TY  - JOUR
AU  - Raffel, Simon
AU  - Falcone, Mattia
AU  - Kneisel, Niclas
AU  - Hansson, Jenny
AU  - Wang, Wei
AU  - Lutz, Christoph
AU  - Bullinger, Lars
AU  - Poschet, Gernot
AU  - Nonnenmacher, Yannic
AU  - Barnert, Andrea
AU  - Bahr, Carsten
AU  - Zeisberger, Petra
AU  - Przybylla, Adriana
AU  - Sohn, Markus
AU  - Tönjes, Martje
AU  - Erez, Ayelet
AU  - Adler, Lital
AU  - Jensen, Patrizia
AU  - Scholl, Claudia
AU  - Fröhling, Stefan
AU  - Cocciardi, Sibylle
AU  - Wuchter, Patrick
AU  - Thiede, Christian
AU  - Flörcken, Anne
AU  - Westermann, Jörg
AU  - Ehninger, Gerhard
AU  - Lichter, Peter
AU  - Hiller, Karsten
AU  - Hell, Rüdiger
AU  - Herrmann, Carl
AU  - Ho, Anthony D
AU  - Krijgsveld, Jeroen
AU  - Radlwimmer, Bernhard
AU  - Trumpp, Andreas
TI  - BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation.
JO  - Nature 
VL  - 551
IS  - 7680
SN  - 1476-4687
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2017-06135
SP  - 384 - 388
PY  - 2017
AB  - 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 (BCAT1high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHWTTET2WT, but not IDHmut or TET2mut AML. Gene sets characteristic for IDHmut AML were enriched in samples from patients with an IDHWTTET2WTBCAT1high status. BCAT1high 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 IDHWTTET2WT AML.
LB  - PUB:(DE-HGF)16
C6  - pmid:29144447
DO  - DOI:10.1038/nature24294
UR  - https://inrepo02.dkfz.de/record/131068
ER  -