Pathways of retinoic acid- or arsenic trioxide-induced PML/RAR alpha catabolism, role of oncogene degradation in disease remission

Although there is evidence to suggest that PML/RAR alpha expression is not the sole genetic event required for the development of acute promyelocytic leukemia (APL), there is little doubt that the fusion protein plays a centr al role in the initiation of leukemogenesis. The two therapeutic agents, re tinoic acid and arsenic, that induce clinical remissions in APL, both targe t the oncogenic fusion protein, representing the first example of oncogene- directed cancer therapy. This review focuses on the molecular mechanisms ac counting for PML/RAR alpha degradation. Each drug targets a specific moiety of the fusion protein (RAR alpha for retinoic acid, PML for arsenic) to th e proteasome. Moreover, both activate a common caspase-dependent cleavage i n the PML part of the fusion protein. Specific molecular determinants (the AF2 transactivator domain of RAR alpha for retinoic acid and the K160 SUMO- binding site in PML for arsenic) are respectively implicated in RA- or arse nic-triggered catabolism. The respective roles of PML/RAR alpha activation versus its catabolism are discussed with respect to differentiation or apop tosis induction in the context of single or dual therapies.