The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
γ-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia
Open accessAbstract
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.
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Puthalakath, H., Villunger, A., O'Reilly, L. A., Beaumont, J. G., Coultas, L., Cheney, R. E., Huang, D. C. S., & Strasser, A. (2001) · Science · doi:10.1126/science.1062257 · Cited by 656
Cited by
Notch signaling pathway: architecture, disease, and therapeutics
Zhou, B., Lin, W., Long, Y., Yang, Y., Zhang, H., Wu, K., & Chu, Q. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00934-y · Cited by 1,114
Mammalian Krüppel-Like Factors in Health and Diseases
McConnell, B. B., & Yang, V. W. (2010) · Physiological Reviews · doi:10.1152/physrev.00058.2009 · Cited by 1,018
Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways
Takebe, N., Harris, P. J., Warren, R. Q., & Ivy, S. P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.196 · Cited by 992
Direct inhibition of the NOTCH transcription factor complex
Moellering, R. E., Cornejo, M., Davis, T. N., Bianco, C. D., Aster, J. C., Blacklow, S. C., Kung, A. L., Gilliland, D. G., Verdine, G. L., & Bradner, J. E. (2009) · Nature · doi:10.1038/nature08543 · Cited by 752
The Varied Roles of Notch in Cancer
Aster, J. C., Pear, W. S., & Blacklow, S. C. (2017) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-052016-100127 · Cited by 710
Metadata
- Authors
- Real, P. J., Tosello, V., Palomero, T., Castillo, M., Hernando, E., de Stanchina, E., Sulis, M. L., Barnes, K., Sawai, C., Homminga, I., Meijerink, J., Aifantis, I., Basso, G., Cordon-Cardo, C., Ai, W., & Ferrando, A.
- Venue
- Nature Medicine
- Published
- 2008-12-21
- Volume
- 15
- Issue
- 1
- Pages
- 50-58
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1982023788
- Cited by
- 445
- References
- 1
- FWCI
- 42.77
- Type
- journal article
- Language
- en
- Open access
- green
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- Real, P. J., Tosello, V., Palomero, T., Castillo, M., Hernando, E., de Stanchina, E., Sulis, M. L., Barnes, K., Sawai, C., Homminga, I., Meijerink, J., Aifantis, I., Basso, G., Cordon-Cardo, C., Ai, W., & Ferrando, A. (2009). γ-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nature Medicine. https://doi.org/10.1038/nm.1900
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