EFFECTS ON DIFFERENTIATION BY THE PROMYELOCYTIC LEUKEMIA PML RAR-ALPHA PROTEIN DEPEND ON THE FUSION OF THE PML PROTEIN DIMERIZATION AND RAR-ALPHA DNA-BINDING DOMAINS/

The block of terminal differentiation is a prominent feature of acute promyelocytic leukemia (APL) and its release by retinoic acid correlat es with disease remission, Expression of the APL-specific PML/RAR alph a fusion protein in hematopoietic precursor cell lines blocks terminal differentiation, suggesting that PML/RAR alpha may have the same acti vity in APL blasts. We expressed different PML/RAR alpha mutants in U9 37 and TF-1 cells and demonstrated that the integrity of the PML prote in dimerization and RAR alpha DNA binding domains is crucial for the d ifferentiation block induced by PML/RAR alpha, and that these domains exert their functions only within the context of the fusion protein, A nalysis of the in vivo dimerization and cell localization properties o f the PML/RAR alpha mutants revealed that PML/RAR alpha-PML and PML/RA R alpha-RXR heterodimers are not necssary for PML/RAR alpha activity o n differentiation. We propose that a crucial mechanism underlying PML/ RAR alpha oncogenic activity is the deregulation of a transcription fa ctor, RAR alpha, through its fusion with the dimerization interface of another nuclear protein, PML.