ENAGenomicsInstitute for Cancer Genetics, Columbia Universityhttps://www.ebi.ac.uk/ena/browser/view/PRJNA106885Mus musculusxref:PubMed:19098907Gamma-secretase inhibitors (GSIs), which block the activation of NOTCH receptors, are being tested in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Thus far, 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. Additionally, cotreatment with glucocorticoids induced Ccnd2 upregulation in the gut which protected mice from the intestinal secretory metaplasia typically induced by loss of NOTCH signaling. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL. Keywords: drug treatment in vivo, dibenzazepine DBZ, T-ALL, glucocorticoid Overall design: Experiments analyzing the interacition of dexamethasone and the gamma-secretase inhibitor DBZ were carried out in 6-week-old C57/Black6 female mice (Jackson Laboratory). In these studies we treated mice with vehicle (DMSO) (n=2), dexamethasone (15 mg/kg) (n=2), DBZ (10 micromol/kg) (n=2) and dexamethasone (15 mg/kg) plus DBZ (10 micromol/kg) (n=2) daily by intraperitoneal injection for 5 days. At the end of the treatment, animals were euthanized and segments of the small intestine were collected and processed for RNA extraction, histological and immunohistochemical analysis.ENAAPP, beta-Secretase, alpha Secretase, GCR Deficiency, Acute T-Cell Leukemias, Lymphocytic Leukemia, glucocorticoid receptor deficiency, APP Secretase, With Hypokalemia, Glucocorticoid Resistance, generalized, gamma Secretase, Leukemias, T-Cell Leukemia, T-Cell Leukemias, Precursor T Cell Lymphoblastic Lymphoma, Acute., Gccr deficiency, Beneficial, T-Cell Acute Lymphocytic Leukemia, Acute T-Cell Leukemia, Grl deficiency, cortisol resistance from glucocorticoid receptor defect, T-Cell, GCRES, Gcr deficiency, T-Lymphocytic Leukemia, acute T cell leukaemia, Amyloid Precursor Protein Secretase, Precursor T-Cell Lymphoblastic Leukemia, beta Secretase, Precursor T Cell Lymphoblastic Leukemia, Acute T Cell, T-ALL, T-Lymphocytic Leukemias, Body Composition, Lymphoblastic Leukemia, Lymphocytic, Leukemia, T Cell Leukemia, Acute T-Lymphocytic Leukemias, Precursor T-Cell Lymphoblastic Lymphoma, Cortisol Resistance from Glucocorticoid Receptor Defect, gamma-Secretase, Lymphoblastic, alpha-Secretase, Acute T-Lymphocytic Leukemia, Female, generalised, T Lymphocytic Leukemia, Due To Glucocorticoid Resistance, GCCR Deficiency, Secretases, Pseudohermaphroditism, Acute, Acute T-Lymphocytic, GCCR, glucocorticoid resistance, Precursor T Cell Lymphoblastic Leukemia Lymphoma, T Cell, Acute T-Cell, SecretaseMus musculus, Laboratory Mice., House, Mus, Laboratory, Swiss, Mus domesticus, mouse, Mus musculus domesticus, Swiss Mouse, mouse <Mus musculus>, Mouse, House Mice, Swiss Mice, house mouse, Mice, Laboratory Mouse, House Mouse, mice C57BL/6xCBA/CaJ hybrid, domesticus, Mus muscarisfalseMus musculusGamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL2025-09-242014-02-11PRJNA106885GSE111841009019098907