Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia

Nature
Ayuna HattoriTakahiro Ito

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 ...Continue Reading

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Datasets Mentioned

BETA
AK056255
GSE4170
GSE14671
GSE10327
GSE20916
GSE14548
PR000423

Methods Mentioned

BETA
NMR
gene knockdown
immunoprecipitation
RIP
flow cytometry
PCRs
immunoprecipitations

Software Mentioned

GraphPad Prism
MestReNova
SciPy
Metabolomics Workbench
FlowJo
GraphPad
Agilent

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