Évaluation de la mise en place de deux maisons médicales de garde dans le Doubs (original) (raw)

Polycomb complexes in normal and malignant hematopoiesis

The Journal of Cell Biology

Epigenetic mechanisms are crucial for sustaining cell type–specific transcription programs. Among the distinct factors, Polycomb group (PcG) proteins are major negative regulators of gene expression in mammals. These proteins play key roles in regulating the proliferation, self-renewal, and differentiation of stem cells. During hematopoietic differentiation, many PcG proteins are fundamental for proper lineage commitment, as highlighted by the fact that a lack of distinct PcG proteins results in embryonic lethality accompanied by differentiation biases. Correspondingly, proteins of these complexes are frequently dysregulated in hematological diseases. In this review, we present an overview of the role of PcG proteins in normal and malignant hematopoiesis, focusing on the compositional complexity of PcG complexes, and we briefly discuss the ongoing clinical trials for drugs targeting these factors.

Polycomb proteins in hematologic malignancies

Blood, 2010

The Polycomb group (PcG) of proteins is a major mechanism of epigenetic regulation that has been broadly linked to cancer. This system can repress gene expression by chromatin modification and is essential for establishing cell identity. PcG proteins are important for stem cell function and differentiation and have a profound impact during hematopoiesis. In recent years, several published studies have deepened our knowledge of the biology of the PcG in health and disease. In this article, we review the current understanding of the mechanisms of PcG-mediated repression and their relation to DNA methylation, and we discuss the role of the PcG system in hematopoiesis and hematologic malignancies. We suggest that alteration of different PcG members is a frequent event in leukemia and lymphomas that confers the stem cell properties on tumor cells. Thus, drugs targeting Polycomb complexes could be useful for treating patients with these diseases.

Enhanced Self-Renewal of Hematopoietic Stem Cells Mediated by the Polycomb Gene Product Bmi-1

Immunity, 2004

genes. At least two distinct PcG complexes have been 1 Laboratory of Stem Cell Therapy identified and well characterized. One complex includes Center for Experimental Medicine Eed, EzH1, and EzH2, and the other includes Bmi-1, The Institute of Medical Science Mel-18, Mph1/Rae28, M33, Scmh1, and Ring1A/B. Eed-University of Tokyo containing complexes control gene repression through Tokyo 108-8639 recruitment of histone deacetylase followed by local Japan chromatin deacetylation and by methylation of histone 2 Department of Pediatrics H3 Lysine 27 by EzH2. In contrast, no enzymatic activity Shinshu University School of Medicine has yet been reported with regard to Bmi-1-containing Nagano 390-8621 complexes. However, Bmi-1 complexes antagonize Japan chromatin remodeling by the SWI-SNF complex (Shao 3 Department of Developmental Biology et al., 1999) and are recruited to methylated histone H3 National Institute for Basic Biology Lysine 27 via M33 chromodomain to contribute to the Aichi 444-8585 static maintenance of epigenetic memory (Fischle et Japan al., 2003). These two types of complexes coordinately 4 Laboratory for Developmental Genetics maintain positional memory along the anterior-posterior RIKEN Research Center for Allergy and Immunology axis by regulating Hox gene expression patterns during Yokohama 230-0045 development (Jacobs and van Lohuizen, 2002; Orland, Japan 2003). On the other hand, these two complexes play 5 Division of Molecular Genetics reciprocal roles in definitive hematopoiesis: negative The Netherlands Cancer Institute regulation by the Eed-containing complex and positive 1066 CX Amsterdam regulation by Bmi-1-containing complex (Lessard et The Netherlands al., 1999). The Bmi-1-containing complex has been implicated in the maintenance of hematopoietic and leukemic stem Summary cells (HSC) (Ohta et al., 2002; Park et al., 2003; Lessard and Sauvageau, 2003). Mph1/Rae28 Ϫ/Ϫ fetal liver con-The Polycomb group (PcG) gene Bmi-1 has recently tains 20-fold fewer long-term lymphohematopoietic rebeen implicated in the maintenance of hematopoietic populating HSCs than wild-type (wt) (Ohta et al., 2002). stem cells (HSC) from loss-of-function analysis. Here, More importantly, although Bmi-1 Ϫ/Ϫ mice show normal we demonstrate that increased expression of Bmi-1 development of embryonic hematopoiesis, Bmi-1 Ϫ/Ϫ promotes HSC self-renewal. Forced expression of HSCs have a profound defect in self-renewal capacity. Bmi-1 enhanced symmetrical cell division of HSCs and They cannot repopulate hematopoiesis long term, leadmediated a higher probability of inheritance of steming to progressive postnatal pancytopenia (Park et al., ness through cell division. Correspondingly, forced ex-2003; van der Lugt et al.,

Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells

Blood, 2010

Polycomb group (PcG) proteins are transcriptional repressors with a central role in the establishment and maintenance of gene expression patterns during development. We have investigated the role of polycomb repressive complexes (PRCs) in hematopoietic stem cells (HSCs) and progenitor populations. We show that mice with loss of function mutations in PRC2 components display enhanced HSC/progenitor population activity, whereas mutations that disrupt PRC1 or pleiohomeotic repressive complex are associated with HSC/progenitor cell defects. Because the hierarchical model of PRC action would predict synergistic effects of PRC1 and PRC2 mutation, these opposing effects suggest this model does not hold true in HSC/progenitor cells. To investigate the molecular targets of each complex in HSC/progenitor cells, we measured genome-wide expression changes associated with PRC deficiency, and identified transcriptional networks that are differentially regulated by PRC1 and PRC2. These studies provide new insights into the mechanistic interplay between distinct PRCs and have important implications for approaching PcG proteins as therapeutic targets. (Blood. 2010; 116(5):731-739)

Polycomb Group Gene rae28 Is Required for Sustaining Activity of Hematopoietic Stem Cells

Journal of Experimental Medicine, 2002

The rae28 gene (rae28), also designated as mph1, is a mammalian ortholog of the Drosophila polyhomeotic gene, a member of Polycomb group genes (PcG). rae28 constitutes PcG complex 1 for maintaining transcriptional states which have been once initiated, presumably through modulation of the chromatin structure. Hematopoietic activity was impaired in the fetal liver of rae28-deficient animals (rae28−/−), as demonstrated by progressive reduction of hematopoietic progenitors of multilineages and poor expansion of colony forming units in spleen (CFU-S12) during embryonic development. An in vitro long-term culture-initiating cell assay suggested a reduction in hematopoietic stem cells (HSCs), which was confirmed in vivo by reconstitution experiments in lethally irradiated congenic recipient mice. The competitive repopulating units (CRUs) reflect HSCs supporting multilineage blood-cell production. CRUs were generated, whereas the number of CRUs was reduced by a factor of 20 in the rae28−/− ...

Maintenance of leukemic cell identity by the activity of the Polycomb complex PRC1 in mice

Science advances, 2016

Leukemia is a complex heterogeneous disease often driven by the expression of oncogenic fusion proteins with different molecular and biochemical properties. Whereas several fusion proteins induce leukemogenesis by activating Hox gene expression (Hox-activating fusions), others impinge on different pathways that do not involve the activation of Hox genes (non-Hox-activating fusions). It has been postulated that one of the main oncogenic properties of the HOXA9 transcription factor is its ability to control the expression of the p16/p19 tumor suppressor locus (Cdkn2a), thereby compensating Polycomb-mediated repression, which is dispensable for leukemias induced by Hox-activating fusions. We show, by genetically depleting the H2A ubiquitin ligase subunits of the Polycomb repressive complex 1 (PRC1), Ring1a and Ring1b, that Hoxa9 activation cannot repress Cdkn2a expression in the absence of PRC1 and its dependent deposition of H2AK119 monoubiquitination (H2AK119Ub). This demonstrates th...

Role of Polycomb Complexes in Normal and Malignant Plasma Cells

International Journal of Molecular Sciences

Plasma cells (PC) are the main effectors of adaptive immunity, responsible for producing antibodies to defend the body against pathogens. They are the result of a complex highly regulated cell differentiation process, taking place in several anatomical locations and involving unique genetic events. Pathologically, PC can undergo tumorigenesis and cause a group of diseases known as plasma cell dyscrasias, including multiple myeloma (MM). MM is a severe disease with poor prognosis that is characterized by the accumulation of malignant PC within the bone marrow, as well as high clinical and molecular heterogeneity. MM patients frequently develop resistance to treatment, leading to relapse. Polycomb group (PcG) proteins are epigenetic regulators involved in cell fate and carcinogenesis. The emerging roles of PcG in PC differentiation and myelomagenesis position them as potential therapeutic targets in MM. Here, we focus on the roles of PcG proteins in normal and malignant plasma cells, ...