. Nucleic Acids Res. 44 (D1), D463–D470 (2016)

Download references


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


  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


  1. Search for Ayuna Hattori in:

  2. Search for Makoto Tsunoda in:

  3. Search for Takaaki Konuma in:

  4. Search for Masayuki Kobayashi in:

  5. Search for Tamas Nagy in:

  6. Search for John Glushka in:

  7. Search for Fariba Tayyari in:

  8. Search for Daniel McSkimming in:

  9. Search for Natarajan Kannan in:

  10. Search for Arinobu Tojo in:

  11. Search for Arthur S. Edison in:

  12. Search for Takahiro Ito in:


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.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains a Supplementary Discussion, Supplementary References and the uncropped blots.

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.