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@PHDTHESIS{Maletzke:811546,
      author       = {Maletzke, Saskia},
      othercontributors = {Koschmieder, Steffen and Gess, Burkhard},
      title        = {{D}ie duale {H}emmung der {BCR}-{ABL}1 {K}inase und des
                      {P}roteasoms als neuer {T}herapieansatz in der {BCR}-{ABL}
                      positiven akuten lymphatischen {L}eukämie},
      school       = {Rheinisch-Westfälische Technische Hochschule Aachen},
      type         = {Dissertation},
      address      = {Aachen},
      publisher    = {RWTH Aachen University},
      reportid     = {RWTH-2021-01251},
      pages        = {1 Online-Ressource : Illustrationen, Diagramme},
      year         = {2021},
      note         = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
                      University; Dissertation, Rheinisch-Westfälische Technische
                      Hochschule Aachen, 2021},
      abstract     = {Acute lymphoblastic leukemia (ALL) is a disease of lymphoid
                      progenitor cells with an often aggressive course and is
                      frequently driven by the BCR-ABL fusion gene t(9;22) in
                      adults. The fusion gene results from the Philadelphia
                      translocation t(9;22) and codes for a constitutively active
                      tyrosine kinase which can be efficiently inhibited by
                      Tyrosine kinase inhibitors like imatinib or dasatinib.
                      However, BCR-ABL+ ALL cells rapidly develop mutations
                      against these targeted agents, leading to relapse and an
                      overall still dismal prognosis for patients with this
                      disease. To date, allogeneic stem cell transplantation is
                      the only known curative option. Older patients can still
                      often not undergo this strenuous procedure because of
                      comorbidities or frailty. In this work, we show that the
                      combination of TKIs with proteasome inhibitors efficiently
                      kills Ph+ ALL cells by induction of apoptosis and thereby
                      broadens the spectrum of therapeutic options for patients
                      with Ph+ ALL. We show the efficacy of proteasome inhibitors
                      in cell lines generated from primary refractory cases of
                      this disease in the study at hand. The single agent as well
                      as combined bortezomib or ixazomib and dasatinib treatment
                      had greater effects on cell viability in both cell lines
                      than the dasatinib single agent treatment. Outstanding we
                      did not observe an antagonistic effect between TKI and
                      proteasome inhibitor in all our experiments. Proteasome
                      inhibition as well as TKI treatment and the combination of
                      both inhibitor classes mainly results in apoptosis in our
                      Ph+ ALL cell lines, as shown by the results of the annexin V
                      staining und the western blot. In addition, proteasome
                      inhibitor treatment affects the unfolded protein response of
                      Ph+ ALL cells and cause significant cell stress. To
                      summarize, our results demonstrate a significant
                      pro-apoptotic effect of proteasome inhibitors on Ph+ ALL
                      cell lines. Treatment of BCR-ABL1 positive acute
                      lymphoblastic leukemia with a combined therapeutic regime
                      including the current standard therapy dasatinib together
                      with proteasome inhibitors appears to be an encouraging
                      approach but needs further validation in vivo and in the
                      clinical setting.},
      cin          = {531040-2},
      ddc          = {610},
      cid          = {$I:(DE-82)531040-2_20140620$},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.18154/RWTH-2021-01251},
      url          = {https://publications.rwth-aachen.de/record/811546},
}