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Updated: Feb 9, 2026
Vaccines, APCs and Memory Cells
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia
Pedro J Real1, Valeria Tosello, Teresa Palomero
1Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
Abstract:
Gamma-secretase inhibitors (GSIs) block the activation of the oncogenic protein Notch homolog-1 (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 autoupregulation and induced apoptotic cell death through induction of the gene encoding BCL-2-like apoptosis initiator-11 (BCL2L11). GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of the gene encoding the transcription factor Krüppel-like factor-4 (Klf4), a negative regulator of the cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of cyclin D2 (Ccnd2) and protected mice from developing the 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.
Insights
Combination therapy with gamma-secretase inhibitors (GSIs) and glucocorticoids enhances anti-leukemic effects and reduces gut toxicity in T-ALL. This approach restores glucocorticoid sensitivity and promotes apoptosis in resistant T-ALL cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gamma-secretase inhibitors (GSIs) target Notch homolog-1 (NOTCH1) in T cell acute lymphoblastic leukemia (T-ALL).
- Clinical use of GSIs is limited by poor anti-leukemic activity and significant gastrointestinal toxicity.
- Glucocorticoid resistance is a challenge in T-ALL treatment.
Purpose of the Study:
- To investigate the efficacy of combining GSIs with glucocorticoids for T-ALL treatment.
- To elucidate the mechanisms underlying the combined therapy's effects on leukemia and gut toxicity.
- To explore the potential of this combination for glucocorticoid-resistant T-ALL.
Main Methods:
- Inhibition of NOTCH1 signaling using GSIs in glucocorticoid-resistant T-ALL models.
- Assessment of antileukemic effects, including apoptosis and cell cycle arrest.
- Evaluation of gut toxicity, goblet cell accumulation, and related gene expression (BCL2L11, Klf4, Ccnd2).
Main Results:
- Combination therapy improved anti-leukemic effects and reduced gut toxicity in vivo.
- NOTCH1 inhibition in resistant T-ALL restored glucocorticoid receptor signaling and induced apoptosis via BCL2L11.
- GSIs induced cell cycle arrest and goblet cell accumulation via Klf4; glucocorticoids counteracted this via Ccnd2.
Conclusions:
- Combination therapy with GSIs and glucocorticoids offers a promising strategy for treating T-ALL, including glucocorticoid-resistant cases.
- Glucocorticoids can mitigate GSI-induced gut toxicity while enhancing anti-leukemic activity.
- The findings support the clinical application of combined GSI and glucocorticoid therapy in T-ALL.
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