h1

TY  - THES
AU  - Maletzke, Saskia
TI  - Die duale Hemmung der BCR-ABL1 Kinase und des Proteasoms als neuer Therapieansatz in der BCR-ABL positiven akuten lymphatischen Leukämie
PB  - Rheinisch-Westfälische Technische Hochschule Aachen
VL  - Dissertation
CY  - Aachen
M1  - RWTH-2021-01251
SP  - 1 Online-Ressource : Illustrationen, Diagramme
PY  - 2021
N1  - Veröffentlicht auf dem Publikationsserver der RWTH Aachen University
N1  - Dissertation, Rheinisch-Westfälische Technische Hochschule Aachen, 2021
AB  - 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.
LB  - PUB:(DE-HGF)11
DO  - DOI:10.18154/RWTH-2021-01251
UR  - https://publications.rwth-aachen.de/record/811546
ER  -