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.
In this study, we aimed to investigate the role of DLL4 in the regulation of NOTCH signaling in T-ALL cells in the context of different types of NOTCH1 mutation or wild-type NOTCH receptor, as well as the effects of DLL4 neutralization on T-ALL engraftment in mice.
The nuclear expression of NOTCH1 protein was detected in 25% and 5% of cases of T-ALL/LBL and CLL/SLL, respectively, whereas cytoplasmic expression was detected in 33.3% and 15% cases, respectively.
Activation of the Notch pathway occurs commonly in T acute lymphoblastic leukemia (T-ALL) because of mutations in Notch1 or Fbw7 and is involved in the regulation of cell proliferation and survival.
Interestingly, the statistically significant difference of survival according to NOTCH1 mutations was only observed in adult patients (>18 years) but not in pediatric patients (< or = 18 years), possibly due to the relatively good overall response of childhood T-ALL to the current chemotherapy.
The clearest example of oncogenic Notch signalling is observed in T acute lymphoblastic leukemia (T-ALL), an aggressive neoplasm of immature T-cells, due to genetic alterations leading to ligand-independent increased Notch1 receptor signalling.
NOTCH1 pathway activation represents a common feature of T-ALL when compared to acute myelogenous leukemia (AML) and B-cell precursor acute lymphoblastic leukemia.