Oligomerization of RAR and AML1 transcription factors as a novel mechanismof oncogenic activation

RAR and AML1 transcription factors are found in leukemias as fusion protein s with PML and ETO, respectively. Association of PML-RAR and AML1-ETO with the nuclear corepressor (N-CoR)/histone deacetylase (HDAC) complex is requi red to block hematopoietic differentiation. We show that PML-RAR and AML1-E TO exist in vivo within high molecular weight (HMW) nuclear complexes, refl ecting their oligomeric state. Oligomerization requires PML or ETO coiled-c oil regions and is responsible for abnormal recruitment of N-CoR, transcrip tional repression, and impaired differentiation of primary hematopoietic pr ecursors. Fusion of RAR to a heterologous oligomerization domain recapitula ted the properties of PML-RAR, indicating that oligomerization per se is su fficient to achieve transforming potential. These results show that oligome rization of a transcription factor, imposing an altered interaction with tr anscriptional coregulators, represents a novel mechanism of oncogenic activ ation.