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 Blood, 1 February 2008, Vol. 111, No. 3, pp. 1634-1643.
Prepublished online as a Blood First Edition Paper on November 19, 2007; DOI 10.1182/blood-2007-04-081125.

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NEOPLASIA

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

Sake van Wageningen1, Marleen C. Breems-de Ridder2, Jeannet Nigten1, Gorica Nikoloski1, Claudia A. J. Erpelinck-Verschueren2, Bob Löwenberg2, Theo de Witte1, Daniel G. Tenen3, Bert A. van der Reijden1, and Joop H. Jansen1

1 Central Hematology Laboratory and Department of Hematology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 2 Institute of Hematology, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands; and 3 Harvard Institutes of Medicine, Harvard Medical School and Harvard Stem Cell Institute, Boston, MA

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-RAR{alpha} 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 RAR{alpha} 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-RAR{alpha} fusion protein not only interferes with the transcription of regular RAR{alpha} target genes. We show that the ID1 and ID2 promoters are activated by PML-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.


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S. van Wageningen, G. Nikoloski, G. Vierwinden, R. Knops, B. A. van der Reijden, and J. H. Jansen
The transcription factor nuclear factor Y regulates the proliferation of myeloid progenitor cells
Haematologica, October 1, 2008; 93(10): 1580 - 1582.
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