BACKGROUND: Alterations in the NOTCH1 signaling pathway are found in about 60% 
of pediatric T-ALL, but its impact on prognosis remains unclear.
PROCEDURE: 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.
RESULTS: 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.
CONCLUSIONS: 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.