Article abstract
Nature Medicine 15, 50 - 58 (2008)
Published online: 21 December 2008 | doi:10.1038/nm.1900
-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia
Pedro J Real1,2, Valeria Tosello1,11, Teresa Palomero1,3,11, Mireia Castillo3, Eva Hernando4, Elisa de Stanchina5, Maria Luisa Sulis1,6, Kelly Barnes1, Catherine Sawai7, Irene Homminga8, Jules Meijerink8, Iannis Aifantis7, Giuseppe Basso9, Carlos Cordon-Cardo3, Walden Ai10 & Adolfo Ferrando1,3,6
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.
- Institute for Cancer Genetics, Columbia University, 1130 St. Nicholas Avenue, New York, New York 10032, USA.
- Andalusian Stem Cell Bank, Centro de Investigación Biomédica, Avenida del Conocimiento, Granada 18100, Spain.
- Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032, USA.
- Department of Pathology, New York University Medical Center, 550 First Avenue, New York, New York 10016, USA.
- Antitumor Assessment Core Facility, Memorial Sloan-Kettering Cancer Center, Zuckerman Research Center, 417 East 68th Street, New York, New York 10021, USA.
- Department of Pediatrics, Columbia University Medical Center, 161 Fort Washington Avenue, New York, New York 10032, USA.
- Department of Pathology, New York University Cancer Institute, 530 First Avenue, New York, New York 10016, USA.
- Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Dr. Molewaterplein 60, Rotterdam 3015GJ, The Netherlands.
- Laboratory of Oncohematology, Department of Pediatrics `Salus Pueri', University of Padua, Via Giustiniani 3, Padua 35128, Italy.
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, 6311 Garners Ferry Road, Columbia, South Carolina 29208, USA.
- These authors contributed equally to this work.
Correspondence to: Adolfo Ferrando1,3,6 e-mail: af2196@columbia.edu
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