The Role of Activated NOTCH Signaling in Childhood T-ALL

We aimed to define novel molecular risk markers in T-ALL. In a first step, we analyzed activating Notch pathway mutations in >300 patients of the pediatric ALL-BFM 2000 study. Activating mutations of the NOTCH1 receptor and inactivating mutations of the NOTCH inactivator FBXW7 are associated with excellent early treatment response and long-term outcome. A detailed comparison with other studies suggested that the intensity of CNS-directed treatment might play a particularly important role in NOTCH activated patients. This interpretation is supported by the finding of the chemokine receptor CCR7 being a NOTCH target and directing T-ALL cells to the CNS. These data indicate that molecular risk factors for T-ALL are strongly treatment-dependent generally and that NOTCH depends on the type and intensity of CNS-directed therapy in particular.

We next performed array-based comparative genomic hybridization (array-CGH) and gene expression analyses in 73 patients. We show that DNA copy-number changes are common in T-ALL. Notably, genomic imbalances predicted to downregulate the TGF-β or upregulate the PI3K-AKT pathways are identified in 36% and 30% of the patients. Furthermore, we identified a 6q15–16.1 deletion, which predicts poor treatment response in 12% of the patients. This deletion includes the CASP8AP2 gene, whose expression is also shown to be downregulated. The data presented here thus implicate the TGF-β and PI3K-AKT pathways in T-ALL leukemogenesis and identify a subgroup of T-ALL patients with CASP8AP2 deletions and poor early treatment response.