This study demonstrates that the simultaneous inhibition of the Hedgehog (Hh) and PI3K/Akt/mTOR signaling pathways exerts a potent and synergistic cytotoxic effect in T-cell acute lymphoblastic leukemia (T-ALL) cells, highlighting a functional interdependence between these signaling cascades in maintaining leukemic cell survival. This evidence concerns the gene AKT1 and acute lymphoblastic leukemia.