T-cell acute lymphoblastic leukemia (T-ALL) is an heterogeneous disease, characterized by several genetic alterations and polymorphic clinical features both in children and adults. The Notch pathway, an evolutionary conserved pathway involved in many biological processes including T cell differentiation, has been implicated in the pathogenesis of this disease. Notably, about 50-55% of T-ALL samples show increased Notch1 activity, due to mutations in NOTCH1 or FBW7 genes. Among T-ALL patients, only 70-80% of children and 40% of adults reach long-term remission, therefore new therapeutic approaches are required. Here, we investigated the biologic and therapeutic effects of a human Notch1-specific neutralizing antibody in xenograft models of pediatric T-ALL, obtained from patients with different clinical features and NOTCH1/FBW7 mutational status. We demonstrated that anti-Notch1 treatment greatly delayed engraftment of T-ALL cells bearing NOTCH1/FBW7 mutations, including samples derived from relapsed and clinically difficult-to-treat patients. In these xenografts we observed increased levels of apoptosis, decreased proliferation of leukemic cells and a marked inhibitory effects on Notch transcriptional profile. Moreover, modulation of T-ALL cells metabolism was detected following anti-Notch1 therapy. Serial transplantation experiments suggested that anti-Notch1 therapy could compromise leukemia initiating cell functions and a preliminary experiment showed that resistance may arise in a regimen of continuous administration of anti-Notch1 mAb. Finally, we demonstrated that combination of anti-Notch1 and dexamethasone – a leading drug in T-ALL treatment - could further improve therapeutic effect.
Altogether these results indicate that NOTCH1/FBW7 mutations identify suitable candidates for Notch targeted therapy and highlight the potential of Notch target genes and CD7 expression as candidate predictive markers of response to anti-Notch1 therapy
