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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2014-02

AUTHORS

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

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. More... »

PAGES

278

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/leu.2013.183

DOI

http://dx.doi.org/10.1038/leu.2013.183

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1042003074

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23774673


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