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@ARTICLE{Uras:130701,
      author       = {I. Z. Uras and G. Walter$^*$ and R. Scheicher and F.
                      Bellutti and M. Prchal-Murphy and A. S. Tigan and P. Valent
                      and F. H. Heidel and S. Kubicek and C. Scholl$^*$ and S.
                      Fröhling$^*$ and V. Sexl},
      title        = {{P}albociclib treatment of {FLT}3-{ITD}+ {AML} cells
                      uncovers a kinase-dependent transcriptional regulation of
                      {FLT}3 and {PIM}1 by {CDK}6.},
      journal      = {Blood},
      volume       = {127},
      number       = {23},
      issn         = {1528-0020},
      address      = {Stanford, Calif.},
      publisher    = {HighWire Press},
      reportid     = {DKFZ-2017-05779},
      pages        = {2890 - 2902},
      year         = {2016},
      abstract     = {Up to $30\%$ of patients with acute myeloid leukemia have
                      constitutively activating internal tandem duplications
                      (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations
                      are associated with a poor prognosis and a high propensity
                      to relapse after remission. FLT3 inhibitors are being
                      developed as targeted therapy for FLT3-ITD(+) acute myeloid
                      leukemia; however, their use is complicated by rapid
                      development of resistance, which illustrates the need for
                      additional therapeutic targets. We show that the US Food and
                      Drug Administration-approved CDK4/6 kinase inhibitor
                      palbociclib induces apoptosis of FLT3-ITD leukemic cells.
                      The effect is specific for FLT3-mutant cells and is ascribed
                      to the transcriptional activity of CDK6: CDK6 but not its
                      functional homolog CDK4 is found at the promoters of the
                      FLT3 and PIM1 genes, another important leukemogenic driver.
                      There CDK6 regulates transcription in a kinase-dependent
                      manner. Of potential clinical relevance, combined treatment
                      with palbociclib and FLT3 inhibitors results in synergistic
                      cytotoxicity. Simultaneously targeting two critical
                      signaling nodes in leukemogenesis could represent a
                      therapeutic breakthrough, leading to complete remission and
                      overcoming resistance to FLT3 inhibitors.},
      keywords     = {Mutant Proteins (NLM Chemicals) / Piperazines (NLM
                      Chemicals) / Protein Kinase Inhibitors (NLM Chemicals) /
                      Proto-Oncogene Proteins (NLM Chemicals) / Pyridines (NLM
                      Chemicals) / FLT3 protein, human (NLM Chemicals) / fms-Like
                      Tyrosine Kinase 3 (NLM Chemicals) / PIM3 protein, human (NLM
                      Chemicals) / Protein-Serine-Threonine Kinases (NLM
                      Chemicals) / CDK6 protein, human (NLM Chemicals) /
                      Cyclin-Dependent Kinase 6 (NLM Chemicals) / palbociclib (NLM
                      Chemicals)},
      cin          = {G100 / G102 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)G100-20160331 / I:(DE-He78)G102-20160331 /
                      I:(DE-He78)L101-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27099147},
      pmc          = {pmc:PMC4920675},
      doi          = {10.1182/blood-2015-11-683581},
      url          = {https://inrepo02.dkfz.de/record/130701},
}