Identification of novel NOTCH1 mutations: increasing our knowledge of the NOTCH signaling pathway. 
Alterations in the NOTCH1 signaling pathway are found in about 60% of pediatric T-ALL, but its impact on prognosis remains unclear.  We extended the previously published CoALL cohort (n = 74) to a larger cohort (n = 127) and additionally included 38 Argentine patients from ALL IC-BFM to potentially identify novel mutations and decipher a stronger discriminatory effect on the genotype/phenotype relationship with regard to early treatment response and long-term outcome.  Overall, 101 out of 165 (61.2%) T-ALL samples revealed at least one NOTCH1 mutation, 28 of whom had combined NOTCH1 and FBXW7 mutations.  Eight T-ALL samples (4.8%) exclusively revealed FBXW7 mutations.  Fifty-six T-ALL (33.9%) exhibited a wild-type configuration of either gene.  Four novel NOTCH1 mutations were identified localized in the C-terminal PEST domain, in the rarely affected LNR repeat domain and in the ankyrin domain.  Novel LNR mutations may contribute to a better understanding of the structure of the NOTCH1 negative regulatory region (NRR) and the R1946 mutation in the ankyrin domain may represent an unusual loss-of-function mutation.  Overall, NOTCH1 pathway mutations did not affect the relapse rate and outcome of the extended T-ALL cohort uniformly treated according to CoALL protocols, although NOTCH1 mutations were associated with good response to induction therapy (P = 0.009).  Individually, HD and PEST domain mutations might exert distinct functional effects on cellular homeostasis under treatment NOTCH1 pathway activity with prognostic implications.