Figure 4.

Interaction of NOTCH inhibition and dexamethasone treatment in tumor response and gut toxicity in vivo. (a) Bioimaging quantitation of tumor mass changes in subcutaneous CUTLL1 T-ALL xenografts in mice treated with vehicle (control), dexamethasone, GSI (DBZ) or GSI plus dexamethasone (Dexamethasone + DBZ) for 4 days. (b) Representative examples of bioluminiscence in vivo imaging showing changes in tumor load in representative mice (animals with closest values to the median are shown) treated with vehicle (control), dexamethasone (Dexa), DBZ and dexamethasone plus DBZ (Dexa + DBZ). (c) Tumor mass changes induced by dexamethasone plus DBZ treatment compared to controls in CUTLL1 T-ALL xenografts (CUTLL1) and CUTLL1 xenografts expressing an intracellular form of NOTCH1 (CUTLL1 ICN1), which does not require γ-secretase cleavage for activation. (d) Kaplan-Meier plot of overall survival among mice treated with vehicle (Control), dexamethasone, DBZ or DBZ plus dexamethasone after xenograft transplantation of human T-ALL cells via tail vein injection. (e) Histological analysis of small intestine, spleen and thymus from mice treated with vehicle, dexamethasone, DBZ and dexamethasone plus DBZ for 5 days. (f) Goblet cell analysis and quantitation in the ileum of RBPJ(fl/fl) Cre-Tam conditional knockout mice in basal conditions (RBPJ(fl/fl) Cre-Tam), following conditional deletion of CSL/RBPJ with tamoxifen (RBPJ(fl/fl) Cre-Tam TMX) and upon conditional deletion of CSL/RBPJ followed by dexamethasone treatment (RBPJ(fl/fl) Cre-Tam TMX + Dexa). TMX: tamoxifen. H&E: haemotoxylin and eosin staining. Scale bars represent 100 µm in the intestine and 400 µm in spleen and thymus.