Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia
Open accessAbstract
Reprogrammed cellular metabolism is a common characteristic observed in various cancers. 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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Tumors of other lineages, including some glioblastomas and blast crisis chronic myeloid leukemia, are also dependent on BCAA transaminases.
“Tumors of other lineages are also dependent on BCAA transaminases, including some glioblastomas and blast crisis chronic myeloid leukemia (Hattori et al., 2017; Tonjes et al., 2013).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Hattori et al., 2017
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Self-citation
- Authors
- Hattori, A., Tsunoda, M., Konuma, T., Kobayashi, M., Nagy, T., Glushka, J., Tayyari, F., McSkimming, D., Kannan, N., Tojo, A., Edison, A. S., & Ito, T.
- Affiliations
- University of Georgia (US)
- The University of Tokyo (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Corresponding author
- Ito, Takahiro
- ORCID
- Venue
- Nature
- Published
- 2017-05
- Volume
- 545
- Issue
- 7655
- Pages
- 500-504
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5554449
- OpenAlex
- W2615073964
- Cited by
- 401
- References
- 37
- Citations by year
- 2026: 31 · 2025: 42 · 2024: 45 · 2023: 52 · 2022: 60 · 2021: 54 · 2020: 46 · 2019: 33 · 2018: 28 · 2017: 8
- FWCI
- 24.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (17K08234, 16K19570, 16J02129, 16H06277)
- National Institute of General Medical Sciences (R01GM114409, P41GM103390)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK097209)
- Topics
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- BCAT1, branched-chain amino acids, branched-chain amino acid metabolism, chronic myeloid leukemia, blast crisis, Musashi-2, RNA-binding proteins, cancer metabolism, leukemia progression, prognostic factors, acute myeloid leukemia
- MeSH terms
- Amino Acids, Branched-Chain, Transaminases, Animals, Blast Crisis, Cell Differentiation, Enzyme Activation, Female, Humans, Male, Mice, Inbred C57BL, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, RNA-Binding Proteins, Disease Progression, Cell Proliferation, Mice
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