The PML/RARα oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells

John V. Raelson, Clara Nervi, Angelika Rosenauer, Laura Benedetti, Yury Monczak, Mark Pearson, Pier Giuseppe Pelicci, Wilson H. Miller

Research output: Contribution to journalArticle


Acute promyelocytic leukemia (APL) is characterized by the translocation, t(15;17) and the expression of a PML/RARα fusion protein that is diagnostic of the disease. There is evidence that PML/RARα protein acts as a dominant negative inhibitor of normal retinoid receptor function and myeloid differentiation. We now show that the PML/RARα 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/RARα 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 PML/RARα. We further show that this loss of PML/RAR-α is not limited to the unique APL cell line, NB4, because PML/RARα protein is selectively downregulated by tRA when expressed in the transfected myeloid cell line U937. The loss of PML/RARα may be directly linked to tRA-induced differentiation, because in a retinoid-resistant subclone of NB4, tRA does not decrease PML/RARα protein expression. In NB4 cells, the specific downregulation of the fusion protein decreases the ratio of PML/RARα to wild-type RARα. Because the ratio of expression of PML/RARα to wild-type RARα and PML may be important in maintaining the dominant negative block of myelocytic differentiation, these data suggest a molecular mechanism for restoration by tRA normal myeloid differentiation in APL cells.

Original languageEnglish
Pages (from-to)2826-2832
Number of pages7
Issue number8
Publication statusPublished - Oct 15 1996


ASJC Scopus subject areas

  • Hematology

Cite this

Raelson, J. V., Nervi, C., Rosenauer, A., Benedetti, L., Monczak, Y., Pearson, M., Pelicci, P. G., & Miller, W. H. (1996). The PML/RARα oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood, 88(8), 2826-2832.