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

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Item Type:	Article
Title:	BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation
Creators Name:	Raffel, S., Falcone, M., Kneisel, N., Hansson, J., Wang, W., Lutz, C., Bullinger, L., Poschet, G., Nonnenmacher, Y., Barnert, A., Bahr, C., Zeisberger, P., Przybylla, A., Sohn, M., Tönjes, M., Erez, A., Adler, L., Jensen, P., Scholl, C., Fröhling, S., Cocciardi, S., Wuchter, P., Thiede, C., Flörcken, A., Westermann, J., Ehninger, G., Lichter, P., Hiller, K., Hell, R., Herrmann, C., Ho, A.D., Krijgsveld, J., Radlwimmer, B. and Trumpp, A.
Abstract:	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 gro(WT)h 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 (mut)ant isocitrate dehydrogenase (IDH(mut)), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. (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 characteristic for IDH(mut) AML were enriched in samples from patients with an IDH(WT)TET2(WT)BCAT1(high) status. BCAT1(high) 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 (mut)ations. Our results suggest the BCAA-BCAT1-αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDH(WT)TET2(WT) AML.
Keywords:	Acute Myeloid Leukemia, alpha Subunit Hypoxia-Inducible Factor 1, Animals, Branched-Chain Amino Acids, Cell Proliferation, DNA Methylation, DNA-Binding Proteins, Dioxygenases, Genetic Epistasis, Hypoxia-Inducible Factor-Proline Dioxygenases, Isocitrate Dehydrogenase, Ketoglutaric Acids, Mice, Molecular Targeted Therapy, Mutation, Neoplastic Stem Cells, Prognosis, Proteolysis, Proteomics, Proto-Oncogene Proteins, Transaminases
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	551
Number:	7680
Page Range:	384-388
Date:	16 November 2017
Additional Information:	Erratum in: Nature 560(7718):E28.
Official Publication:	https://doi.org/10.1038/nature24294
PubMed:	View item in PubMed

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