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

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Abstract
In acute promyelocytic leukemia (APL), the typical t(15;17) and the rare t(11;17) translocations express, respectively, the PML/RARα and PLZF/RARα fusion proteins (where RARα is retinoic acid receptor α). 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/RARα and PLZF/RARα localize to the same microspeckled nuclear domains that appear to be common targets for the two fusion proteins in APL. Although PLZF/RARα does not affect the localization of PML, PML/RARα 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 RARα gene translocations and stress the importance of alterations of PLZF and RARα nuclear localizations in this disease.