In T-ALL with gain-of-function mutations of Notch1, GSI treatment led to rapid clearance of Notch1 signaling and resulted in G1 cell cycle arrest or apoptosis, whereas GSI resistance was related to PTEN and FBXW7 mutations that sustained leukemic cell proliferation despite Notch signaling inhibition [75,85,86,104,183,184]. The gene discussed is FBXW7; the disease is acute lymphoblastic leukemia.