BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation

The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic an...

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Published in:Nature (London) 2017-11, Vol.551 (7680), p.384-388
Main Authors: Raffel, Simon, Falcone, Mattia, Kneisel, Niclas, Hansson, Jenny, Wang, Wei, Lutz, Christoph, Bullinger, Lars, Poschet, Gernot, Nonnenmacher, Yannic, Barnert, Andrea, Bahr, Carsten, Zeisberger, Petra, Przybylla, Adriana, Sohn, Markus, Tönjes, Martje, Erez, Ayelet, Adler, Lital, Jensen, Patrizia, Scholl, Claudia, Fröhling, Stefan, Cocciardi, Sibylle, Wuchter, Patrick, Thiede, Christian, Flörcken, Anne, Westermann, Jörg, Ehninger, Gerhard, Lichter, Peter, Hiller, Karsten, Hell, Rüdiger, Herrmann, Carl, Ho, Anthony D, Krijgsveld, Jeroen, Radlwimmer, Bernhard, Trumpp, Andreas
Format: Article
Language:English
Subjects:
Amino Acids, Branched-Chain - metabolism
Animals
Cell Proliferation
DNA Methylation
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Epistasis, Genetic
Female
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism
Isocitrate Dehydrogenase - genetics
Isocitrate Dehydrogenase - metabolism
Ketoglutaric Acids - metabolism
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - enzymology
Leukemia, Myeloid, Acute - metabolism
Leukemia, Myeloid, Acute - pathology
Mice
Molecular Targeted Therapy
Mutation
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Prognosis
Proteolysis
Proteomics
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Transaminases - deficiency
Transaminases - genetics
Transaminases - metabolism
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Summary:The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Further to its role in the tricarboxylic acid cycle, αKG is an essential cofactor for αKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG, leading to EGLN1-mediated HIF1α protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1 ) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDH ), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDH TET2 , but not IDH or TET2 AML. Gene sets characteristic for IDH AML were enriched in samples from patients with an IDH TET2 BCAT1 status. BCAT1 AML showed robust enrichment for leukaemia stem-cell signatures, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1α stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA-BCAT1-αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDH TET2 AML.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature24294