Molecular and Cellular Pathobiology PML-RARa and Its Phosphorylation Regulate PML Oligomerization and HIPK2 Stability

The PML gene is frequently fused to the retinoic acid receptor a (RARa) gene in acute promyelocytic leukemia (APL), generating a characteristic PML-RARa oncogenic chimera. PML-RARa disrupts the discrete nuclear speckles termed nuclear bodies, which are formed in PML, suggesting that nuclear body disruption is involved in leukemogenesis. Nuclear body formation that relies upon PML oligomerization and its stabilization of the hypoxia-inducible protein kinase (HIPK)-2 is disrupted by expression of the PML-RARa chimera. Here, we report that disruption of nuclear bodies is also mediated by PML-RARa inhibition of PML oligomerization. PKAmediated phosphorylation of PML-RARa blocked its ability to inhibit PML oligomerization and destabilize HIPK2. Our results establish that both PML oligomerization and HIPK2 stabilization at nuclear bodies are important for APL cell differentiation, offering insights into the basis for the most common prodifferentiation therapies of APL used clinically. Cancer Res; 73(14); 1–11. 2013 AACR.