Effects on differentiation by the promyelocytic leukemia PML/RARα protein depend on the fusion of the PML protein dimerization and RARα 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/RARα fusion protein in hematopoietic precursor cell lines blocks terminal differentiation, suggesting that PML/RARα may have the same activity in APL blasts. We expressed different PML/RARα mutants in U937 and TF-1 cells and demonstrated that the integrity of the PML protein dimerization and RARα DNA binding domains is crucial for the differentiation block induced by PML/RARα, 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/RARα mutants revealed that PML/RARα-PML and PML/RARα-RXR heterodimers are not necessary for PML/RARα activity on differentiation. We propose that a crucial mechanism underlying PML/RARα oncogenic activity is the deregulation of a transcription factor, RARα, through its fusion with the dimerization interface of another nuclear protein, PML.