Although GOF mutations in NOTCH3 are infrequent in T-ALL, active NOTCH3 signaling, correlating with overall high NOTCH3 expression, was recently detected at higher than expected frequencies in T-ALL patient samples and patient-derived xenograft (PDX) models (Bernasconi-Elias et al., 2016). This evidence concerns the gene NOTCH3 and acute lymphoblastic leukemia.