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@ARTICLE{Chatain:280470,
      author       = {Chatain, N. and Perera, R. C. and Rossetti, G. and Rossa,
                      J. and Carloni, P. and Schemionek, M. and Haferlach, T. and
                      Brümmendorf, T. H. and Schnittger, S. and Koschmieder, S.},
      title        = {{R}are {FLT}3 deletion mutants may provide additional
                      treatment options to patients with {AML}: an approach to
                      individualized medicine},
      journal      = {Leukemia},
      volume       = {29},
      number       = {12},
      issn         = {1476-5551},
      address      = {Basingstoke},
      publisher    = {Nature Publ. Group},
      reportid     = {FZJ-2016-00244},
      pages        = {2434 - 2438},
      year         = {2015},
      abstract     = {The receptor tyrosine kinase (RTK) FLT3 (Fms-like tyrosine
                      kinase-3) is essential for the proliferation,
                      differentiation and survival of hematopoietic cells.1, 2
                      Mutations in the gene for FLT3 have been described in acute
                      myeloid leukemia (AML) as internal tandem duplications (ITD)
                      localized in the juxtamembrane (JM) domain and FLT3 tyrosine
                      kinase domain (TKD) mutations amounting to $2–30\%$ and
                      $7–10\%$ of patients, respectively. In patients with AML,
                      FLT3-ITD confers an unfavorable prognosis.3 In AML, recently
                      discovered FLT3 mutations involve point mutations as well as
                      short deletions in the JM domain, highlighting the
                      importance for a deeper understanding and further studies of
                      these aberrations.4, 5 The FLT3 JM domain (Supplementary
                      Figure 1a) is indeed the critical regulator region of
                      receptor autoinhibition.6 Kiyoi et al.7 had shown
                      constitutive activation of the FLT3 receptor by deletion of
                      a stretch of amino acids in the JM domain, generally
                      duplicated in FLT3-ITD.In this study, during diagnostic
                      screening for ITD and TKD mutations, we have identified and
                      functionally characterized deletion mutations of FLT3 in the
                      diagnostic work-up of over 6843 AML patients. Deletions were
                      detected in seven patients $(0.1\%)$ with newly diagnosed or
                      relapsed AML. All deletions detected by gene scan were in
                      the range of 3–18 base pairs (Supplementary Table 1 and
                      Figure 1a). Subsequent sequencing revealed that all but one
                      of these deletions, which was situated in the transmembrane
                      domain, were in the JM domain, and were simple deletions
                      (n=5) or indels (n=2). In three cases out of seven, the
                      mutations resulted in a premature stop codon. As loss of the
                      wild-type (WT) allele in FLT3-ITD knock-in mice led to a
                      more severe phenotype,8 we analyzed whether the FLT3
                      mutations were biallelic. However, we could not detect ITD
                      or TKD mutations on the other allele of these patients.
                      Remission samples of patient Id 2–7 confirmed the somatic
                      character of the mutations. We analyzed the transforming
                      potential of such deletions and performed computational
                      modeling to predict the structural effect of two deletions
                      (Id 5: $p.Glu598_Tyr599del—delEY;$ Id 6:
                      $p.Phe590_Asp593delinsLeuTyr—delIns).$},
      cin          = {JSC / INM-9 / IAS-5},
      ddc          = {610},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)INM-9-20140121 /
                      I:(DE-Juel1)IAS-5-20120330},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / 572 - (Dys-)function and Plasticity (POF3-572)},
      pid          = {G:(DE-HGF)POF3-511 / G:(DE-HGF)POF3-572},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000366393900030},
      doi          = {10.1038/leu.2015.131},
      url          = {https://juser.fz-juelich.de/record/280470},
}