Conversely, activation of NOTCH1 signaling through gain-of-function mutations in NOTCH1, first described in T-ALL [24], or loss-of-function mutations in NOTCH1 regulators, such as FBXW7 and NUMB, has been linked to therapeutic recalcitrance of hematologic malignancies [40], [41]. This evidence concerns the gene NUMB and acute lymphoblastic leukemia.