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Nature. 2017 May 25;545(7655):500-504. doi: 10.1038/nature22314. Epub 2017 May 17.

Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia.

Author information

1
Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, The University of Georgia, Athens, Georgia 30602, USA.
2
The University of Georgia Cancer Center, The University of Georgia, Athens, Georgia 30602, USA.
3
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.
4
Department of Hematology and Oncology, The Institute of Medical Science, The University of Tokyo, Minato, Tokyo 108-8639, Japan.
5
Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602, USA.
6
Complex Carbohydrate Research Center, The University of Georgia, Athens, Georgia 30602, USA.
7
Institute of Bioinformatics, The University of Georgia, Athens, Georgia 30602, USA.
8
Department of Genetics, Franklin College of Arts and Sciences, The University of Georgia, Athens, Georgia 30602, USA.

Abstract

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.

PMID:
28514443
PMCID:
PMC5554449
DOI:
10.1038/nature22314
[Indexed for MEDLINE]
Free PMC Article

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