Gene transactivation without direct DNA binding defines a novel gain-of-function for PML-RAR alpha

S van Wageningen, MC (Marleen) de Ridder, J Nigten, G (Gorica) Nikoloski, Claudia Erpelinck - Verschueren, Bob Löwenberg, T de Witte, DG Tenen, BA Reijden, JH (Joop) Jansen

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27 Citations (Scopus)

Abstract

PML-RAR alpha is the causative oncogene in 5% to 10% of the cases of acute myeloid leukemia. At physiological concentrations of retinoic acid, PML-RARa silences RAR alpha 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 RARa 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-RARa fusion protein not only interferes with the transcription of regular RARa, target genes. We show that the ID1 and ID2 promoters are activated by IDMIL-RAR alpha but, unexpectedly, not by wild-type RAR alpha/RXR. Our data support a model in which the PML-RAR alpha 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.
Original languageUndefined/Unknown
Pages (from-to)1634-1643
Number of pages10
JournalBlood
Volume111
Issue number3
DOIs
Publication statusPublished - 2008

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