The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation (original) (raw)
- Hanane Boukarabila1,2,3,10,
- Andrew J. Saurin4,5,10,12,
- Eric Batsché6,
- Noushine Mossadegh1,2,3,
- Maarten van Lohuizen7,
- Arie P. Otte8,
- Jacques Pradel4,5,9,
- Christian Muchardt6,
- Michael Sieweke1,2,3,9 and
- Estelle Duprez1,2,3,9,11
- 1Centre d'Immunologie de Marseille-Luminy (CIML), Université de la Méditerranée, Campus de Luminy, 13288 Marseille Cedex 09, France;
- 2Institut National de la Santé et de la Recherche Médicale (INSERM) U631, 13288 Marseille, France;
- 3Centre National de la Recherche Scientifique (CNRS), UMR 6102, 13288 Marseille, France;
- 4Institut de Biologie du Développement de Marseille Luminy, Université de la Méditerranée, Campus de Luminy, 13288 Marseille Cedex 09, France;
- 5Centre National de la Recherche Scientifique (CNRS), UMR 6216, 13288 Marseille, France;
- 6Unit of Epigenetic Regulation Avenir INSERM, URA2578 CNRS Institut Pasteur, 75015 Paris, France;
- 7Division of Molecular Genetics, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
- 8Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 SM Amsterdam, The Netherlands
- 10
↵10 These authors contributed equally to this work.
Abstract
Ectopic repression of retinoic acid (RA) receptor target genes by PML/RARA and PLZF/RARA fusion proteins through aberrant recruitment of nuclear corepressor complexes drives cellular transformation and acute promyelocytic leukemia (APL) development. In the case of PML/RARA, this repression can be reversed through treatment with all-trans RA (ATRA), leading to leukemic remission. However, PLZF/RARA ectopic repression is insensitive to ATRA, resulting in persistence of the leukemic diseased state after treatment, a phenomenon that is still poorly understood. Here we show that, like PML/RARA, PLZF/RARA expression leads to recruitment of the Polycomb-repressive complex 2 (PRC2) Polycomb group (PcG) complex to RA response elements. However, unlike PML/RARA, PLZF/RARA directly interacts with the PcG protein Bmi-1 and forms a stable component of the PRC1 PcG complex, resulting in PLZF/RARA-dependent ectopic recruitment of PRC1 to RA response elements. Upon treatment with ATRA, ectopic recruitment of PRC2 by either PML/RARA or PLZF/RARA is lost, whereas PRC1 recruited by PLZF/RARA remains, resulting in persistent RA-insensitive gene repression. We further show that Bmi-1 is essential for the PLZF/RARA cellular transformation property and implicates a central role for PRC1 in PLZF/RARA-mediated myeloid leukemic development.
Footnotes
9
↵9 These authors are considered cosenior authors.11
↵11 Corresponding authors.
↵E-MAIL eduprez{at}ciml.univ-mrs.fr; FAX 33(0)49126919430.12
↵12 E-MAIL saurin{at}ibdml.univ-mrs.fr; FAX 33(0)491820682.Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.512009.
Supplemental material is available at http://www.genesdev.org.
- Received October 28, 2008.
- Accepted April 3, 2009.
Copyright © 2009 by Cold Spring Harbor Laboratory Press