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• W2981625093 abstract "Abstract Gamma-secretase inhibitors (GSIs), which block the activation of the NOTCH1 receptor, are currently being tested in the treatment of T-cell lymphoblastic leukemias (T-ALL) with activating mutations in the NOTCH1 gene. However, inhibition of NOTCH1 signaling induces only a delayed cytostatic antileukemic effect with little or no apoptosis and GSI treatment is associated with severe gastrointestinal toxicity, which limits the clinical application of these molecularly targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids reverses glucocorticoid resistance and is highly effective against T-ALL. Inhibition of NOTCH1 signaling with CompE, a highly active GSI, in combination with dexamethasone, induced apoptotic cell death in glucocorticoid-resistant T-ALL cell lines. The synergistic antileukemic effect of GSIs and glucocorticoids was effectively rescued by forced expression of ICN1, an intracellular form of NOTCH1 that does not require gamma-secretase processing; or by treatment with the glucocorticoid receptor antagonist RU486. Reversal of glucocorticoid resistance by CompE treatment was mediated by transcriptional upregulation of BIM, a BH3-only proapototic factor previously involved in glucocorticoid induced cell death. Thus, shRNA knock down of BIM effectively impaired the ability of CompE plus dexamethasone to induce programmed cell death in leukemic lymphoblasts. Using a mouse xenograft model of glucocorticoid-resistant T-ALL we demonstrated that the combination of DBZ, a GSI with well established activity in vivo, and dexamethasone is highly effective against glucocorticoid resistant T-ALL in vivo. All animals treated with DBZ plus dexamethasone showed complete clearance of leukemic lymphoblasts and improved survival, while mice treated with vehicle or dexamethasone alone died because of disease progression (P&lt;0.05). In these studies, treatment with DBZ alone was associated with accelerated mortality because of severe intestinal toxicity characterized by goblet cell metaplasia in the small intestine. Surprisingly, mice treated with DBZ plus dexamethasone were protected clinically and histologically from GSI-induced intestinal toxicity. Pharmacokinetic analysis demonstrated that the interaction of dexamethasone and DBZ in the gut was not mediated by increased DBZ metabolism induced by dexamethasone. Molecular characterization of GSI induced gut toxicity demonstrated transcriptional upregulation of Klf4, a critical regulator of goblet cell differentiation, in the intestines of animals treated with DBZ. Klf4 regulation downstream of NOTCH signaling is mediated by HES1, a transcriptional repressor regulated by NOTCH. Importantly, dexamethasone treatment blocked the upregulation Klf4 induced by GSI treatment in vivo, suggesting that modulation of Klf4 expression may mediate the enteroprotective effects of glucocorticoids against GSI-induced toxicity. Overall, these results support a role for the combination of glucocorticoids plus GSIs in the treatment of glucocorticoid resistant T-ALL." @default.
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• W2981625093 date "2007-11-16" @default.
• W2981625093 modified "2023-10-18" @default.
• W2981625093 title "Inhibition of NOTCH1 Signaling Reverses Glucocorticoid Resistance in T-ALL." @default.
• W2981625093 doi "https://doi.org/10.1182/blood.v110.11.151.151" @default.
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