Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Spotlight Review
  • Published:

Spotlight On Signaling Pathways Regulating Human Stem Cells

Polycomb-group proteins in hematopoietic stem cell regulation and hematopoietic neoplasms

Leukemia volume 27, pages 523–533 (2013)Cite this article

Subjects

Abstract

The equilibrium between self-renewal and differentiation of hematopoietic stem cells is regulated by epigenetic mechanisms. In particular, Polycomb-group (PcG) proteins have been shown to be involved in this process by repressing genes involved in cell-cycle regulation and differentiation. PcGs are histone modifiers that reside in two multi-protein complexes: Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2). The existence of multiple orthologs for each Polycomb gene allows the formation of a multitude of distinct PRC1 and PRC2 sub-complexes. Changes in the expression of individual PcG genes are likely to cause perturbations in the composition of the PRC, which affect PRC enzymatic activity and target selectivity. An interesting recent development is that aberrant expression of, and mutations in, PcG genes have been shown to occur in hematopoietic neoplasms, where they display both tumor-suppressor and oncogenic activities. We therefore comprehensively reviewed the latest research on the role of PcG genes in normal and malignant blood cell development. We conclude that future research to elucidate the compositional changes of the PRCs and methods to intervene in PRC assembly will be of great therapeutic relevance to combat hematological malignancies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Lewis EB . A gene complex controlling segmentation in Drosophila. Nature 1978; 276: 565–570.

    Article  CAS  PubMed  Google Scholar 

  2. Levine SS, Weiss A, Erdjument-Bromage H, Shao Z, Tempst P, Kingston RE . The core of the polycomb repressive complex is compositionally and functionally conserved in flies and humans. Mol Cell Biol 2002; 22: 6070–6078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Simon JA, Kingston RE . Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol 2009; 10: 697–708.

    Article  CAS  PubMed  Google Scholar 

  4. Morey L, Helin K . Polycomb group protein-mediated repression of transcription. Trends Biochem Sci 2010; 35: 323–332.

    Article  CAS  PubMed  Google Scholar 

  5. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 2002; 298: 1039–1043.

    Article  CAS  PubMed  Google Scholar 

  6. Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V . Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 2002; 111: 185–196.

    Article  CAS  PubMed  Google Scholar 

  7. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D . Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev 2002; 16: 2893–2905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kuzmichev A, Jenuwein T, Tempst P, Reinberg D . Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. Mol Cell 2004; 14: 183–193.

    Article  CAS  PubMed  Google Scholar 

  9. Nekrasov M, Wild B, Muller J . Nucleosome binding and histone methyltransferase activity of Drosophila PRC2. EMBO Rep 2005; 6: 348–353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kirmizis A, Bartley SM, Kuzmichev A, Margueron R, Reinberg D, Green R et al. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev 2004; 18: 1592–1605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Margueron R, Li G, Sarma K, Blais A, Zavadil J, Woodcock CL et al. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol Cell 2008; 32: 503–518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Margueron R, Justin N, Ohno K, Sharpe ML, Son J, Drury WJ et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 2009; 461: 762–767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cao R, Zhang Y . SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell 2004; 15: 57–67.

    Article  CAS  PubMed  Google Scholar 

  14. Nekrasov M, Klymenko T, Fraterman S, Papp B, Oktaba K, Kocher T et al. Pcl-PRC2 is needed to generate high levels of H3-K27 trimethylation at Polycomb target genes. EMBO J 2007; 26: 4078–4088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sarma K, Margueron R, Ivanov A, Pirrotta V, Reinberg D . Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo. Mol Cell Biol 2008; 28: 2718–2731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Savla U, Benes J, Zhang J, Jones RS . Recruitment of Drosophila Polycomb-group proteins by Polycomblike, a component of a novel protein complex in larvae. Development 2008; 135: 813–817.

    Article  CAS  PubMed  Google Scholar 

  17. Kim H, Kang K, Kim J . AEBP2 as a potential targeting protein for Polycomb Repression Complex PRC2. Nucleic Acids Res 2009; 37: 2940–2950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li G, Margueron R, Ku M, Chambon P, Bernstein BE, Jarid2 ReinbergD . and PRC2, partners in regulating gene expression. Genes Dev 2010; 24: 368–380.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Hunkapiller J, Shen Y, Diaz A, Cagney G, McCleary D, Ramalho-Santos M et al. Polycomb-like 3 promotes polycomb repressive complex 2 binding to CpG islands and embryonic stem cell self-renewal. PLoS Genet 2012; 8: e1002576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shao Z, Raible F, Mollaaghababa R, Guyon JR, Wu CT, Bender W et al. Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 1999; 98: 37–46.

    Article  CAS  PubMed  Google Scholar 

  21. Vandamme J, Volkel P, Rosnoblet C, Le Faou P, Angrand PO . Interaction proteomics analysis of polycomb proteins defines distinct PRC1 complexes in mammalian cells. Mol Cell Proteomics 2011; 10: 002642.

    Article  PubMed  CAS  Google Scholar 

  22. Wang L, Brown JL, Cao R, Zhang Y, Kassis JA, Jones RS . Hierarchical recruitment of polycomb group silencing complexes. Mol Cell 2004; 14: 637–646.

    Article  CAS  PubMed  Google Scholar 

  23. Bernstein E, Duncan EM, Masui O, Gil J, Heard E, Allis CD . Mouse polycomb proteins bind differentially to methylated histone H3 and RNA and are enriched in facultative heterochromatin. Mol Cell Biol 2006; 26: 2560–2569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cao R, Tsukada Y, Zhang Y . Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell 2005; 20: 845–854.

    Article  CAS  PubMed  Google Scholar 

  25. Breiling A, Turner BM, Bianchi ME, Orlando V . General transcription factors bind promoters repressed by Polycomb group proteins. Nature 2001; 412: 651–655.

    Article  CAS  PubMed  Google Scholar 

  26. Stock JK, Giadrossi S, Casanova M, Brookes E, Vidal M, Koseki H et al. Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells. Nat Cell Biol 2007; 9: 1428–1435.

    Article  CAS  PubMed  Google Scholar 

  27. Zhou W, Zhu P, Wang J, Pascual G, Ohgi KA, Lozach J et al. Histone H2A monoubiquitination represses transcription by inhibiting RNA polymerase II transcriptional elongation. Mol Cell 2008; 29: 69–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Whitcomb SJ, Basu A, Allis CD, Bernstein E . Polycomb Group proteins: an evolutionary perspective. Trends Genet 2007; 23: 494–502.

    Article  CAS  PubMed  Google Scholar 

  29. Senthilkumar R, Mishra RK . Novel motifs distinguish multiple homologues of Polycomb in vertebrates: expansion and diversification of the epigenetic toolkit. BMC Genomics 2009; 10: 549.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Volkel P, Le Faou P, Vandamme J, Pira D, Angrand PO . A human Polycomb isoform lacking the Pc box does not participate to PRC1 complexes but forms protein assemblies and represses transcription. Epigenetics 2012; 7: 482–491.

    Article  CAS  PubMed  Google Scholar 

  31. Shaver S, Casas-Mollano JA, Cerny RL, Cerutti H . Origin of the polycomb repressive complex 2 and gene silencing by an E(z) homolog in the unicellular alga Chlamydomonas. Epigenetics 2010; 5: 301–312.

    Article  CAS  PubMed  Google Scholar 

  32. Hennig L, Derkacheva M . Diversity of Polycomb group complexes in plants: same rules, different players? Trends Genet 2009; 25: 414–423.

    Article  CAS  PubMed  Google Scholar 

  33. Butenko Y, Ohad N . Polycomb-group mediated epigenetic mechanisms through plant evolution. Biochim Biophys Acta 2011; 1809: 395–406.

    Article  CAS  PubMed  Google Scholar 

  34. Margueron R, Reinberg D . The Polycomb complex PRC2 and its mark in life. Nature 2011; 469: 343–349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Le Faou P, Volkel P, Angrand PO . The zebrafish genes encoding the Polycomb repressive complex (PRC) 1. Gene 2011; 475: 10–21.

    Article  CAS  PubMed  Google Scholar 

  36. Morey L, Pascual G, Cozzuto L, Roma G, Wutz A, Benitah SA et al. Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells. Cell Stem Cell 2012; 10: 47–62.

    Article  CAS  PubMed  Google Scholar 

  37. O’Loghlen A, Munoz-Cabello AM, Gaspar-Maia A, Wu HA, Banito A, Kunowska N et al. MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation. Cell Stem Cell 2012; 10: 33–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F et al. PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes. Mol Cell 2012; 45: 344–356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM . Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell 1991; 65: 753–763.

    Article  CAS  PubMed  Google Scholar 

  40. Jacobs JJ, Kieboom K, Marino S, DePinho RA, Van Lohuizen M . The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 1999; 397: 164–168.

    Article  CAS  PubMed  Google Scholar 

  41. Tetsu O, Ishihara H, Kanno R, Kamiyasu M, Inoue H, Tokuhisa T et al. mel-18 negatively regulates cell cycle progression upon B cell antigen receptor stimulation through a cascade leading to c-myc/cdc25. Immunity 1998; 9: 439–448.

    Article  CAS  PubMed  Google Scholar 

  42. Guo W-J, Datta S, Band V, Dimri GP . Mel-18 a Polycomb Group Protein, Regulates Cell Proliferation and Senescence via Transcriptional Repression of Bmi-1 and c-Myc Oncoproteins. Mol Biol Cell 2007; 18: 536–546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Guo WJ, Zeng MS, Yadav A, Song LB, Guo BH, Band V et al. Mel-18 acts as a tumor suppressor by repressing Bmi-1 expression and down-regulating Akt activity in breast cancer cells. Cancer Res 2007; 67: 5083–5089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Vincenz C, Kerppola TK . Different polycomb group CBX family proteins associate with distinct regions of chromatin using nonhomologous protein sequences. Proc Natl Acad Sci USA 2008; 105: 16572–16577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mousavi K, Zare H, Wang AH, Sartorelli V . Polycomb protein Ezh1 promotes RNA polymerase II elongation. Mol Cell 2012; 45: 255–262.

    Article  CAS  PubMed  Google Scholar 

  46. Tavares L, Dimitrova E, Oxley D, Webster J, Poot R, Demmers J et al. RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3. Cell 2012; 148: 664–678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X et al. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell 2008; 32: 491–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ezhkova E, Lien W-H, Stokes N, Pasolli HA, Silva JM, Fuchs E . EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes Dev 2011; 25: 485–498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mochizuki-Kashio M, Mishima Y, Miyagi S, Negishi M, Saraya A, Konuma T et al. Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood 2011; 118: 6553–6561.

    Article  CAS  PubMed  Google Scholar 

  50. Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K . Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 2006; 20: 1123–1136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ku M, Koche RP, Rheinbay E, Mendenhall EM, Endoh M, Mikkelsen TS et al. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet 2008; 4: e1000242.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Schoeftner S, Sengupta AK, Kubicek S, Mechtler K, Spahn L, Koseki H et al. Recruitment of PRC1 function at the initiation of X inactivation independent of PRC2 and silencing. EMBO J 2006; 25: 3110–3122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wilkinson FH, Park K, Atchison ML . Polycomb recruitment to DNA in vivo by the YY1 REPO domain. Proc Natl Acad Sci USA 2006; 103: 19296–19301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Klymenko T, Papp B, Fischle W, Köcher T, Schelder M, Fritsch C et al. A Polycomb group protein complex with sequence-specific DNA-binding and selective methyl-lysine-binding activities. Genes Dev 2006; 20: 1110–1122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Woo CJ, Kharchenko PV, Daheron L, Park PJ, Kingston RE . A region of the human HOXD cluster that confers polycomb-group responsiveness. Cell 2010; 140: 99–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Xi H, Yu Y, Fu Y, Foley J, Halees A, Weng Z . Analysis of overrepresented motifs in human core promoters reveals dual regulatory roles of YY1. Genome Res 2007; 17: 798–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Deng Z, Cao P, Wan M, Sui G, Yin Yang . A multifaceted protein beyond a transcription factor. Transcription 2010; 1: 81–84.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ross J, Mavoungou L, Bresnick EH, Milot E . GATA-1 utilizes Ikaros and the Polycomb Repressive Complex 2 to suppress Hes1 and to promote erythropoiesis. Mol Cell Biol 2012; 32: 3624–3638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Boulay G, Dubuissez M, Van Rechem C, Forget A, Helin K, Ayrault O et al. Hypermethylated in cancer 1 (HIC1) recruits polycomb repressive complex 2 (PRC2) to a subset of its target genes through interaction with human polycomb-like (hPCL) proteins. J Biol Chem 2012; 1: 10509–10524.

    Article  CAS  Google Scholar 

  60. Dietrich N, Lerdrup M, Landt E, Agrawal-Singh S, Bak M, Tommerup N et al. REST-mediated recruitment of polycomb repressor complexes in mammalian cells. PLoS Genet 2012; 8: e1002494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yu M, Mazor T, Huang H, Huang H-T, Kathrein KL, Woo AJ et al. Direct recruitment of polycomb repressive complex 1 to chromatin by core binding transcription factors. Mol Cell 2012; 45: 330–343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. García E, Marcos-Gutiérrez C, Del Mar Lorente M, Moreno JC, Vidal M . RYBP a new repressor protein that interacts with components of the mammalian Polycomb complex, and with the transcription factor YY1. EMBO J 1999; 18: 3404–3418.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H et al. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 2004; 21: 843–851.

    Article  CAS  PubMed  Google Scholar 

  64. Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003; 423: 302–305.

    Article  CAS  PubMed  Google Scholar 

  65. van der Lugt NM, Domen J, Linders K, van Roon M, Robanus-Maandag E, te Riele H et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 1994; 8: 757–769.

    Article  CAS  PubMed  Google Scholar 

  66. Rizo A, Olthof S, Han L, Vellenga E, de Haan G, Schuringa JJ . Repression of BMI1 in normal and leukemic human CD34(+) cells impairs self-renewal and induces apoptosis. Blood 2009; 114: 1498–1505.

    Article  CAS  PubMed  Google Scholar 

  67. Akasaka T, Tsuji K, Kawahira H, Kanno M, Harigaya K, Hu L et al. The role of mel-18, a mammalian Polycomb group gene, during IL-7-dependent proliferation of lymphocyte precursors. Immunity 1997; 7: 135–146.

    Article  CAS  PubMed  Google Scholar 

  68. Kajiume T, Ninomiya Y, Ishihara H, Kanno R, Kanno M . Polycomb group gene mel-18 modulates the self-renewal activity and cell cycle status of hematopoietic stem cells. Exp Hematol 2004; 32: 571–578.

    Article  CAS  PubMed  Google Scholar 

  69. Lessard J, Baban S, Sauvageau G . Stage-specific expression of polycomb group genes in human bone marrow cells. Blood 1998; 91: 1216–1224.

    Article  CAS  PubMed  Google Scholar 

  70. Kim WY, Sharpless NE . The regulation of INK4/ARF in cancer and aging. Cell 2006; 127: 265–275.

    Article  CAS  PubMed  Google Scholar 

  71. Oguro H, Yuan J, Ichikawa H, Ikawa T, Yamazaki S, Kawamoto H et al. Poised lineage specification in multipotential hematopoietic stem and progenitor cells by the polycomb protein Bmi1. Cell Stem Cell 2010; 6: 279–286.

    Article  CAS  PubMed  Google Scholar 

  72. Oguro H, Iwama A, Morita Y, Kamijo T, van Lohuizen M, Nakauchi H . Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J Exp Med 2006; 203: 2247–2253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Liu J, Cao L, Chen J, Song S, Lee IH, Quijano C et al. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 2009; 459: 387–392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ismail IH, Andrin C, McDonald D, Hendzel MJ . BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair. J Cell Biol 2010; 191: 45–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Facchino S, Abdouh M, Chatoo W, Bernier G . BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J Neurosci 2010; 30: 10096–10111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gieni RS, Ismail IH, Campbell S, Hendzel MJ . Polycomb group proteins in the DNA damage response: a link between radiation resistance and ‘stemness’. Cell Cycle 2011; 10: 883–894.

    Article  CAS  PubMed  Google Scholar 

  77. Core N, Bel S, Gaunt SJ, Aurrand-Lions M, Pearce J, Fisher A et al. Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice. Development 1997; 124: 721–729.

    Article  CAS  PubMed  Google Scholar 

  78. Raaphorst FM, Otte AP, Meijer CJ . Polycomb-group genes as regulators of mammalian lymphopoiesis. Trends Immunol 2001; 22: 682–690.

    Article  CAS  PubMed  Google Scholar 

  79. Kato Y, Koseki H, Vidal M, Nakauchi H, Iwama A . Unique composition of polycomb repressive complex 1 in hematopoietic stem cells. Int J Hematol 2007; 85: 179–181.

    Article  CAS  PubMed  Google Scholar 

  80. Forzati F, Federico A, Pallante P, Abbate A, Esposito F, Malapelle U et al. CBX7 is a tumor suppressor in mice and humans. J Clin Invest 2012; 122: 612–623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Scott CL, Gil J, Hernando E, Teruya-Feldstein J, Narita M, Martinez D et al. Role of the chromobox protein CBX7 in lymphomagenesis. Proc Natl Acad Sci USA 2007; 104: 5389–5394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Takihara Y, Tomotsune D, Shirai M, Katoh-Fukui Y, Nishii K, Motaleb MA et al. Targeted disruption of the mouse homologue of the Drosophila polyhomeotic gene leads to altered anteroposterior patterning and neural crest defects. Development 1997; 124: 3673–3682.

    Article  CAS  PubMed  Google Scholar 

  83. Tokimasa S, Ohta H, Sawada A, Matsuda Y, Kim JY, Nishiguchi S et al. Lack of the Polycomb-group gene rae28 causes maturation arrest at the early B-cell developmental stage. Exp Hematol 2001; 29: 93–103.

    Article  CAS  PubMed  Google Scholar 

  84. Ohta H, Sawada A, Kim JY, Tokimasa S, Nishiguchi S, Humphries RK et al. Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells. J Exp Med 2002; 195: 759–770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kim JY, Sawada A, Tokimasa S, Endo H, Ozono K, Hara J et al. Defective long-term repopulating ability in hematopoietic stem cells lacking the Polycomb-group gene rae28. Eur J Haematol 2004; 73: 75–84.

    Article  CAS  PubMed  Google Scholar 

  86. Cales C, Roman-Trufero M, Pavon L, Serrano I, Melgar T, Endoh M et al. Inactivation of the polycomb group protein Ring1B unveils an antiproliferative role in hematopoietic cell expansion and cooperation with tumorigenesis associated with Ink4a deletion. Mol Cell Biol 2008; 28: 1018–1028.

    Article  CAS  PubMed  Google Scholar 

  87. Majewski IJ, Ritchie ME, Phipson B, Corbin J, Pakusch M, Ebert A et al. Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood 2010; 116: 731–739.

    Article  CAS  PubMed  Google Scholar 

  88. Pan X, Jones M, Jiang J, Zaprazna K, Yu D, Pear W et al. Increased expression of PcG protein YY1 negatively regulates B cell development while allowing accumulation of myeloid cells and LT-HSC cells. PLoS ONE 2012; 7: e30656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. De Haan G, Gerrits A . Epigenetic control of hematopoietic stem cell aging the case of Ezh2. Ann NY Acad Sci 2007; 1106: 233–239.

    Article  CAS  PubMed  Google Scholar 

  90. Kamminga LM, Bystrykh LV, de Boer A, Houwer S, Douma J, Weersing E et al. The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood 2006; 107: 2170–2179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Herrera-Merchan A, Arranz L, Ligos JM, de Molina A, Dominguez O, Gonzalez S . Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nat Commun 2012; 3: 623.

    Article  CAS  PubMed  Google Scholar 

  92. O’Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T . The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 2001; 21: 4330–4336.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Su IH, Basavaraj A, Krutchinsky AN, Hobert O, Ullrich A, Chait BT et al. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol 2003; 4: 124–131.

    Article  CAS  PubMed  Google Scholar 

  94. Lessard J, Schumacher A, Thorsteinsdottir U, van Lohuizen M, Magnuson T, Sauvageau G . Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev 1999; 13: 2691–2703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Majewski IJ, Blewitt ME, de Graaf CA, McManus EJ, Bahlo M, Hilton AA et al. Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity. PLoS Biol 2008; 6: e93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Jacobs JJ, Scheijen B, Voncken JW, Kieboom K, Berns A, van Lohuizen M . Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev 1999; 13: 2678–2690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Oguro H, Yuan J, Tanaka S, Miyagi S, Mochizuki-Kashio M, Ichikawa H et al. Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes. J Exp Med 2012; 209: 445–454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Martin-Perez D, Piris MA, Sanchez-Beato M . Polycomb proteins in hematologic malignancies. Blood 2010; 116: 5465–5475.

    Article  CAS  PubMed  Google Scholar 

  99. Sauvageau M, Sauvageau G . Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell 2010; 7: 299–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A . Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 1991; 65: 737–752.

    Article  CAS  PubMed  Google Scholar 

  101. Mihara K, Chowdhury M, Nakaju N, Hidani S, Ihara A, Hyodo H et al. Bmi-1 is useful as a novel molecular marker for predicting progression of myelodysplastic syndrome and patient prognosis. Blood 2006; 107: 305–308.

    Article  CAS  PubMed  Google Scholar 

  102. Xu F, Li X, Wu L, Zhang Q, Yang R, Yang Y et al. Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring. Ann Hematol 2011; 90: 643–653.

    Article  CAS  PubMed  Google Scholar 

  103. Chowdhury M, Mihara K, Yasunaga S, Ohtaki M, Takihara Y, Kimura A . Expression of Polycomb-group (PcG) protein BMI-1 predicts prognosis in patients with acute myeloid leukemia. Leukemia 2007; 21: 1116–1122.

    Article  CAS  PubMed  Google Scholar 

  104. Mohty M, Yong AS, Szydlo RM, Apperley JF, Melo JV . The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia. Blood 2007; 110: 380–383.

    Article  CAS  PubMed  Google Scholar 

  105. Yong AS, Stephens N, Weber G, Li Y, Savani BN, Eniafe R et al. Improved outcome following allogeneic stem cell transplantation in chronic myeloid leukemia is associated with higher expression of BMI-1 and immune responses to BMI-1 protein. Leukemia 2011; 25: 629–637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Raaphorst FM, van Kemenade FJ, Blokzijl T, Fieret E, Hamer KM, Satijn DP et al. Coexpression of BMI-1 and EZH2 polycomb group genes in Reed-Sternberg cells of Hodgkin’s disease. Am J Pathol 2000; 157: 709–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. van Kemenade FJ, Raaphorst FM, Blokzijl T, Fieret E, Hamer KM, Satijn DP et al. Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma. Blood 2001; 97: 3896–3901.

    Article  CAS  PubMed  Google Scholar 

  108. Ma Y, Cui W, Yang J, Qu J, Di C, Amin HM et al. SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood 2006; 108: 2726–2735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yang J, Chai L, Liu F, Fink LM, Lin P, Silberstein LE et al. Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc Natl Acad Sci USA 2007; 104: 10494–10499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G . Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J 1998; 17: 3714–3725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lessard J, Sauvageau G . Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003; 423: 255–260.

    Article  CAS  PubMed  Google Scholar 

  112. Yuan J, Takeuchi M, Negishi M, Oguro H, Ichikawa H, Iwama A . Bmi1 is essential for leukemic reprogramming of myeloid progenitor cells. Leukemia 2011; 25: 1335–1343.

    Article  CAS  PubMed  Google Scholar 

  113. Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 2006; 442: 818–822.

    Article  CAS  PubMed  Google Scholar 

  114. Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247: 824–830.

    Article  CAS  PubMed  Google Scholar 

  115. Rizo A, Horton SJ, Olthof S, Dontje B, Ausema A, van Os R et al. BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells. Blood 2010; 116: 4621–4630.

    Article  CAS  PubMed  Google Scholar 

  116. Sengupta A, Ficker AM, Dunn SK, Madhu M, Cancelas JA . Bmi1 reprograms CML B-lymphoid progenitors to become B-ALL-initiating cells. Blood 2012; 119: 494–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dukers DF, van Galen JC, Giroth C, Jansen P, Sewalt RG, Otte AP et al. Unique polycomb gene expression pattern in Hodgkin’s lymphoma and Hodgkin's lymphoma-derived cell lines. Am J Pathol 2004; 164: 873–881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Raaphorst FM, Vermeer M, Fieret E, Blokzijl T, Dukers D, Sewalt RG et al. Site-specific expression of polycomb-group genes encoding the HPC-HPH/PRC1 complex in clinically defined primary nodal and cutaneous large B-cell lymphomas. Am J Pathol 2004; 164: 533–542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Grubach L, Juhl-Christensen C, Rethmeier A, Olesen LH, Aggerholm A, Hokland P et al. Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia. Eur J Haematol 2008; 81: 112–122.

    Article  CAS  PubMed  Google Scholar 

  120. Tan J, Jones M, Koseki H, Nakayama M, Muntean AG, Maillard I et al. CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell 2011; 20: 563–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Garcia-Cuellar MP, Zilles O, Schreiner SA, Birke M, Winkler TH, Slany RK . The ENL moiety of the childhood leukemia-associated MLL-ENL oncoprotein recruits human Polycomb 3. Oncogene 2001; 20: 411–419.

    Article  CAS  PubMed  Google Scholar 

  122. Wang SS, Menashe I, Cerhan JR, Cozen W, Severson RK, Davis S et al. Variations in chromosomes 9 and 6p21.3 with risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 2011; 20: 42–49.

    Article  PubMed  Google Scholar 

  123. Sanchez-Beato M, Sanchez E, Gonzalez-Carrero J, Morente M, Diez A, Sanchez-Verde L et al. Variability in the expression of polycomb proteins in different normal and tumoral tissues. A pilot study using tissue microarrays. Mod Pathol 2006; 19: 684–694.

    Article  CAS  PubMed  Google Scholar 

  124. Raimondi SC, Shurtleff SA, Downing JR, Rubnitz J, Mathew S, Hancock M et al. 12p abnormalities and the TEL gene (ETV6) in childhood acute lymphoblastic leukemia. Blood 1997; 90: 4559–4566.

    Article  CAS  PubMed  Google Scholar 

  125. Sato Y, Bohlander SK, Kobayashi H, Reshmi S, Suto Y, Davis EM et al. Heterogeneity in the breakpoints in balanced rearrangements involving band 12p13 in hematologic malignancies identified by fluorescence in situ hybridization: TEL (ETV6 ) is involved in only one half. Blood 1997; 90: 4886–4893.

    Article  CAS  PubMed  Google Scholar 

  126. Faderl S, Kantarjian HM, Talpaz M, Estrov Z . Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood 1998; 91: 3995–4019.

    Article  CAS  PubMed  Google Scholar 

  127. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010; 42: 181–185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bodor C, O’Riain C, Wrench D, Matthews J, Iyengar S, Tayyib H et al. EZH2 Y641 mutations in follicular lymphoma. Leukemia 2011; 25: 726–729.

    Article  CAS  PubMed  Google Scholar 

  129. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci USA 2010; 107: 20980–20985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012; 492: 108–112.

    Article  CAS  PubMed  Google Scholar 

  131. Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med 2012; 18: 298–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 2012; 481: 157–163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010; 42: 722–726.

    Article  CAS  PubMed  Google Scholar 

  134. Nikoloski G, Langemeijer SM, Kuiper RP, Knops R, Massop M, Tonnissen ER et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 2010; 42: 665–667.

    Article  CAS  PubMed  Google Scholar 

  135. Guglielmelli P, Biamonte F, Score J, Hidalgo-Curtis C, Cervantes F, Maffioli M et al. EZH2 mutational status predicts poor survival in myelofibrosis. Blood 2011; 118: 5227–5234.

    Article  CAS  PubMed  Google Scholar 

  136. Score J, Hidalgo-Curtis C, Jones AV, Winkelmann N, Skinner A, Ward D et al. Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Blood 2012; 119: 1208–1213.

    Article  CAS  PubMed  Google Scholar 

  137. Hock H . A complex Polycomb issue: the two faces of EZH2 in cancer. Genes Dev 2012; 26: 751–755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Simon C, Chagraoui J, Krosl J, Gendron P, Wilhelm B, Lemieux S et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev 2012; 26: 651–656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Neff T, Sinha AU, Kluk MJ, Zhu N, Khattab MH, Stein L et al. Polycomb repressive complex 2 is required for MLL-AF9 leukemia. Proc Natl Acad Sci USA 2012; 109: 5028–5033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cedar H, Bergman Y . Epigenetics of haematopoietic cell development. Nat Rev Immunol 2011; 11: 478–488.

    Article  CAS  PubMed  Google Scholar 

  141. Donohoe ME, Zhang X, McGinnis L, Biggers J, Li E, Shi Y . Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality. Mol Cell Biol 1999; 19: 7237–7244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Faust C, Schumacher A, Holdener B, Magnuson T . The eed mutation disrupts anterior mesoderm production in mice. Development 1995; 121: 273–285.

    Article  CAS  PubMed  Google Scholar 

  143. Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K . Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 2004; 23: 4061–4071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Visser HP, Gunster MJ, Kluin-Nelemans HC, Manders EM, Raaphorst FM, Meijer CJ et al. The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma. Br J Haematol 2001; 112: 950–958.

    Article  CAS  PubMed  Google Scholar 

  145. Richie ER, Schumacher A, Angel JM, Holloway M, Rinchik EM, Magnuson T . The Polycomb-group gene eed regulates thymocyte differentiation and suppresses the development of carcinogen-induced T-cell lymphomas. Oncogene 2002; 21: 299–306.

    Article  CAS  PubMed  Google Scholar 

  146. Sauvageau M, Miller M, Lemieux S, Lessard J, Hebert J, Sauvageau G . Quantitative expression profiling guided by common retroviral insertion sites reveals novel and cell type specific cancer genes in leukemia. Blood 2008; 111: 790–799.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all members of the Stem Cell Biology department for their participation in productive discussions. This work was supported by grants from the Dutch Cancer Society (RUG 2007-3729), the Netherlands Organization for Scientific Research (NWO-ALW and VICI to GdH) and the Netherlands Institute for Regenerative Medicine (NIRM).

Author information

Authors and Affiliations

  1. Section Stem Cell Biology, European Institute for the Biology of Ageing (ERIBA), University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

    V Radulović, G de Haan & K Klauke

Authors
  1. V Radulović
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G de Haan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Klauke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G de Haan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Radulović, V., de Haan, G. & Klauke, K. Polycomb-group proteins in hematopoietic stem cell regulation and hematopoietic neoplasms. Leukemia 27, 523–533 (2013). https://doi.org/10.1038/leu.2012.368

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.368

Keywords

This article is cited by

Search

Advanced search

Quick links