γ-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia

Abstract

Summary Gamma-secretase inhibitors (GSIs) block the activation of oncogenic NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of Klf4, a negative regulator of cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of Ccnd2 and protected mice from developing intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.

Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

“…34 This combination treatment improved anti-leukemic effects and reduced their gut toxicity in vivo. 34 Similarly, glucocorticoid treatment is part of the polychemotherapy regimens used in cHL, and might be tested in future studies in combination with GSI for treatment of lymphoma patients.…”

“…33 GSI treatment was hampered by severe gastrointestinal toxicity and limited anti-leukemic efficacy. 34 However, a study in mice showed very promising results when using GSI in combination with glucocorticoids in T-ALL. 34 This combination treatment improved anti-leukemic effects and reduced their gut toxicity in vivo.…”

Hes1 expression and CYLD repression are essential events downstream of Notch1 in T-cell leukemia

“…In fact, glucocorticoids, which are widely used for T-ALL treatment are well-known, although non-specific, NFκB inhibitors 29 and it has been previously published that combination of GSI and glucocorticoids is effective on leukemic treatment in mice models while reducing the intestinal toxicity effects of Notch inhibition. 30 In addition, the proteasome inhibitor bortezomib, which is also a well-known NFkB inhibitor, is used for the treatment of multiple myeloma and mantle cell lymphoma. 31 In summary, we here show that Hes1 directly represses CYLD promoter and that Hes1 activation and CYLD repression are both obligatory events to maintain predominant role in maintaining T-ALL in vivo.…”

γ-Secretase inhibitor DAPT attenuates intimal hyperplasia of vein grafts by inhibition of Notch1 signaling

“…Although gastrointestinal side effects have been reported for g-secretase inhibitor administration in mice, we did not observe any overt side effects of DAPT administration at this dose. 16 Histological and Immunofluorescence Analyses These rats were anaesthetized by the method as described earlier, and the venous grafts of rats were harvested at the given time point. Grafts were obtained by cutting the transplanted segments from the native vessels at the cuff end.…”