The activation of this signaling is mainly due to abnormalities/mutations of genes encoding for PI3K members, AKT, and/or PTEN. Deletions and/or loss-of-function mutations of PTEN, the main negative regulator of the PI3K/AK/mTOR pathway, were first described in 2007 [100], and linked to resistance to NOTCH1 inhibition in T-ALL cell lines [101]. This evidence concerns the gene PTEN and acute lymphoblastic leukemia.