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

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Abstract

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
JournalBlood
Volume88
Issue number8
Publication statusPublished - Oct 15 1996

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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.