Apoptosis pathways and their alterations in lymphomas.

Activation of death receptors by their respective ligands (extrinsic pathway) leads to the activation of caspase-8, which subsequently activates the caspase cascade. Some receptors, such as TNFRα, have the ability to activate either cell survival (through IAP proteins, components of the TNFR complex) or apoptosis. The intrinsic or mitochondrial apoptotic pathway is controlled by BCL2 family members, including proapoptotic BID (activated by caspase-8) or BAX, or antiapoptotic proteins, such as BCL2, MCL1, and BCL-X_L. Activation of the mitochondrial pathway involves release of cytochrome c from mitochondria and its association with APAF-1 and procaspase-9 to form the apoptosome. Caspase-9 is activated within this complex. IAP (inhibitor of apoptosis proteins) are, in turn, inhibited by second mitochondria-derived activator of caspase (SMAC). The extrinsic and intrinsic pathways are connected via BID and caspase-3. Some of the receptors also exert prosurvival functions through NF-κB pathway activation. API2/MLT1 fusion proteins and BCL10 also activate NF-κB, inducing cell survival. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway also has a role in cell survival control through NF-κB activation and by inhibiting BAD protein (an inducer of apoptosis). Those proteins known to be involved in lymphomagenesis are marked in red. Casp, Caspase.