PURPOSE: NOTCH signaling pathway is essential in T-cell development and NOTCH1 
mutations are frequently present in T-cell acute lymphoblastic leukemia (T-ALL). 
To gain insight into its clinical significance, NOTCH1 mutation was investigated 
in 77 patients with T-ALL.
EXPERIMENTAL DESIGN: Detection of NOTCH1 mutation was done using reverse 
transcription-PCR amplification and direct sequencing, and thereby compared 
according to the clinical/biological data of the patients.
RESULTS: Thirty-two mutations were identified in 29 patients (with dual 
mutations in 3 cases), involving not only the heterodimerization and 
proline/glutamic acid/serine/threonine domains as previously reported but also 
the transcription activation and ankyrin repeat domains revealed for the first 
time. These mutations were significantly associated with elevated WBC count at 
diagnosis and independently linked to short survival time. 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. NOTCH1 mutations could coexist with 
HOX11, HOX11L2, or SIL-TAL1 expression. The negative effect of NOTCH1 mutation 
on prognosis was potentiated by HOX11L2 but was attenuated by HOX11.
CONCLUSION: NOTCH1 mutation is an important prognostic marker in T-ALL and its 
predictive value could be even further increased if coevaluated with other 
T-cell-related regulatory genes. NOTCH pathway thus acts combinatorially with 
oncogenic transcriptional factors on T-ALL pathogenesis.