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

• 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: 13/100; 13/106; 13/31; 631/1647/2067; 631/1647/320; 631/337/176/1988; 631/532/71; 631/67/1990/283/1897; 64/60; 82/58; Amino Acids, Branched-Chain - metabolism; Animals; Cell Proliferation; DNA Methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epistasis, Genetic; Female; Humanities and Social Sciences; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Ketoglutaric Acids - metabolism; letter; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; Molecular Targeted Therapy; multidisciplinary; Mutation; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Prognosis; Proteolysis; Proteomics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Science; Transaminases - deficiency; Transaminases - genetics; Transaminases - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature24294

The mechanistic basis for the role of the metabolic enzyme BCAA transaminase 1 (BCAT1) in acute myeloid leukaemias. BCAT1 behind DNA hypermethylation Overexpression of the metabolic enzyme BCAT1 has been observed in multiple cancer types. Andreas Trumpp, Bernhard Radlwimmer and colleagues have investigated the mechanistic basis of its role in acute myeloid leukaemia. They find that increased BCAT1 activity leads to a decrease in the metabolite αKG, which is known to inhibit members of the αKG-dependent dioxygenase enzyme family, including those that regulate DNA methylation. Accordingly, BCAT1 overexpression results in increased DNA methylation. Interestingly, the same phenotype is caused by mutations in TET and IDH genes that are also found in leukaemia patients. The findings suggest that BCAT1 could be a therapeutic target. 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 1 , 2 , 3 , 4 , 5 , 6 . 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 7 , 8 , 9 , 10 . 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 high ) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDH mut ), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate 11 , 12 . High levels of BCAT1 strongly correlate with shorter overall survival in IDH WT TET2 WT , but not IDH mut or TET2 mut AML. Gene sets characteristi