RESUMEN

RAR and AML1 transcription factors are found in leukemias as fusion proteins with PML and ETO, respectively. Association of PML-RAR and AML1-ETO with the nuclear corepressor (N-CoR)/histone deacetylase (HDAC) complex is required to block hematopoietic differentiation. We show that PML-RAR and AML1-ETO exist in vivo within high molecular weight (HMW) nuclear complexes, reflecting their oligomeric state. Oligomerization requires PML or ETO coiled-coil regions and is responsible for abnormal recruitment of N-CoR, transcriptional repression, and impaired differentiation of primary hematopoietic precursors. Fusion of RAR to a heterologous oligomerization domain recapitulated the properties of PML-RAR, indicating that oligomerization per se is sufficient to achieve transforming potential. These results show that oligomerization of a transcription factor, imposing an altered interaction with transcriptional coregulators, represents a novel mechanism of oncogenic activation.

Asunto(s)

Transformación Celular Neoplásica , Leucemia/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Factores de Transcripción/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Histona Desacetilasas/metabolismo , Humanos , Leucemia/etiología , Leucemia Mieloide/etiología , Leucemia Mieloide/genética , Leucemia Promielocítica Aguda/etiología , Leucemia Promielocítica Aguda/genética , Proteínas Nucleares/metabolismo , Co-Represor 1 de Receptor Nuclear , Fragmentos de Péptidos/metabolismo , Unión Proteica , Estructura Cuaternaria de Proteína , Proteína 1 Compañera de Translocación de RUNX1 , Proteínas Represoras/metabolismo , Elementos de Respuesta , Transcripción Genética , Tretinoina