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 correlates with disease remission, Expression of the APL-specific PML/RAR alpha fusion protein in hematopoietic precursor cell lines blocks terminal differentiation, suggesting that PML/RAR alpha may have the same activity in APL blasts. We expressed different PML/RAR alpha mutants in U937 and TF-1 cells and demonstrated that the integrity of the PML protein dimerization and RAR alpha DNA binding domains is crucial for the differentiation block induced by PML/RAR alpha, and that these domains exert their functions only within the context of the fusion protein, Analysis of the in vivo dimerization and cell localization properties of the PML/RAR alpha mutants revealed that PML/RAR alpha-PML and PML/RAR alpha-RXR heterodimers are not necssary for PML/RAR alpha activity on differentiation. We propose that a crucial mechanism underlying PML/RAR alpha oncogenic activity is the deregulation of a transcription factor, RAR alpha, through its fusion with the dimerization interface of another nuclear protein, PML.