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.

  • Review
  • Published:

Imprinted genes in myeloid lineage commitment in normal and malignant hematopoiesis

Abstract

Genomic imprinting is characterized by the parent-of-origin monoallelic expression of several diploid genes because of epigenetic regulation. Imprinted genes (IGs) are key factors in development, supporting the ability of a genotype to produce phenotypes in response to environmental stimuli. IGs are highly expressed during prenatal stages but are downregulated after birth. They also affect aspects of life other than growth such as cognition, behavior, adaption to novel environments, social dominance and memory consolidation. Deregulated genomic imprinting leads to developmental disorders and is associated with solid and blood cancer as well. Several data have been published highlighting the involvement of IGs in as early as the very small embryonic-like stem cells stage and further during myeloid lineage commitment in normal and malignant hematopoiesis. Therefore, we have assembled the current knowledge on the topic, based mainly on recent findings, trying not to focus on a particular cluster but rather to have a global view of several different IGs in hematopoiesis.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Peters J . The role of genomic imprinting in biology and disease: an expanding view. Nat Rev Genet 2014; 15: 517–530.

    Article  CAS  PubMed  Google Scholar 

  2. Barlow DP, Bartolomei MS . Genomic imprinting in mammals. Cold Spring Harb Perspect Biol 2014; 6, pii: a018382.

  3. Bartolomei MS, Ferguson-Smith AC . Mammalian genomic imprinting. Cold Spring Harb Perspect Biol 2011; 3, pii: a002592.

  4. Patten MM, Ross L, Curley JP, Queller DC, Bonduriansky R, Wolf JB . The evolution of genomic imprinting: theories, predictions and empirical tests. Heredity (Edinb) 2014; 113: 119–128.

    Article  CAS  Google Scholar 

  5. Li Y, Sasaki H . Genomic imprinting in mammals: its life cycle, molecular mechanisms and reprogramming. Cell Res 2011; 21: 466–473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yamaguchi S, Shen L, Liu Y, Sendler D, Zhang Y . Role of Tet1 in erasure of genomic imprinting. Nature 2013; 504: 460–464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wang L, Zhang J, Duan J, Gao X, Zhu W, Lu X et al. Programming and inheritance of parental DNA methylomes in mammals. Cell 2014; 157: 979–991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Plasschaert RN, Bartolomei MS . Genomic imprinting in development, growth, behavior and stem cells. Development 2014; 141: 1805–1813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhao J, Ohsumi TK, Kung JT, Ogawa Y, Grau DJ, Sarma K et al. Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol Cell 2010; 40: 939–953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang H, Zeitz MJ, Wang H, Niu B, Ge S, Li W et al. Long noncoding RNA-mediated intrachromosomal interactions promote imprinting at the Kcnq1 locus. J Cell Biol 2014; 204: 61–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lee JT, Bartolomei MS . X-inactivation imprinting, and long noncoding RNAs in health and disease. Cell 2013; 152: 1308–1323.

    Article  CAS  PubMed  Google Scholar 

  12. Benetatos L, Hatzimichael E, Londin E, Vartholomatos G, Loher P, Rigoutsos I et al. The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis. Cell Mol Life Sci 2013; 70: 795–814.

    Article  CAS  PubMed  Google Scholar 

  13. Boucher J, Charalambous M, Zarse K, Mori MA, Kleinridders A, Ristow M et al. Insulin and insulin-like growth factor 1 receptors are required for normal expression of imprinted genes. Proc Natl Acad Sci USA 2014; 111: 14512–14517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shin DM, Zuba-Surma EK, Wu W, Ratajczak J, Wysoczynski M, Ratajczak MZ et al. Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct4(+) very small embryonic-like stem cells. Leukemia 2009; 23: 2042–2051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ratajczak MZ, Zuba-Surma E, Wojakowski W, Suszynska M, Mierzejewska K, Liu R et al. Very small embryonic-like stem cells (VSELs) represent a real challenge in stem cell biology: recent pros and cons in the midst of a lively debate. Leukemia 2014; 28: 473–484.

    Article  CAS  PubMed  Google Scholar 

  16. Ratajczak J, Wysoczynski M, Zuba-Surma E, Wan W, Kucia M, Yoder MC et al. Adult murine bone marrow-derived very small embryonic-like stem cells differentiate into the hematopoietic lineage after coculture over OP9 stromal cells. Exp Hematol 2011; 39: 225–237.

    Article  CAS  PubMed  Google Scholar 

  17. Shin DM, Liu R, Klich I, Wu W, Ratajczak J, Kucia M et al. Molecular signature of adult bone marrow-purified very small embryonic-like stem cells supports their developmental epiblast/germ line origin. Leukemia 2010; 24: 1450–1461.

    Article  CAS  PubMed  Google Scholar 

  18. Chiba H, Hiura H, Okae H, Miyauchi N, Sato F, Sato A et al. DNA methylation errors in imprinting disorders and assisted reproductive technology. Pediatr Int 2013; 55: 542–549.

    Article  PubMed  Google Scholar 

  19. Benetatos L, Vartholomatos G, Hatzimichael E . DLK1-DIO3 imprinted cluster in induced pluripotency: landscape in the mist. Cell Mol Life Sci 2014; 71: 4421–4430.

    Article  CAS  PubMed  Google Scholar 

  20. Johannesson B, Sagi I, Gore A, Paull D, Yamada M, Golan-Lev T et al. Comparable frequencies of coding mutations and loss of imprinting in human pluripotent cells derived by nuclear transfer and defined factors. Cell Stem Cell 2014; 15: 634–642.

    Article  CAS  PubMed  Google Scholar 

  21. da Rocha ST, Charalambous M, Lin SP, Gutteridge I, Ito Y, Gray D et al. Gene dosage effects of the imprinted delta-like homologue 1 (dlk1/pref1) in development: implications for the evolution of imprinting. PLoS Genet 2009; 5: e1000392.

    Article  PubMed  CAS  Google Scholar 

  22. Wood MD, Hiura H, Tunster SJ, Arima T, Shin JY, Higgins MJ et al. Autonomous silencing of the imprinted Cdkn1c gene in stem cells. Epigenetics 2010; 5: 214–221.

    Article  CAS  PubMed  Google Scholar 

  23. Charalambous M, Ferron SR, da Rocha ST, Murray AJ, Rowland T, Ito M et al. Imprinted gene dosage is critical for the transition to independent life. Cell Metab 2012; 15: 209–221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. McNamara GI, Isles AR . Dosage-sensitivity of imprinted genes expressed in the brain: 15q11-q13 and neuropsychiatric illness. Biochem Soc Trans 2013; 41: 721–726.

    Article  CAS  PubMed  Google Scholar 

  25. Radford EJ, Ferrón SR, Ferguson-Smith AC . Genomic imprinting as an adaptative model of developmental plasticity. FEBS Lett 2011; 585: 2059–2066.

    Article  CAS  PubMed  Google Scholar 

  26. Hancock AL, Brown KW, Moorwood K, Moon H, Holmgren C, Mardikar SH et al. A CTCF-binding silencer regulates the imprinted genes AWT1 and WT1-AS and exhibits sequential epigenetic defects during Wilms' tumourigenesis. Hum Mol Genet 2007; 16: 343–354.

    Article  CAS  PubMed  Google Scholar 

  27. Anwar SL, Krech T, Hasemeier B, Schipper E, Schweitzer N, Vogel A et al. Deregulation of RB expression by loss of imprinting in human hepatocellular carcinoma. J Pathol 2014; 233: 392–401.

    Article  CAS  PubMed  Google Scholar 

  28. Ratajczak MZ, Shin DM, Schneider G, Ratajczak J, Kucia M . Parental imprinting regulates insulin-like growth factor signaling: a Rosetta Stone for understanding the biology of pluripotent stem cells, aging and cancerogenesis. Leukemia 2013; 27: 773–779.

    Article  CAS  PubMed  Google Scholar 

  29. Rumbajan JM, Maeda T, Souzaki R, Mitsui K, Higashimoto K, Nakabayashi K et al. Comprehensive analyses of imprinted differentially methylated regions reveal epigenetic and genetic characteristics in hepatoblastoma. BMC Cancer 2013; 13: 608.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Holm TM, Jackson-Grusby L, Brambrink T, Yamada Y, Rideout WM 3rd, Jaenisch R . Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 2005; 8: 275–285.

    Article  CAS  PubMed  Google Scholar 

  31. Ellberg C, Olsson H . Breast cancer patients with lobular cancer more commonly have a father than a mother diagnosed with cancer. BMC Cancer 2011; 11: 497.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kong A, Steinthorsdottir V, Masson G, Thorleifsson G, Sulem P, Besenbacher S et al. Parental origin of sequence variants associated with complex diseases. Nature 2009; 462: 868–874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ciau-Uitz A, Monteiro R, Kirmizitas A, Patient R . Developmental hematopoiesis: ontogeny, genetic programming and conservation. Exp Hematol 2014; 42: 669–683.

    Article  CAS  PubMed  Google Scholar 

  34. Chambers SM, Boles NC, Lin KY, Tierney MP, Bowman TV, Bradfute SB et al. Hematopoietic fingerprints: an expression database of stem cells and their progeny. Cell Stem Cell 2007; 1: 578–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ratajczak MZ . A novel view of the adult bone marrow stem cell hierarchy and stem cell trafficking. Leukemia 2014; e-pub ahead of print 9 December 2014; doi:10.1038/leu.2014.346.

    Article  PubMed  Google Scholar 

  36. Doulatov S, Notta F, Laurenti E, Dick JE . Hematopoiesis: a human perspective. Cell Stem Cell 2012; 10: 120–136.

    Article  CAS  PubMed  Google Scholar 

  37. Schönheit J, Leutz A, Rosenbauer F . Chromatin dynamics during differentiation of myeloid cells. J Mol Biol 2014; pii S0022-2836: 00458–6.

    Google Scholar 

  38. Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ . Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 2014; 15: 37–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Snoeck HW . Aging of the hematopoietic system. Curr Opin Hematol 2013; 20: 355–361.

    Article  CAS  PubMed  Google Scholar 

  40. Sawamiphak S, Kontarakis Z, Stainier DY . Interferon gamma signaling positively regulates hematopoietic stem cell emergence. Dev Cell 2014; 31: 640–653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cabezas-Wallscheid N, Klimmeck D, Hansson J, Lipka DB, Reyes A, Wang Q et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell 2014; 15: 507–522.

    Article  CAS  PubMed  Google Scholar 

  42. Chau YY, Brownstein D, Mjoseng H, Lee WC, Buza-Vidas N, Nerlov C et al. Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1. PLoS Genet 2011; 7: e1002404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Frost JM, Monk D, Stojilkovic-Mikic T, Woodfine K, Chitty LS, Murrell A et al. Evaluation of allelic expression of imprinted genes in adult human blood. PLoS One 2010; 5: e13556.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Morison IM, Eccles MR, Reeve AE . Imprinting of insulin-like growth factor 2 is modulated during hematopoiesis. Blood 2000; 96: 3023–3028.

    Article  CAS  PubMed  Google Scholar 

  45. Berg JS, Lin KK, Sonnet C, Boles NC, Weksberg DC, Nguyen H et al. Imprinted genes that regulate early mammalian growth are coexpressed in somatic stem cells. PLoS One 2011; 6: e26410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Venkatraman A, He XC, Thorvaldsen JL, Sugimura R, Perry JM, Tao F et al. Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence. Nature 2013; 500: 345–349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Goodell MA . Parental permissions: H19 and keeping the stem cell progeny under control. Cell Stem Cell 2013; 13: 137–138.

    Article  CAS  PubMed  Google Scholar 

  48. Varrault A, Gueydan C, Delalbre A, Bellmann A, Houssami S, Aknin C et al. Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Dev Cell 2006; 11: 711–722.

    Article  CAS  PubMed  Google Scholar 

  49. Garrett RW, Emerson SG . The role of parathyroid hormone and insulin-like growth factors in hematopoietic niches: physiology and pharmacology. Mol Cell Endocrinol 2008; 288: 6–10.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang CC, Lodish HF . Insulin-like growth factor 2 expressed in a novel fetal liver cell population is a growth factor for hematopoietic stem cells. Blood 2004; 103: 2513–2521.

    Article  CAS  PubMed  Google Scholar 

  51. Wu Q, Kawahara M, Kono T . Synergistic role of Igf2 and Dlk1 in fetal liver development and hematopoiesis in bi-maternal mice. J Reprod Dev 2008; 54: 177–182.

    Article  CAS  PubMed  Google Scholar 

  52. Benetatos L, Hatzimichael E . Delta-like homologue 1 and its role in the bone marrow niche and hematologic malignancies. Clin Lymphoma Myeloma Leuk 2014; 14: 451–455.

    Article  PubMed  Google Scholar 

  53. Klimmeck D, Cabezas-Wallscheid N, Reyes A, von Paleske L, Renders S, Hansson J et al. Transcriptome-wide profiling and posttranscriptional analysis of hematopoietic stem/progenitor cell differentiation toward myeloid commitment. Stem Cell Rep 2014; 3: 858–875.

    Article  CAS  Google Scholar 

  54. Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 2014; 14: 673–688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zou P, Yoshihara H, Hosokawa K, Tai I, Shinmyozu K, Tsukahara F et al. p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell 2011; 9: 247–261.

    Article  CAS  PubMed  Google Scholar 

  56. Rossi L, Lin KK, Boles NC, Yang L, King KY, Jeong M et al. Less is more: unveiling the functional core of hematopoietic stem cells through knockout mice. Cell Stem Cell 2012; 11: 302–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Liu Y, Elf SE, Miyata Y, Sashida G, Liu Y, Huang G et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell 2009; 4: 37–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Matsumoto A, Takeishi S, Kanie T, Susaki E, Onoyama I, Tateishi Y et al. p57 is required for quiescence and maintenance of adult hematopoietic stem cells. Cell Stem Cell 2011; 9: 262–271.

    Article  CAS  PubMed  Google Scholar 

  59. Das R, Lee YK, Strogantsev R, Jin S, Lim YC, Ng PY et al. DNMT1 and AIM1 Imprinting in human placenta revealed through a genome-wide screen for allele-specific DNA methylation. BMC Genomics 2013; 14: 685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Li KK, Luo LF, Shen Y, Xu J, Chen Z, Chen SJ . DNA methyltransferases in hematologic malignancies. Semin Hematol 2013; 50: 48–60.

    Article  CAS  PubMed  Google Scholar 

  61. Trowbridge JJ, Snow JW, Kim J, Orkin SH . DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell 2009; 5: 442–449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Civini S, Jin P, Ren J, Sabatino M, Castiello L, Jin J et al. Leukemia cells induce changes in human bone marrow stromal cells. J Transl Med 2013; 11: 298.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Reinisch A, Etchart N, Thomas D, Hofmann NA, Fruehwirth M, Sinha S et al. Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation. Blood 2014; 125: 249–260.

    Article  PubMed  CAS  Google Scholar 

  64. Lin SP, Chiu FY, Wang Y, Yen ML, Kao SY, Hung SC . RB maintains quiescence and prevents premature senescence through upregulation of DNMT1 in mesenchymal stromal cells. Stem Cell Rep 2014; 3: 975–986.

    Article  CAS  Google Scholar 

  65. Elias HK, Schinke C, Bhattacharyya S, Will B, Verma A, Steidl U . Stem cell origin of myelodysplastic syndromes. Oncogene 2014; 33: 5139–5150.

    Article  CAS  PubMed  Google Scholar 

  66. Miraki-Moud F, Anjos-Afonso F, Hodby KA, Griessinger E, Rosignoli G, Lillington D et al. Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation. Proc Natl Acad Sci USA 2013; 110: 13576–13581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Matchett KB, Lappin TR . Concise reviews: cancer stem cells: from concept to cure. Stem Cells 2014; 32: 2563–2570.

    Article  CAS  PubMed  Google Scholar 

  68. Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012; 150: 264–278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 2011; 19: 138–152.

    Article  CAS  PubMed  Google Scholar 

  70. Wu HK, Weksberg R, Minden MD, Squire JA . Loss of imprinting of human insulin-like growth factor II gene, IGF2, in acute myeloid leukemia. Biochem Biophys Res Commun 1997; 231: 466–472.

    Article  CAS  PubMed  Google Scholar 

  71. Hofmann WK, Takeuchi S, Frantzen MA, Hoelzer D, Koeffler HP . Loss of genomic imprinting of insulin-like growth factor 2 is strongly associated with cellular proliferation in normal hematopoietic cells. Exp Hematol 2002; 30: 318–323.

    Article  CAS  PubMed  Google Scholar 

  72. Bock O, Schlué J, Kreipe H . Reduced expression of H19 in bone marrow cells from chronic myeloproliferative disorders. Leukemia 2003; 17: 815–816.

    Article  PubMed  Google Scholar 

  73. Zumkeller W, Burdach S . The insulin-like growth factor system in normal and malignant hematopoietic cells. Blood 1999; 94: 3653–3657.

    Article  CAS  PubMed  Google Scholar 

  74. Núnêz C, Bashein AM, Brunet CL, Hoyland JA, Freemont AJ, Buckle AM et al. Expression of the imprinted tumour-suppressor gene H19 is tightly regulated during normal haematopoiesis and is reduced in haematopoietic precursors of patients with the myeloproliferative disease polycythaemia vera. J Pathol 2000; 190: 61–68.

    Article  PubMed  Google Scholar 

  75. Randhawa GS, Cui H, Barletta JA, Strichman-Almashanu LZ, Talpaz M, Kantarjian H, Deisseroth AB, Champlin RC, Feinberg AP . Loss of imprinting in disease progression in chronic myelogenous leukemia. Blood 1998; 91: 3144–3147.

    Article  CAS  PubMed  Google Scholar 

  76. Guo G, Kang Q, Chen Q, Chen Z, Wang J, Tan L et al. High expression of long non-coding RNA H19 is required for efficient tumorigenesis induced by Bcr-Abl oncogene. FEBS Lett 2014; 588: 1780–1786.

    Article  CAS  PubMed  Google Scholar 

  77. Dluhosova M, Curik N, Vargova J, Jonasova A, Zikmund T, Stopka T . Epigenetic control of SPI1 gene by CTCF and ISWI ATPase SMARCA5. PLoS One 2014; 9: e87448.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Guglielmelli P, Zini R, Bogani C, Salati S, Pancrazzi A, Bianchi E et al. Molecular profiling of CD34+ cells in idiopathic myelofibrosis identifies a set of disease-associated genes and reveals the clinical significance of Wilms' tumor gene 1 (WT1). Stem Cells 2007; 25: 165–173.

    Article  CAS  PubMed  Google Scholar 

  79. Zhang W, Shao Z, Fu R, Wang H, Li L, Yue L . Effect of DLK1 on tumorigenesis in CD34+CD38- bone marrow cells in myelodysplastic syndromes. Oncol Lett 2013; 6: 203–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Li L, Forman SJ, Bhatia R . Expression of DLK1 in hematopoietic cells results in inhibition of differentiation and proliferation. Oncogene 2005; 24: 4472–4476.

    Article  CAS  PubMed  Google Scholar 

  81. Argiropoulos B, Palmqvist L, Imren S, Miller M, Rouhi A, Mager DL et al. Meis1 disrupts the genomic imprint of Dlk1 in a NUP98-HOXD13 leukemia model. Leukemia 2010; 24: 1788–1791.

    Article  CAS  PubMed  Google Scholar 

  82. Benetatos L, Hatzimichael E, Dasoula A, Dranitsaris G, Tsiara S, Syrrou M et al. CpG methylation analysis of the MEG3 and SNRPN imprinted genes in acute myeloid leukemia and myelodysplastic syndromes. Leuk Res 2010; 34: 148–153.

    Article  CAS  PubMed  Google Scholar 

  83. Khoury H, Suarez-Saiz F, Wu S, Minden MD . An upstream insulator regulates DLK1 imprinting in AML. Blood 2010; 115: 2260–2263.

    Article  CAS  PubMed  Google Scholar 

  84. Manodoro F, Marzec J, Chaplin T, Miraki-Moud F, Moravcsik E, Jovanovic JV et al. Loss of imprinting at the 14q32 domain is associated with microRNA overexpression in acute promyelocytic leukemia. Blood 2014; 123: 2066–2074.

    Article  CAS  PubMed  Google Scholar 

  85. Pennucci V, Zini R, Norfo R, Guglielmelli P, Bianchi E, Salati S et al. Abnormal expression patterns of WT1-as, MEG3 and ANRIL long non-coding RNAs in CD34+ cells from patients with primary myelofibrosis and their clinical correlations. Leuk Lymphoma 2014; 56: 492–496.

    Article  PubMed  Google Scholar 

  86. Benetatos L, Vartholomatos G, Hatzimichael E . MEG3 imprinted gene contribution in tumorigenesis. Int J Cancer 2011; 129: 773–779.

    Article  CAS  PubMed  Google Scholar 

  87. Kustikova OS, Schwarzer A, Stahlhut M, Brugman MH, Neumann T, Yang M et al. Activation of Evi1 inhibits cell cycle progression and differentiation of hematopoietic progenitor cells. Leukemia 2013; 27: 1127–1138.

    Article  CAS  PubMed  Google Scholar 

  88. Zhang Y, Stehling-Sun S, Lezon-Geyda K, Juneja SC, Coillard L, Chatterjee G et al. PR-domain-containing Mds1-Evi1 is critical for long-term hematopoietic stem cell function. Blood 2011; 118: 3853–3861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Scandura JM, Boccuni P, Massagué J, Nimer SD . Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation. Proc Natl Acad Sci USA 2004; 101: 15231–15236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hatzimichael E, Dasoula A, Benetatos L, Makis A, Stebbing J, Crook T et al. The absence of CDKN1C (p57KIP2) promoter methylation in myeloid malignancies also characterizes plasma cell neoplasms. Br J Haematol 2008; 141: 557–558.

    Article  CAS  PubMed  Google Scholar 

  91. Brakensiek K, Länger F, Kreipe H, Lehmann U . Absence of p21(CIP 1), p27(KIP 1) and p 57(KIP 2) methylation in MDS and AML. Leuk Res 2005; 29: 1357–1360.

    Article  CAS  PubMed  Google Scholar 

  92. Li Y, Nagai H, Ohno T, Yuge M, Hatano S, Ito E et al. Aberrant DNA methylation of p57(KIP2) gene in the promoter region in lymphoid malignancies of B-cell phenotype. Blood 2002; 100: 2572–2577.

    Article  CAS  PubMed  Google Scholar 

  93. Borriello A, Caldarelli I, Bencivenga D, Cucciolla V, Oliva A, Usala E et al. p57Kip2 is a downstream effector of BCR-ABL kinase inhibitors in chronic myelogenous leukemia cells. Carcinogenesis 2011; 32: 10–18.

    Article  CAS  PubMed  Google Scholar 

  94. Li J, Bench AJ, Vassiliou GS, Fourouclas N, Ferguson-Smith AC, Green AR . Imprinting of the human L3MBTL gene, a polycomb family member located in a region of chromosome 20 deleted in human myeloid malignancies. Proc Natl Acad Sci USA 2004; 101: 7341–7346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gurvich N, Perna F, Farina A, Voza F, Menendez S, Hurwitz J et al. L3MBTL1 polycomb protein, a candidate tumor suppressor in del(20q12) myeloid disorders, is essential for genome stability. Proc Natl Acad Sci USA 2010; 107: 22552–22557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bench AJ, Li J, Huntly BJ, Delabesse E, Fourouclas N, Hunt AR et al. Characterization of the imprinted polycomb gene L3MBTL, a candidate 20q tumour suppressor gene, in patients with myeloid malignancies. Br J Haematol 2004; 127: 509–518.

    Article  CAS  PubMed  Google Scholar 

  97. Perna F, Gurvich N, Hoya-Arias R, Abdel-Wahab O, Levine RL, Asai T et al. Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q- polycythemia vera. Blood 2010; 116: 2812–2821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Aziz A, Baxter EJ, Edwards C, Cheong CY, Ito M, Bench A et al. Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions. J Clin Invest 2013; 123: 2169–2182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yang L, Han Y, Suarez Saiz F, Minden MD . A tumor suppressor and oncogene: the WT1 story. Leukemia 2007; 21: 868–876.

    Article  CAS  PubMed  Google Scholar 

  100. Rosenfeld C, Cheever MA, Gaiger A . WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies. Leukemia 2003; 17: 1301–1312.

    Article  CAS  PubMed  Google Scholar 

  101. Brown KW, Power F, Moore B, Charles AK, Malik KT . Frequency and timing of loss of imprinting at 11p13 and 11p15 in Wilms' tumor development. Mol Cancer Res 2008; 6: 1114–1123.

    Article  CAS  PubMed  Google Scholar 

  102. Guillaumet-Adkins A, Richter J, Odero MD, Sandoval J, Agirre X, Catala A et al. Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels. J. Hematol Oncol 2014; 7: 4.

    Article  CAS  Google Scholar 

  103. Messina C, Candoni A, Carrabba MG, Tresoldi C, Sala E, Tassara M et al. Wilms' tumor gene 1 transcript levels in leukapheresis of peripheral blood hematopoietic cells predict relapse risk in patients autografted for acute myeloid leukemia. Biol Blood Marrow Transplant 2014; 20: 1586–1591.

    Article  CAS  PubMed  Google Scholar 

  104. Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122: 3616–3627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Malcovati L, Papaemmanuil E, Ambaglio I, Elena C, Gallì A, Della Porta MG et al. Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia. Blood 2014; 124: 1513–1521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Marcucci G, Haferlach T, Döhner H . Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 2011; 29: 475–486.

    Article  CAS  PubMed  Google Scholar 

  107. Gaidzik VI, Schlenk RF, Moschny S, Becker A, Bullinger L, Corbacioglu A et al. Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. Blood 2009; 113: 4505–4511.

    Article  CAS  PubMed  Google Scholar 

  108. Hosen N, Shirakata T, Nishida S, Yanagihara M, Tsuboi A, Kawakami M et al. The Wilms' tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis. Leukemia 2007; 21: 1783–1791.

    Article  CAS  PubMed  Google Scholar 

  109. Nishida S, Hosen N, Shirakata T, Kanato K, Yanagihara M et al. AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1. Blood 2006; 107: 3303–3312.

    Article  CAS  PubMed  Google Scholar 

  110. Becker H, Marcucci G, Maharry K, Radmacher MD, Mrózek K, Margeson D et al. Mutations of the Wilms tumor 1 gene (WT1) in older patients with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood 2010; 116: 788–792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bansal H, Bansal S, Rao M, Foley KP, Sang J, Proia DA et al. Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias. Blood 2010; 116: 4591–4599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sinha S, Thomas D, Yu L, Gentles A, Jung N, Corces-Zimmerman MR et al. Mutant WT1 is associated with DNA hypermethylation of PRC2 targets in AML and responds to EZH2 inhibition. Blood 2014; 125: 316–326.

    Article  PubMed  CAS  Google Scholar 

  113. Rampal R, Alkalin A, Madzo J, Vasanthakumar A, Pronier E, Patel J et al. DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia. Cell Rep 2014; 9: 1841–1855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L et al. WT1 Recruits TET2 to Regulate Its Target Gene Expression and Suppress Leukemia Cell Proliferation. Mol Cell 2015; pii S1097-2765: 01001–01006.

    Google Scholar 

  115. Bröske AM, Vockentanz L, Kharazi S, Huska MR, Mancini E, Scheller M et al. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet 2009; 41: 1207–1215.

    Article  PubMed  CAS  Google Scholar 

  116. Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CE, Callegari E et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 2009; 113: 6411–6418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Shen N, Yan F, Pang J, Wu LC, Al-Kali A, Litzow MR, Liu S . A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis. Oncotarget 2014; 5: 5494–5509.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 2013; 503: 371–376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Trowbridge JJ, Sinha AU, Zhu N, Li M, Armstrong SA, Orkin SH . Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains. Genes Dev 2012; 26: 344–349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Nogami M, Kohda A, Taguchi H, Nakao M, Ikemura T, Okumura K . Relative locations of the centromere and imprinted SNRPN gene within chromosome 15 territories during the cell cycle in HL60 cells. J Cell Sci 2000; 113 (Pt 12): 2157–2165.

    Article  CAS  PubMed  Google Scholar 

  121. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 20: 1472–1478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014; 28: 241–247.

    Article  CAS  PubMed  Google Scholar 

  123. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364: 2496–2506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Sun J, Li W, Sun Y, Yu D, Wen X, Wang H et al. A novel antisense long noncoding RNA within the IGF1R gene locus is imprinted in hematopoietic malignancies. Nucleic Acids Res 2014; 42: 9588–9601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kuerbitz SJ, Pahys J, Wilson A, Compitello N, Gray TA . Hypermethylation of the imprinted NNAT locus occurs frequently in pediatric acute leukemia. Carcinogenesis 2002; 23: 559–564.

    Article  CAS  PubMed  Google Scholar 

  126. Laursen KB, Wong PM, Gudas LJ . Epigenetic regulation by RARα maintains ligand-independent transcriptional activity. Nucleic Acids Res 2012; 40: 102–115.

    Article  CAS  PubMed  Google Scholar 

  127. Gentles AJ, Plevritis SK, Majeti R, Alizadeh AA . Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia. JAMA 2010; 304: 2706–2715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Horton SJ, Huntly BJ . Recent advances in acute myeloid leukemia stem cell biology. Haematologica 2012; 97: 966–974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Craddock C, Quek L, Goardon N, Freeman S, Siddique S, Raghavan M et al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia 2013; 27: 1028–1036.

    Article  CAS  PubMed  Google Scholar 

  130. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141: 69–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Schoofs T, Berdel WE, Müller-Tidow C . Origins of aberrant DNA methylation in acute myeloid leukemia. Leukemia 2014; 28: 1–14.

    Article  CAS  PubMed  Google Scholar 

  132. Cullen SM, Mayle A, Rossi L, Goodell MA . Hematopoietic stem cell development: an epigenetic journey. Curr Top Dev Biol 2014; 107: 39–75.

    Article  CAS  PubMed  Google Scholar 

  133. Zhu NL, Asahina K, Wang J, Ueno A, Lazaro R, Miyaoka Y et al. Hepatic stellate cell-derived delta-like homolog 1 (DLK1) protein in liver regeneration. J Biol Chem 2012; 287: 10355–10367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N et al. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 2014; 506: 240–244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. White AC, Lowry WE . Refining the role of adult stem cells as cancer cells of origin. Trends Cell Biol 2015; 25: 11–20.

    Article  CAS  PubMed  Google Scholar 

  136. Visvader JE . Cells of origin in cancer. Nature 2011; 469: 314–322.

    Article  CAS  PubMed  Google Scholar 

  137. Woll PS, Kjällquist U, Chowdhury O, Doolittle H, Wedge DC, Thongjuea S et al. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell 2014; 25: 794–808.

    Article  CAS  PubMed  Google Scholar 

  138. Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014; 506: 328–333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R . Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA 2014; 111: 2548–2553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med 2012; 4: 149ra118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Abdel-Wahab O, Levine RL . Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood 2013; 121: 3563–3572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to L Benetatos.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Benetatos, L., Vartholomatos, G. Imprinted genes in myeloid lineage commitment in normal and malignant hematopoiesis. Leukemia 29, 1233–1242 (2015). https://doi.org/10.1038/leu.2015.47

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.47

This article is cited by

Search

Quick links