Role of PML and PML-RAR alpha in Mad-mediated transcriptional repression

Fusion of the promyelocytic leukemia (PML) protein to the retinoic acid rec eptor-alpha (RAR alpha) generates the transforming protein of acute promyel ocytic leukemias. PML appears to be involved in multiple functions, includi ng apoptosis and transcriptional activation by RAR, whereas PML-RAR alpha b locks these functions of PML. However, the mechanisms of leukemogenesis by PML-RAR alpha remain elusive. Here we show that PML interacts with multiple corepressors (c-Ski, N-CoR, and mSin3A) and histone deacetylase 1, and tha t this interaction is required for transcriptional repression mediated by t he tumor suppressor Mad. PML-RAR alpha has the two corepressor-interacting sites and inhibits Mad-mediated repression, suggesting that aberrant bindin g of PML-RAR alpha to the corepressor complexes may lead to abrogation of t he corepressor function. These mechanisms may contribute to events leading to leukemogenesis.