The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation
- 15 May 2009
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 23 (10), 1195-1206
- https://doi.org/10.1101/gad.512009
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.Keywords
This publication has 43 references indexed in Scilit:
- Comparing active and repressed expression states of genes controlled by the Polycomb/Trithorax group proteinsProceedings of the National Academy of Sciences, 2007
- Concise Review: Roles of Polycomb Group Proteins in Development and Disease: A Stem Cell PerspectiveThe International Journal of Cell Cloning, 2007
- Polycomb/Trithorax response elements and epigenetic memory of cell identityDevelopment, 2007
- From genetics to epigenetics: the tale of Polycomb group and trithorax group genesChromosome Research, 2006
- Enhanced Self-Renewal of Hematopoietic Stem Cells Mediated by the Polycomb Gene Product Bmi-1Immunity, 2004
- Chromatin Compaction by a Polycomb Group Protein ComplexScience, 2004
- Propagation of Silencing: Recruitment and Repression of Naive Chromatin In trans by Polycomb Repressed ChromatinMolecular Cell, 2004
- Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27Genes & Development, 2003
- The Core of the Polycomb Repressive Complex Is Compositionally and Functionally Conserved in Flies and HumansMolecular and Cellular Biology, 2002
- Methyltransferase Recruitment and DNA Hypermethylation of Target Promoters by an Oncogenic Transcription FactorScience, 2002