Activating NOTCH1 Mutations Are Associated with Good Treatment Response in Childhood T-Cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10–15 % of pediatric ALL. Very rare cases of T-ALL (< 1 %) harbor the chromosomal translocation t(7;9) that involves NOTCH1, a gene encoding a single-pass, heterodimeric transmembrane receptor. NOTCH1 has an essential function in early intrathymic T-cell development. Recently, it has been demonstrated that more than 50 % of childhood T-ALLs carry activating mutations within the NOTCH1 gene (Weng et al., Science 2004). In the present study, we systematically analyzed the impact of activating NOTCH1 mutations on treatment response in 108 pediatric T-ALLs, registered in the ongoing ALL-BFM 2000 trial. In 56 cases (51.8%) activating NOTCH1 mutations were identified, located either in the heterodimerization (38/56 mutations; 65.5%), in the PEST (10/56; 17.9%) or in both domains (8/56; 14.3%). The presence of activating NOTCH1 mutations was significantly correlated with good prednisolone (p = 0.001, c2 or Fisher’s exact test) and MRD response (p = 0.002). T-ALLs with NOTCH1 mutations were 3.7 times more likely to show a good prednisolone response (95% confidence interval = 1.64–8.33; p = 0.002) and 4.8 times more likely to show a favorable MRD response (95% confidence interval = 2.04–11.11; p = 0.0003) when compared to patients with wild type NOTCH1. Patients with mutated NOTCH1 were thus underrepresented in the high risk group of the ALL-BFM 2000 protocol. This influence of NOTCH1 mutational status on risk stratification was independent from other commonly used criteria, like age and initial white blood cell count (WBC) at the time of diagnosis. Considering the impact of NOTCH1 mutations on long term prognosis, we analyzed those 49 patients of this cohort with a median follow-up of > 4 years. Eight patients relapsed within this follow-up period, 2 patients with mutated and 6 with wild type NOTCH1. With this small number of relapses, this trend towards a favorable influence of activating NOTCH1 mutations on EFS did not reach statistical significance. In conclusion, T-ALLs with NOTCH1 mutations are demonstrated to be more sensitive than those without to the ALL-BFM 2000 treatment strategy and may show a lower rate of relapse.