PML-RARα is the causative oncogene in 5% to 10% of the cases of acute myeloid leukemia. At physiological concentrations of retinoic acid, PML-RARα silences RARα target genes, blocking differentiation of the cells. At high concentrations of ligand, it (re)activates the transcription of target genes, forcing terminal differentiation. The study of RARα target genes that mediate this differentiation has identified several genes that are important for proliferation and differentiation control in normal and malignant hematopoietic cells. In this paper, we show that the PML-RARα fusion protein not only interferes with the transcription of regular RARα target genes. We show that the ID1 and ID2 promoters are activated by PML-RARα but, unexpectedly, not by wildtype RARα/RXR. Our data support a model in which the PML-RARα fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein.

Additional Metadata
Persistent URL,
Journal Blood
Note Free full text at PubMed
van Wageningen, S, Breems-de Ridder, M.C, Nigten, J, Nikoloski, G, Erpelinck, C.A.J, Löwenberg, B, … Jansen, J.H. (2008). Gene transactivation without direct DNAbinding defines a novel gain-of-function for PML-RARα. Blood, 111(3), 1634–1643. doi:10.1182/blood-2007-04-081125