Fig. 7

Loss-of-functional mutation in FBW7 gene leading to anti-apoptotic MCL1 stabilization and resistance to Bcl-2 inhibitor in T-cell acute lymphoblastic leukemia. FBW7 gene mutation causes the accumulation of oncogenic driver molecules such as c-Myc, c-Jun, Notch-1, which then results in the activation of cellular proliferation signal pathways. On the other hand, the loss-of-functional mutation of FBW7 gene enhances the stabilization of MCL1, one of the major anti-apoptotic molecules which is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL). In the clinical settings, increased expression of MCL1 in FBW7-deficient T-ALL cells induces the therapeutic resistance to the BH3 mimetic ABT-737, a pan-inhibitor of the Bcl-2 family of anti-apoptotic proteins [211,212,213]. Note that red arrows indicate up-regulation, whereas blue bars show the inhibitory effect. In addition, the yellow particles in the mitochondrion correspond to cytochrome c