The PML / RARa ! Oncoprotein Is a Direct Molecular Target of Retinoic Acid in Acute Promyelocytic Leukemia Cells

Acute promyelocytic leukemia (APL) is characterized by the translocation, t(15;17) and the expression of a PMLIRARa fusion protein that is diagnostic of the disease. There is evidence that PMLlRARa protein acts as a dominant negative inhibitor of normal retinoid receptor function and myeloid differentiation. We now show that the PMLlRARa fusion product is directly downregulated in response to retinoic acid (tRA) treatment in the human APL cell line, NB4. tRA treatment induces loss of PML/RARa at the protein level but not at the level of mRNA, as determined by Northern blots, by Western blots, and by ligand binding assays and in binding to RA-responsive DNA elements. We present evidence that this regulation is posttranslational. This evidence suggests that tRA induces synthesis of a protein that selectively degrades PMLIRARa. We further show that this loss of PMLI