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@ARTICLE{Raffel:131068,
      author       = {S. Raffel$^*$ and M. Falcone$^*$ and N. Kneisel$^*$ and J.
                      Hansson and W. Wang$^*$ and C. Lutz and L. Bullinger and G.
                      Poschet and Y. Nonnenmacher and A. Barnert$^*$ and C.
                      Bahr$^*$ and P. Zeisberger$^*$ and A. Przybylla$^*$ and M.
                      Sohn$^*$ and M. Tönjes and A. Erez and L. Adler and P.
                      Jensen$^*$ and C. Scholl$^*$ and S. Fröhling$^*$ and S.
                      Cocciardi and P. Wuchter and C. Thiede and A. Flörcken and
                      J. Westermann and G. Ehninger and P. Lichter$^*$ and K.
                      Hiller and R. Hell and C. Herrmann$^*$ and A. D. Ho and J.
                      Krijgsveld$^*$ and B. Radlwimmer$^*$ and A. Trumpp$^*$},
      title        = {{BCAT}1 restricts α{KG} levels in {AML} stem cells leading
                      to {IDH}mut-like {DNA} hypermethylation.},
      journal      = {Nature},
      volume       = {551},
      number       = {7680},
      issn         = {1476-4687},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2017-06135},
      pages        = {384 - 388},
      year         = {2017},
      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 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.},
      cin          = {G102 / A010 / B060 / B230 / B080 / G100 / V960 / A060 /
                      L101 / L301},
      ddc          = {070},
      cid          = {I:(DE-He78)G102-20160331 / I:(DE-He78)A010-20160331 /
                      I:(DE-He78)B060-20160331 / I:(DE-He78)B230-20160331 /
                      I:(DE-He78)B080-20160331 / I:(DE-He78)G100-20160331 /
                      I:(DE-He78)V960-20160331 / I:(DE-He78)A060-20160331 /
                      I:(DE-He78)L101-20160331 / I:(DE-He78)L301-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29144447},
      doi          = {10.1038/nature24294},
      url          = {https://inrepo02.dkfz.de/record/131068},
}