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@ARTICLE{Rudat:141140,
      author       = {S. Rudat$^*$ and A. Pfaus$^*$ and Y. Y. Cheng$^*$ and J.
                      Holtmann$^*$ and J. M. Ellegast and C. Bühler and D. D.
                      Marcantonio and E. Martinez and S. Göllner and C.
                      Wickenhauser and C. Müller-Tidow and C. Lutz and L.
                      Bullinger and M. Milsom$^*$ and S. M. Sykes and S.
                      Fröhling$^*$ and C. Scholl$^*$},
      title        = {{RET}-mediated autophagy suppression as targetable
                      co-dependence in acute myeloid leukemia.},
      journal      = {Leukemia},
      volume       = {32},
      number       = {10},
      issn         = {1476-5551},
      address      = {London},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2018-01671},
      pages        = {2189 - 2202},
      year         = {2018},
      abstract     = {Many cases of AML are associated with mutational activation
                      of receptor tyrosine kinases (RTKs) such as FLT3. However,
                      RTK inhibitors have limited clinical efficacy as single
                      agents, indicating that AML is driven by concomitant
                      activation of different signaling molecules. We used a
                      functional genomic approach to identify RET, encoding an
                      RTK, as an essential gene in multiple subtypes of AML, and
                      observed that AML cells show activation of RET signaling via
                      ARTN/GFRA3 and NRTN/GFRA2 ligand/co-receptor complexes.
                      Interrogation of downstream pathways identified
                      mTORC1-mediated suppression of autophagy and subsequent
                      stabilization of leukemogenic drivers such as mutant FLT3 as
                      important RET effectors. Accordingly, genetic or
                      pharmacologic RET inhibition impaired the growth of
                      FLT3-dependent AML cell lines and was accompanied by
                      upregulation of autophagy and FLT3 depletion. RET dependence
                      was also evident in mouse models of AML and primary AML
                      patient samples, and transcriptome and immunohistochemistry
                      analyses identified elevated RET mRNA levels and
                      co-expression of RET and FLT3 proteins in a substantial
                      proportion of AML patients. Our results indicate that
                      RET-mTORC1 signaling promotes AML through autophagy
                      suppression, suggesting that targeting RET or, more broadly,
                      depletion of leukemogenic drivers via autophagy induction
                      provides a therapeutic opportunity in a relevant subset of
                      AML patients.},
      cin          = {G100 / A012 / L101 / G102},
      ddc          = {610},
      cid          = {I:(DE-He78)G100-20160331 / I:(DE-He78)A012-20160331 /
                      I:(DE-He78)L101-20160331 / I:(DE-He78)G102-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29654265},
      doi          = {10.1038/s41375-018-0102-4},
      url          = {https://inrepo02.dkfz.de/record/141140},
}