Leukemia-associated retinoic acid receptor α fusion partners, PML and PLZF, heterodimerize and colocalize to nuclear bodies

In acute promyelocytic leukemia (APL), the typical t(15;17) and the rare t(11;17) translocations express, respectively, the PML/RARalpha and PLZF/RARalpha fusion proteins (where RARalpha is retinoic acid receptor alpha). Herein, we demonstrate that the PLZF and PML proteins interact with each other and colocalize onto nuclear bodies (NBs). Furthermore, induction of PML expression by interferons leads to a recruitment of PLZF onto NBs without increase in the levels of the PLZF protein. PML/RARalpha and PLZF/RARalpha localize to the same microspeckled nuclear domains that appear to be common targets for the two fusion proteins in APL. Although PLZF/RARalpha does not affect the localization of PML, PML/RARalpha delocalizes the endogenous PLZF protein in t(15;17)-positive NB4 cells, pointing to a hierarchy in the nuclear targeting of these proteins. Thus, our results unify the molecular pathogenesis of APL with at least two different RARalpha gene translocations and stress the importance of alterations of PLZF and RARalpha nuclear localizations in this disease.