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Polycomb group proteins in hematopoietic stem cell aging and malignancies

  • Progress in Hematology
  • Hematopoietic stem cell aging
  • Published:
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Abstract

Protection of the transcriptional “stemness” network is important to maintain a healthy hematopoietic stem cells (HSCs) compartment during the lifetime of the organism. Recent evidence shows that fundamental changes in the epigenetic status of HSCs might be one of the driving forces behind many age-related HSC changes and might pave the way for HSC malignant transformation and subsequent leukemia development, the incidence of which increases exponentially with age. Polycomb group (PcG) proteins are key epigenetic regulators of HSC cellular fate decisions and are often found to be misregulated in human hematopoietic malignancies. In this review, we speculate that PcG proteins balance HSC aging against the risk of developing cancer, since a disturbance in PcG genes and proteins affects several important cellular processes such as cell fate decisions, senescence, apoptosis, and DNA damage repair.

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References

  1. Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961;14:213–22.

    PubMed  CAS  Google Scholar 

  2. Till JE, McCulloch EA. Early repair processes in marrow cells irradiated and proliferating in vivo. Radiat Res. 1963;18:96–105.

    PubMed  CAS  Google Scholar 

  3. Till JE, McCulloch EA. Repair processes in irradiated mouse hematopoietic tissue. Ann N Y Acad Sci. 1964;114:115–25.

    PubMed  CAS  Google Scholar 

  4. Harrison DE. Normal function of transplanted mouse erythrocyte precursors for 21 months beyond donor life spans. Nat New Biol. 1972;237:220–2.

    PubMed  CAS  Google Scholar 

  5. Harrison DE, Astle CM. Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure. J Exp Med. 1982;156:1767–79.

    PubMed  CAS  Google Scholar 

  6. Kamminga LM, van Os R, Ausema A, Noach EJ, Weersing E, Dontje B, et al. Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging. Stem Cells. 2005;23:82–92.

    PubMed  CAS  Google Scholar 

  7. 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;107:2170–9.

    PubMed  CAS  Google Scholar 

  8. Mauch P, Botnick LE, Hannon EC, Obbagy J, Hellman S. Decline in bone marrow proliferative capacity as a function of age. Blood. 1982;60:245–52.

    PubMed  CAS  Google Scholar 

  9. Siminovitch L, Till JE, McCulloch EA. Decline in colony-forming ability of marrow cells subjected to serial transplantation into irradiated mice. J Cell Physiol. 1964;64:23–31.

    PubMed  CAS  Google Scholar 

  10. Van Zant G, Holland BP, Eldridge PW, Chen JJ. Genotype-restricted growth and aging patterns in hematopoietic stem cell populations of allophenic mice. J Exp Med. 1990;171:1547–65.

    PubMed  Google Scholar 

  11. Dykstra B, de Haan G. Hematopoietic stem cell aging and self-renewal. Cell Tissue Res. 2008;331:91–101.

    PubMed  Google Scholar 

  12. Waterstrat A, Van Zant G. Effects of aging on hematopoietic stem and progenitor cells. Curr Opin Immunol. 2009;21:408–13.

    PubMed  CAS  Google Scholar 

  13. Dorshkind K, Swain S. Age-associated declines in immune system development and function: causes, consequences, and reversal. Curr Opin Immunol. 2009;21:404–7.

    PubMed  CAS  Google Scholar 

  14. Miller RA. The aging immune system: primer and prospectus. Science. 1996;273:70–4.

    PubMed  CAS  Google Scholar 

  15. Rosendaal M, Hodgson GS, Bradley TR. Haemopoietic stem cells are organised for use on the basis of their generation-age. Nature. 1976;264:68–9.

    PubMed  CAS  Google Scholar 

  16. Fey MF, Liechti-Gallati S, von Rohr A, Borisch B, Theilkas L, Schneider V, et al. Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Blood. 1994;83:931–8.

    PubMed  CAS  Google Scholar 

  17. Swierczek SI, Agarwal N, Nussenzveig RH, Rothstein G, Wilson A, Artz A, Prchal JT. Hematopoiesis is not clonal in healthy elderly women. Blood. 2008;112:3186–93.

    PubMed  CAS  Google Scholar 

  18. de Haan G. Hematopoietic stem cells: self-renewing or aging? Cells Tissues Organs. 2002;171:27–37.

    PubMed  Google Scholar 

  19. Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 2007;5:e201.

    PubMed  Google Scholar 

  20. Noda S, Ichikawa H, Miyoshi H. Hematopoietic stem cell aging is associated with functional decline and delayed cell cycle progression. Biochem Biophys Res Commun. 2009;383:210–5.

    PubMed  CAS  Google Scholar 

  21. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, Weissman IL. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA. 2005;102:9194–9.

    PubMed  CAS  Google Scholar 

  22. Wagner W, Bork S, Horn P, Krunic D, Walenda T, Diehlmann A, et al. Aging and replicative senescence have related effects on human stem and progenitor cells. PLoS One. 2009;4:e5846.

    PubMed  Google Scholar 

  23. Kamminga LM, de Haan G. Cellular memory and hematopoietic stem cell aging. Stem Cells. 2006;24:1143–9.

    PubMed  CAS  Google Scholar 

  24. Konuma T, Oguro H, Iwama A. Role of the polycomb group proteins in hematopoietic stem cells. Dev Growth Differ. 2010;52:505–16.

    PubMed  CAS  Google Scholar 

  25. Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128:635–8.

    PubMed  CAS  Google Scholar 

  26. Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006;6:846–56.

    PubMed  CAS  Google Scholar 

  27. Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem. 2005;74:481–514.

    PubMed  CAS  Google Scholar 

  28. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–54.

    PubMed  CAS  Google Scholar 

  29. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128:693–705.

    PubMed  CAS  Google Scholar 

  30. Imai S, Kitano H. Heterochromatin islands and their dynamic reorganization: a hypothesis for three distinctive features of cellular aging. Exp Gerontol. 1998;33:555–70.

    PubMed  CAS  Google Scholar 

  31. Villeponteau B. The heterochromatin loss model of aging. Exp Gerontol. 1997;32:383–94.

    PubMed  CAS  Google Scholar 

  32. Southworth LK, Owen AB, Kim SK. Aging mice show a decreasing correlation of gene expression within genetic modules. PLoS Genet. 2009;5:e1000776.

    PubMed  Google Scholar 

  33. Calvanese V, Lara E, Kahn A, Fraga MF. The role of epigenetics in aging and age-related diseases. Ageing Res Rev. 2009;8:268–76.

    PubMed  CAS  Google Scholar 

  34. Fraga MF. Genetic and epigenetic regulation of aging. Curr Opin Immunol. 2009;21:446–53.

    PubMed  CAS  Google Scholar 

  35. Gonzalo S. Epigenetic alterations in aging. J Appl Physiol. 2010;109:586–97.

    PubMed  CAS  Google Scholar 

  36. Esteller M. Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet. 2007;16(Spec No 1):R50–9.

    PubMed  CAS  Google Scholar 

  37. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148–59.

    PubMed  CAS  Google Scholar 

  38. Lewis EB. A gene complex controlling segmentation in Drosophila. Nature. 1978;276:565–70.

    PubMed  CAS  Google Scholar 

  39. Akasaka T, Kanno M, Balling R, Mieza MA, Taniguchi M, Koseki H. A role for mel-18, a Polycomb group-related vertebrate gene, during theanteroposterior specification of the axial skeleton. Development. 1996;122:1513–22.

    PubMed  CAS  Google Scholar 

  40. Core N, Bel S, Gaunt SJ, Aurrand-Lions M, Pearce J, Fisher A, Djabali M. Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice. Development. 1997;124:721–9.

    PubMed  CAS  Google Scholar 

  41. del Mar Lorente M, Marcos-Gutierrez C, Perez C, Schoorlemmer J, Ramirez A, Magin T, Vidal M. Loss- and gain-of-function mutations show a polycomb group function for Ring1A in mice. Development. 2000;127:5093–100.

    PubMed  CAS  Google Scholar 

  42. 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;8:757–69.

    PubMed  Google Scholar 

  43. Rajasekhar VK, Begemann M. Concise review: roles of polycomb group proteins in development and disease: a stem cell perspective. Stem Cells. 2007;25:2498–510.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  45. 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;298:1039–43.

    PubMed  CAS  Google Scholar 

  46. 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;111:185–96.

    PubMed  CAS  Google Scholar 

  47. 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;16:2893–905.

    PubMed  CAS  Google Scholar 

  48. Muller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B, et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell. 2002;111:197–208.

    PubMed  CAS  Google Scholar 

  49. Kuzmichev A, Jenuwein T, Tempst P, Reinberg D. Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. Mol Cell. 2004;14:183–93.

    PubMed  CAS  Google Scholar 

  50. Kuzmichev A, Margueron R, Vaquero A, Preissner TS, Scher M, Kirmizis A, et al. Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. Proc Natl Acad Sci USA. 2005;102:1859–64.

    PubMed  CAS  Google Scholar 

  51. 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;26:2560–9.

    PubMed  CAS  Google Scholar 

  52. Wang L, Brown JL, Cao R, Zhang Y, Kassis JA, Jones RS. Hierarchical recruitment of polycomb group silencing complexes. Mol Cell. 2004;14:637–46.

    PubMed  CAS  Google Scholar 

  53. Cao R, Tsukada Y, Zhang Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell. 2005;20:845–54.

    PubMed  CAS  Google Scholar 

  54. de Napoles M, Mermoud JE, Wakao R, Tang YA, Endoh M, Appanah R, et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev Cell. 2004;7:663–76.

    PubMed  Google Scholar 

  55. 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;9:1428–35.

    PubMed  CAS  Google Scholar 

  56. 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.

    PubMed  Google Scholar 

  57. 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;20:1123–36.

    PubMed  CAS  Google Scholar 

  58. Puschendorf M, Terranova R, Boutsma E, Mao X, Isono K, Brykczynska U, et al. PRC1 and Suv39 h specify parental asymmetry at constitutive heterochromatin in early mouse embryos. Nat Genet. 2008;40:411–20.

    PubMed  CAS  Google Scholar 

  59. 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;25:3110–22.

    PubMed  CAS  Google Scholar 

  60. 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;105:16572–7.

    PubMed  CAS  Google Scholar 

  61. 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;32:503–18.

    PubMed  CAS  Google Scholar 

  62. Bracken AP, Helin K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer. 2009;9:773–84.

    PubMed  CAS  Google Scholar 

  63. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–93.

    PubMed  CAS  Google Scholar 

  64. Cui K, Zang C, Roh TY, Schones DE, Childs RW, Peng W, Zhao K. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell. 2009;4:80–93.

    PubMed  CAS  Google Scholar 

  65. Weishaupt H, Sigvardsson M, Attema JL. Epigenetic chromatin states uniquely define the developmental plasticity of murine hematopoietic stem cells. Blood. 2010;115:247–56.

    PubMed  CAS  Google Scholar 

  66. 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;6:279–86.

    PubMed  CAS  Google Scholar 

  67. 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;21:843–51.

    PubMed  CAS  Google Scholar 

  68. Lessard J, Baban S, Sauvageau G. Stage-specific expression of polycomb group genes in human bone marrow cells. Blood. 1998;91:1216–24.

    PubMed  CAS  Google Scholar 

  69. 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;13:2691–703.

    PubMed  CAS  Google Scholar 

  70. 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;85:179–81.

    PubMed  CAS  Google Scholar 

  71. 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;65:737–52.

    PubMed  Google Scholar 

  72. 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;423:302–5.

    PubMed  CAS  Google Scholar 

  73. Rizo A, Dontje B, Vellenga E, de Haan G, Schuringa JJ. Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1. Blood. 2008;111:2621–30.

    PubMed  CAS  Google Scholar 

  74. 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;114:1498–505.

    PubMed  CAS  Google Scholar 

  75. 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;32:571–8.

    PubMed  CAS  Google Scholar 

  76. Kajiume T, Ohno N, Sera Y, Kawahara Y, Yuge L, Kobayashi M. Reciprocal expression of Bmi1 and Mel-18 is associated with functioning of primitive hematopoietic cells. Exp Hematol. 2009;37:857–66. (e852).

    PubMed  CAS  Google Scholar 

  77. Voncken JW, Roelen BA, Roefs M, de Vries S, Verhoeven E, Marino S, et al. Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proc Natl Acad Sci USA. 2003;100:2468–73.

    PubMed  CAS  Google Scholar 

  78. 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;28:1018–28.

    PubMed  CAS  Google Scholar 

  79. 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;195:759–70.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  81. de Haan G, Gerrits A, Bystrykh L. Modern genome-wide genetic approaches to reveal intrinsic properties of stem cells. Curr Opin Hematol. 2006;13:249–53.

    PubMed  Google Scholar 

  82. Jansen RC, Nap JP. Genetical genomics: the added value from segregation. Trends Genet. 2001;17:388–91.

    PubMed  CAS  Google Scholar 

  83. de Haan G, Nijhof W, Van Zant G. Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during aging: correlation between lifespan and cycling activity. Blood. 1997;89:1543–50.

    PubMed  Google Scholar 

  84. de Haan G, Van Zant G. Dynamic changes in mouse hematopoietic stem cell numbers during aging. Blood. 1999;93:3294–301.

    PubMed  Google Scholar 

  85. Kamminga LM, Akkerman I, Weersing E, Ausema A, Dontje B, Van Zant G, de Haan G. Autonomous behavior of hematopoietic stem cells. Exp Hematol. 2000;28:1451–9.

    PubMed  CAS  Google Scholar 

  86. Muller-Sieburg CE, Cho RH, Sieburg HB, Kupriyanov S, Riblet R. Genetic control of hematopoietic stem cell frequency in mice is mostly cell autonomous. Blood. 2000;95:2446–8.

    PubMed  CAS  Google Scholar 

  87. De Haan G, Van Zant G. Genetic analysis of hemopoietic cell cycling in mice suggests its involvement in organismal life span. FASEB J. 1999;13:707–13.

    PubMed  Google Scholar 

  88. de Haan G, Van Zant G. Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene. J Exp Med. 1997;186:529–36.

    PubMed  Google Scholar 

  89. Henckaerts E, Langer JC, Snoeck HW. Quantitative genetic variation in the hematopoietic stem cell and progenitor cell compartment and in lifespan are closely linked at multiple loci in BXD recombinant inbred mice. Blood. 2004;104:374–9.

    PubMed  CAS  Google Scholar 

  90. Liang Y, Van Zant G. Genetic control of stem-cell properties and stem cells in aging. Curr Opin Hematol. 2003;10:195–202.

    PubMed  Google Scholar 

  91. Bystrykh L, Weersing E, Dontje B, Sutton S, Pletcher MT, Wiltshire T, et al. Uncovering regulatory pathways that affect hematopoietic stem cell function using ‘genetical genomics’. Nat Genet. 2005;37:225–32.

    PubMed  CAS  Google Scholar 

  92. Su IH, Basavaraj A, Krutchinsky AN, Hobert O, Ullrich A, Chait BT, Tarakhovsky A. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol. 2003;4:124–31.

    PubMed  CAS  Google Scholar 

  93. Su IH, Dobenecker MW, Dickinson E, Oser M, Basavaraj A, Marqueron R, et al. Polycomb group protein ezh2 controls actin polymerization and cell signaling. Cell. 2005;121:425–36.

    PubMed  CAS  Google Scholar 

  94. 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.

    PubMed  CAS  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.

    PubMed  Google Scholar 

  96. 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;116:731–9.

    PubMed  CAS  Google Scholar 

  97. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006;127:265–75.

    PubMed  CAS  Google Scholar 

  98. Sherr CJ. The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol. 2001;2:731–7.

    PubMed  CAS  Google Scholar 

  99. 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;397:164–8.

    PubMed  CAS  Google Scholar 

  100. Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, et al. Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus. EMBO J. 2007;26:1637–48.

    PubMed  CAS  Google Scholar 

  101. Gil J, Peters G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol. 2006;7:667–77.

    PubMed  CAS  Google Scholar 

  102. Maertens GN, El Messaoudi-Aubert S, Racek T, Stock JK, Nicholls J, Rodriguez-Niedenfuhr M, et al. Several distinct polycomb complexes regulate and co-localize on the INK4a tumor suppressor locus. PLoS One. 2009;4:e6380.

    PubMed  Google Scholar 

  103. Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006;443:421–6.

    PubMed  CAS  Google Scholar 

  104. Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature. 2006;443:453–7.

    PubMed  CAS  Google Scholar 

  105. Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature. 2006;443:448–52.

    PubMed  CAS  Google Scholar 

  106. Prasher JM, Lalai AS, Heijmans-Antonissen C, Ploemacher RE, Hoeijmakers JH, Touw IP, Niedernhofer LJ. Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1−/− mice. EMBO J. 2005;24:861–71.

    PubMed  CAS  Google Scholar 

  107. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007;447:725–9.

    PubMed  CAS  Google Scholar 

  108. Chou DM, Adamson B, Dephoure NE, Tan X, Nottke AC, Hurov KE, et al. A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. Proc Natl Acad Sci USA. 2010;107:18475–80.

    PubMed  CAS  Google Scholar 

  109. 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;30:10096–111.

    PubMed  CAS  Google Scholar 

  110. Hong Z, Jiang J, Lan L, Nakajima S, Kanno S, Koseki H, Yasui A. A polycomb group protein, PHF1, is involved in the response to DNA double-strand breaks in human cell. Nucleic Acids Res. 2008;36:2939–47.

    PubMed  CAS  Google Scholar 

  111. 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.

    PubMed  CAS  Google Scholar 

  112. Armitage P, Doll R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer. 1954;8:1–12.

    PubMed  CAS  Google Scholar 

  113. Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med. 1999;341:1051–62.

    PubMed  CAS  Google Scholar 

  114. Moorman AV, Roman E, Willett EV, Dovey GJ, Cartwright RA, Morgan GJ. Karyotype and age in acute myeloid leukemia. Are they linked? Cancer Genet Cytogenet. 2001;126:155–61.

    PubMed  CAS  Google Scholar 

  115. Nordling CO. A new theory on cancer-inducing mechanism. Br J Cancer. 1953;7:68–72.

    PubMed  CAS  Google Scholar 

  116. Harrison DE. Normal production of erythrocytes by mouse marrow continuous for 73 months. Proc Natl Acad Sci USA. 1973;70:3184–8.

    PubMed  CAS  Google Scholar 

  117. Kay HE. How many cell-generations? Lancet. 1965;2:418–9.

    PubMed  CAS  Google Scholar 

  118. Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135:1118–29.

    PubMed  CAS  Google Scholar 

  119. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.

    PubMed  CAS  Google Scholar 

  120. Jordan CT. Unique molecular and cellular features of acute myelogenous leukemia stem cells. Leukemia. 2002;16:559–62.

    PubMed  CAS  Google Scholar 

  121. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.

    PubMed  CAS  Google Scholar 

  122. Martens JH, Stunnenberg HG. The molecular signature of oncofusion proteins in acute myeloid leukemia. FEBS Lett. 2010;584:2662–9.

    PubMed  CAS  Google Scholar 

  123. Barnes DJ, Melo JV. Cytogenetic and molecular genetic aspects of chronic myeloid leukaemia. Acta Haematol. 2002;108:180–202.

    PubMed  CAS  Google Scholar 

  124. Faderl S, Jeha S, Kantarjian HM. The biology and therapy of adult acute lymphoblastic leukemia. Cancer. 2003;98:1337–54.

    PubMed  Google Scholar 

  125. Lausten-Thomsen U, Madsen HO, Vestergaard TR, Hjalgrim H, Nersting J, Schmiegelow K. Prevalence of t(12;21)[ETV6-RUNX1]-positive cells in healthy neonates. Blood. 2010;117:186–9.

    PubMed  Google Scholar 

  126. Lecluse Y, Lebailly P, Roulland S, Gac AC, Nadel B, Gauduchon P. t(11;14)-positive clones can persist over a long period of time in the peripheral blood of healthy individuals. Leukemia. 2009;23:1190–3.

    PubMed  CAS  Google Scholar 

  127. Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C, et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci USA. 2002;99:8242–7.

    PubMed  CAS  Google Scholar 

  128. Schuler F, Dolken L, Hirt C, Kiefer T, Berg T, Fusch G, et al. Prevalence and frequency of circulating t(14;18)-MBR translocation carrying cells in healthy individuals. Int J Cancer. 2009;124:958–63.

    PubMed  Google Scholar 

  129. Dash AB, Williams IR, Kutok JL, Tomasson MH, Anastasiadou E, Lindahl K, et al. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Natl Acad Sci USA. 2002;99:7622–7.

    PubMed  CAS  Google Scholar 

  130. Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington CJ, et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci USA. 2001;98:10398–403.

    PubMed  CAS  Google Scholar 

  131. Marte B. It takes (at least) two to tango. In: Nature milestones cancer; 2006. doi:10.1038/nrc1851.

  132. Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer. 2004;4:143–53.

    PubMed  CAS  Google Scholar 

  133. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54.

    PubMed  CAS  Google Scholar 

  134. Jones PA. DNA methylation and cancer. Oncogene. 2002;21:5358–60.

    PubMed  CAS  Google Scholar 

  135. Fraga MF, Agrelo R, Esteller M. Cross-talk between aging and cancer: the epigenetic language. Ann N Y Acad Sci. 2007;1100:60–74.

    PubMed  CAS  Google Scholar 

  136. Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK. Global histone modification patterns predict risk of prostate cancer recurrence. Nature. 2005;435:1262–6.

    PubMed  CAS  Google Scholar 

  137. Geiger H, Rennebeck G, Van Zant G. Regulation of hematopoietic stem cell aging in vivo by a distinct genetic element. Proc Natl Acad Sci USA. 2005;102:5102–7.

    PubMed  CAS  Google Scholar 

  138. Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 2005;37:391–400.

    PubMed  CAS  Google Scholar 

  139. Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L, et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007;39:237–42.

    PubMed  CAS  Google Scholar 

  140. Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007;39:232–6.

    PubMed  CAS  Google Scholar 

  141. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C, et al. Epigenetic stem cell signature in cancer. Nat Genet. 2007;39:157–8.

    PubMed  CAS  Google Scholar 

  142. Mohammad HP, Cai Y, McGarvey KM, Easwaran H, Van Neste L, Ohm JE, et al. Polycomb CBX7 promotes initiation of heritable repression of genes frequently silenced with cancer-specific DNA hypermethylation. Cancer Res. 2009;69:6322–30.

    PubMed  CAS  Google Scholar 

  143. Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, Shen H, et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 2010;20:440–6.

    PubMed  CAS  Google Scholar 

  144. Martin-Perez D, Piris MA, Sanchez-Beato M. Polycomb proteins in hematologic malignancies. Blood. 2010;116:5465–75.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  146. Bea S, Tort F, Pinyol M, Puig X, Hernandez L, Hernandez S, et al. BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. Cancer Res. 2001;61:2409–12.

    PubMed  CAS  Google Scholar 

  147. 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;19:684–94.

    PubMed  CAS  Google Scholar 

  148. Sawa M, Yamamoto K, Yokozawa T, Kiyoi H, Hishida A, Kajiguchi T, et al. BMI-1 is highly expressed in M0-subtype acute myeloid leukemia. Int J Hematol. 2005;82:42–7.

    PubMed  CAS  Google Scholar 

  149. 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;97:3896–901.

    PubMed  Google Scholar 

  150. 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;104:5389–94.

    PubMed  CAS  Google Scholar 

  151. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 2003;22:5323–35.

    PubMed  CAS  Google Scholar 

  152. 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;157:709–15.

    PubMed  CAS  Google Scholar 

  153. 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;112:950–8.

    PubMed  CAS  Google Scholar 

  154. 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;42:181–5.

    PubMed  CAS  Google Scholar 

  155. 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;42:722–6.

    PubMed  CAS  Google Scholar 

  156. 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;42:665–7.

    PubMed  CAS  Google Scholar 

  157. Martin GM. Epigenetic gambling and epigenetic drift as an antagonistic pleiotropic mechanism of aging. Aging Cell. 2009;8:761–4.

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Leonid Bystrykh for inspiring discussions and critical reading of the manuscript. This work was supported by the Netherlands Organization for Scientific Research (VICI 918-76-601).

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Correspondence to Gerald de Haan.

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Klauke, K., de Haan, G. Polycomb group proteins in hematopoietic stem cell aging and malignancies. Int J Hematol 94, 11–23 (2011). https://doi.org/10.1007/s12185-011-0857-0

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