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

Shuangyou Liu (1) , Stephen Breit (1) , Sven Danckwardt (1) , Martina U. Muckenthaler (1) , Andreas E. Kulozik (1)

1 Department of Pediatric Oncology, Hematology and Immunology

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, -asparaginase (-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 -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.

Mots clés: Acute lymphoblastic leukemia; Notch; Apoptosis; Chemotherapy

Shuangyou Liu, Stephen Breit, Sven Danckwardt, Martina U. Muckenthaler, Andreas E. Kulozik. Downregulation of Notch signaling by γ-secretase inhibition can abrogate chemotherapy-induced apoptosis in T-ALL cell lines. Annals of Hematology, 2008, 88 (7), pp.613-621. ⟨10.1007/s00277-008-0646-x⟩. ⟨hal-00535008⟩