Fusion proteins involving the retinoic acid receptor α (RARα) and the PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemias (APLs). APLs with the PML-RARα or the PLZF-RARα fusion protein are phenotypically indistinguishable except that they differ in their sensitivity to retinoic acid (RA)-induced differentiation: PML-RAR α blasts are sensitive to RA and patients enter disease remission after RA treatment, while patients with PLZF-RARα do not. We here report that (i) like PML-RAR α expression, PLZF-RARα expression blocks terminal differentiation of hematopoietic precursor cell lines (U937 and HL-60) in response to different stimuli (vitamin D3, transforming growth factor β1, and dimethyl sulfoxide); (ii) PML-RARα, but not PLZF-RARα, increases RA sensitivity of hematopoietic precursor cells and restores RA sensitivity of RA-resistant hematopoietic cells; (iii) PML-RAR α and PLZF-RAR α have similar RA binding affinities; and (iv) PML-RARα enhances the RA response of RA target genes (those for RARβ, RAR gamma, and transglutaminase type II [TGase]) in vivo, while PLZF-RARα expression has either no effect (RARβ) or an inhibitory activity (RAR gamma and type II TGase). These data demonstrate that PML-RARα and PLZF-RARα have similar (inhibitory) effects on RA-independent differentiation and opposite (stimulatory or inhibitory) effects on RA-dependent differentiation and that they behave in vivo as RA-dependent enhancers or inhibitors of RA-responsive genes, respectively. Their different activities on the RA signalling pathway might underlie the different responses of PML-RARα and PLZF-RARα APLs to RA treatment. The PLZF-RARα fusion protein contains an approximately 120-amino-acid N-terminal motif (called the POZ domain), which is also found in a variety of zinc finger proteins and a group of poxvirus proteins and which mediates protein-protein interactions. Deletion of the PLZF POZ domain partially abrogated the inhibitory effect of PLZF-RARα on RA-induced differentiation and on RA-mediated type II TGase up-regulation, suggesting that POZ-mediated protein interactions might be responsible for the inhibitory transcriptional activities of PLZF-RARα.