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Downregulation of Notch signaling by γ-secretase inhibition can abrogate chemotherapy-induced apoptosis in T-ALL cell lines

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Abstract

Activation of Notch1 signaling plays an important role in the pathogenesis of precursor T-cell lymphoblastic leukemia (T-ALL). The Notch1 receptor is cleaved and activated via the γ-secretase complex. Downregulation of Notch1 signaling by γ-secretase inhibitors (GSIs) thus represents a potential novel therapeutic approach. In this study, we analyzed the response of four T-ALL cell lines to compound E, a potent γ-secretase inhibitor, and to the combination of compound E with vincristine, daunorubicin, l-asparaginase (l-ASP), and dexamethasone (DEX). We identified two distinct types of responses: In type 1 cell lines, represented by TALL1 and HSB2, GSI-induced apoptosis followed cell cycle arrest and enhanced the induction of apoptosis caused by DEX and l-ASP. In type 2 cell lines, represented by CEM and Jurkat J6, GSI caused neither cell cycle block nor cell death. Notably, the combination of GSI with chemotherapy-induced resistance by decreasing apoptosis. In type 2 cells, GSI induced the upregulation of Bcl-xl mRNA and protein, which was thus identified as a candidate mechanism for the inhibition of apoptosis. In conclusion, the data presented here caution against clinical use of a combination treatment of GSI and chemotherapy in T-ALL.

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Acknowledgments

This work was supported by a grant from the German Federal Ministry of Education and Research (NGFNplus) and by generous support by “Tour der Hoffnung”.

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Correspondence to Andreas E. Kulozik.

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Liu, S., Breit, S., Danckwardt, S. et al. Downregulation of Notch signaling by γ-secretase inhibition can abrogate chemotherapy-induced apoptosis in T-ALL cell lines. Ann Hematol 88, 613–621 (2009). https://doi.org/10.1007/s00277-008-0646-x

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  • DOI: https://doi.org/10.1007/s00277-008-0646-x

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