Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts

V. Agnusdei, S. Minuzzo, C. Frasson, A. Grassi, F. Axelrod, S. Satyal, A. Gurney, T. Hoey, E. Seganfreddo, G. Basso, S. Valtorta, R. M. Moresco, A. Amadori, S. Indraccolo

Research output: Contribution to journalArticlepeer-review

Abstract

T-acute lymphoblastic leukemia (T-ALL) is characterized by several genetic alterations and poor prognosis in about 20-25% of patients. Notably, about 60% of T-ALL shows increased Notch1 activity, due to activating NOTCH1 mutations or alterations in the FBW7 gene, which confer to the cell a strong growth advantage. Therapeutic targeting of Notch signaling could be clinically relevant, especially for chemotherapy refractory patients. This study investigated the therapeutic efficacy of a novel anti-Notch1 monoclonal antibody by taking advantage of a collection of pediatric T-ALL engrafted systemically in NOD/SCID mice and genetically characterized with respect to NOTCH1/FBW7 mutations. Anti-Notch1 treatment greatly delayed engraftment of T-ALL cells bearing Notch1 mutations, including samples derived from poor responders or relapsed patients. Notably, the therapeutic efficacy of anti-Notch1 therapy was significantly enhanced in combination with dexamethasone. Anti-Notch1 treatment increased T-ALL cell apoptosis, decreased proliferation and caused strong inhibitory effects on Notch-target genes expression along with complex modulations of gene expression profiles involving cell metabolism. Serial transplantation experiments suggested that anti-Notch1 therapy could compromise leukemia-initiating cell functions. These results show therapeutic efficacy of Notch1 blockade for T-ALL, highlight the potential of combination with dexamethasone and identify surrogate biomarkers of the therapeutic response.

Original languageEnglish
Pages (from-to)278-288
Number of pages11
JournalLeukemia
Volume28
Issue number2
DOIs
Publication statusPublished - Feb 2014

Keywords

  • apoptosis
  • Notch1
  • predictive biomarkers
  • T-ALL
  • targeted therapy

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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