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Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL
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 t...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692090/ https://www.ncbi.nlm.nih.gov/pubmed/19098907 http://dx.doi.org/10.1038/nm.1900 |
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author | Real, Pedro J. Tosello, Valeria Palomero, Teresa Castillo, Mireia Hernando, Eva de Stanchina, Elisa Sulis, Maria Luisa Barnes, Kelly Sawai, Catherine Homminga, Irene Meijerink, Jules Aifantis, Iannis Basso, Giuseppe Cordon-Cardo, Carlos Ai, Walden Ferrando, Adolfo |
author_facet | Real, Pedro J. Tosello, Valeria Palomero, Teresa Castillo, Mireia Hernando, Eva de Stanchina, Elisa Sulis, Maria Luisa Barnes, Kelly Sawai, Catherine Homminga, Irene Meijerink, Jules Aifantis, Iannis Basso, Giuseppe Cordon-Cardo, Carlos Ai, Walden Ferrando, Adolfo |
author_sort | Real, Pedro J. |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2692090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
record_format | MEDLINE/PubMed |
spelling | pubmed-26920902009-07-01 Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL Real, Pedro J. Tosello, Valeria Palomero, Teresa Castillo, Mireia Hernando, Eva de Stanchina, Elisa Sulis, Maria Luisa Barnes, Kelly Sawai, Catherine Homminga, Irene Meijerink, Jules Aifantis, Iannis Basso, Giuseppe Cordon-Cardo, Carlos Ai, Walden Ferrando, Adolfo Nat Med Article 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. 2008-12-21 2009-01 /pmc/articles/PMC2692090/ /pubmed/19098907 http://dx.doi.org/10.1038/nm.1900 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Real, Pedro J. Tosello, Valeria Palomero, Teresa Castillo, Mireia Hernando, Eva de Stanchina, Elisa Sulis, Maria Luisa Barnes, Kelly Sawai, Catherine Homminga, Irene Meijerink, Jules Aifantis, Iannis Basso, Giuseppe Cordon-Cardo, Carlos Ai, Walden Ferrando, Adolfo Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL |
title | Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL |
title_full | Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL |
title_fullStr | Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL |
title_full_unstemmed | Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL |
title_short | Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL |
title_sort | gamma-secretase inhibitors reverse glucocorticoid resistance in t-all |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692090/ https://www.ncbi.nlm.nih.gov/pubmed/19098907 http://dx.doi.org/10.1038/nm.1900 |
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