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

Raffel, Simon ; Falcone, Mattia ; Kneisel, Niclas ; Hansson, Jenny LU orcid ; Wang, Wei ; Lutz, Christoph ; Bullinger, Lars ; Poschet, Gernot ; Nonnenmacher, Yannic and Barnert, Andrea , et al. (2017) In Nature 551(7680). p.384-388
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... (More)

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.

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keywords
Amino Acids, Branched-Chain, Animals, Cell Proliferation, DNA Methylation, DNA-Binding Proteins, Epistasis, Genetic, Female, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Isocitrate Dehydrogenase, Ketoglutaric Acids, Leukemia, Myeloid, Acute, Mice, Molecular Targeted Therapy, Mutation, Neoplastic Stem Cells, Prognosis, Proteolysis, Proteomics, Proto-Oncogene Proteins, Transaminases, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.
in
Nature
volume
551
issue
7680
pages
5 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:29144447
  • scopus:85034609644
ISSN
0028-0836
DOI
10.1038/nature24294
language
English
LU publication?
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fc7513e8-e0cd-429d-afe9-15564351d103
date added to LUP
2018-04-28 10:45:52
date last changed
2024-06-11 14:39:43
@article{fc7513e8-e0cd-429d-afe9-15564351d103,
  abstract     = {{<p>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.</p>}},
  author       = {{Raffel, Simon and Falcone, Mattia and Kneisel, Niclas and Hansson, Jenny and Wang, Wei and Lutz, Christoph and Bullinger, Lars and Poschet, Gernot and Nonnenmacher, Yannic and Barnert, Andrea and Bahr, Carsten and Zeisberger, Petra and Przybylla, Adriana and Sohn, Markus and Tönjes, Martje and Erez, Ayelet and Adler, Lital and Jensen, Patrizia and Scholl, Claudia and Fröhling, Stefan and Cocciardi, Sibylle and Wuchter, Patrick and Thiede, Christian and Flörcken, Anne and Westermann, Jörg and Ehninger, Gerhard and Lichter, Peter and Hiller, Karsten and Hell, Rüdiger and Herrmann, Carl and Ho, Anthony D and Krijgsveld, Jeroen and Radlwimmer, Bernhard and Trumpp, Andreas}},
  issn         = {{0028-0836}},
  keywords     = {{Amino Acids, Branched-Chain; Animals; Cell Proliferation; DNA Methylation; DNA-Binding Proteins; Epistasis, Genetic; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Isocitrate Dehydrogenase; Ketoglutaric Acids; Leukemia, Myeloid, Acute; Mice; Molecular Targeted Therapy; Mutation; Neoplastic Stem Cells; Prognosis; Proteolysis; Proteomics; Proto-Oncogene Proteins; Transaminases; Journal Article; Research Support, U.S. Gov't, Non-P.H.S.}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{7680}},
  pages        = {{384--388}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation}},
  url          = {{http://dx.doi.org/10.1038/nature24294}},
  doi          = {{10.1038/nature24294}},
  volume       = {{551}},
  year         = {{2017}},
}