The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation

Centre d'Immunologie de Marseille-Luminy (CIML), Université de la Méditerranée, Campus de Luminy, 13288 Marseille Cedex 09, France.
Genes & development (Impact Factor: 10.8). 06/2009; 23(10):1195-206. DOI: 10.1101/gad.512009
Source: PubMed


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.

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Available from: Andrew J Saurin, Feb 10, 2014
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    • "Although transcriptional deregulation has a central role in a large array of cancers including acute leukaemia, it is evident that epigenetic machineries including DNA methylation and posttranslational histone modifications constitute integral functions of the oncogenic transcriptional complexes in mediating the aberrant transcriptional programmes (Cheung and So, 2011). Consistently, we and others have revealed that RARalpha fusions form highorder homotetramers (Lin and Evans, 2000; Minucci et al, 2000; Kwok et al, 2006; Sternsdorf et al, 2006) that aberrantly recruit the DNA-binding cofactor, RXRalpha (Zeisig et al, 2007; Zhu et al, 2007), as well as epigenetic-modifying enzymes such as histone deacetylases (HDACs) (Grignani et al, 1998; Lin et al, 1998), DNA methyltransferases (DNMTs) (Di Croce et al, 2002), SUV39H1 (Carbone et al, 2006), and polycomb repressive complexes (PRCs) 1 and 2 (Villa et al, 2007; Boukarabila et al, 2009; Smith et al, 2011) to suppress expression of downstream targets critical for differentiation and tumour suppression (Figure 1A). On the other hand, epigenetic mechanisms driving APL leukaemogenesis also include the emerging new epigenetic factor, miRNAs (micro RNAs) such as Let-7c (Saumet et al, 2009), which is upregulated to promote granulocytic differentiation of APL cells in part by suppressing PBX2 upon ATRA treatment (Pelosi et al, 2012; Figure 1B). "
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    ABSTRACT: Transcriptional deregulation plays a key role in a large array of cancers, and successful targeting of oncogenic transcription factors that sustain diseases has been a holy grail in the field. Acute promyelocytic leukaemia (APL) driven by chimeric transcription factors encoding retinoic acid receptor alpha fusions is the paradigm of targeted cancer therapy, in which the application of all-trans retinoic acid (ATRA) treatments have markedly transformed this highly fatal cancer to a highly manageable disease. The extremely high complete remission rate resulted from targeted therapies using ATRA in combination with arsenic trioxide will likely be able to minimise or even totally eliminate the use of highly toxic chemotherapeutic agents in APL. In this article, we will review the molecular basis and the upcoming challenges of these targeted therapies in APL, and discuss the recent advance in our understanding of epigenetics underlying ATRA response and their potential use to further improve treatment response and overcome resistance.British Journal of Cancer advance online publication, 23 September 2014; doi:10.1038/bjc.2014.374
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    • "Genes coding for components of the PcG may be amplified or overexpressed, or the PcG may be " ectopically recruited " to nontarget genes in cancer development [72]. Mutations have been detected in a number of PcG components in myeloid disorders, with some, unexpectedly, conferring a loss of function [27, 73–76]. "
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    • "For instance, activation of Meis2 could be induced by mammalian Trithorax group factors, which oppose PcG activity, at the promoter region with or without assistance of MBE, which may contribute only to confer tissue specificity in this scenario (Simon and Kingston, 2009). Consistent with this model, RING1B has been reported to associate not only with PRC1-related complexes but also with MLLrelated complexes, and the Meis2 promoter is indeed bound by H3K4me3 in ESCs (Boukarabila et al., 2009; T.K., unpublished data). Further studies to elucidate the role of the tripartite interaction may be needed. "
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    ABSTRACT: Polycomb-group (PcG) proteins mediate repression of developmental regulators in a reversible manner, contributing to their spatiotemporally regulated expression. However, it is poorly understood how PcG-repressed genes are activated by developmental cues. Here, we used the mouse Meis2 gene as a model to identify a role of a tissue-specific enhancer in removing PcG from the promoter. Meis2 repression in early development depends on binding of RING1B, an essential E3 component of PcG, to its promoter, coupled with its association with another RING1B-binding site (RBS) at the 3' end of the Meis2 gene. During early midbrain development, a midbrain-specific enhancer (MBE) transiently associates with the promoter-RBS, forming a promoter-MBE-RBS tripartite interaction in a RING1-dependent manner. Subsequently, RING1B-bound RBS dissociates from the tripartite complex, leaving promoter-MBE engagement to activate Meis2 expression. This study therefore demonstrates that PcG and/or related factors play a role in Meis2 activation by regulating the topological transition of cis-regulatory elements.
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