Skip to main content
SpringerLink
Log in

The Molecular Basis of Normal Erythroid/Megakaryocyte Development and Mechanisms of Epigenetic/Transcriptional Deregulation Leading to Erythroleukemia and Thalassaemia

  • Chapter
  • First Online:
Transcriptional and Epigenetic Mechanisms Regulating Normal and Aberrant Blood Cell Development

Part of the book series: Epigenetics and Human Health ((EHH))

Abstract

The recent introduction of high-throughput sequencing technology has now provided a very broad picture of the chromatin landscape and transcription factor binding throughout the genome in many cell types, including the different haematopoietic lineages. The epigenetic machinery affecting DNA methylation and histone modification has been well characterised, and large scale screening for inhibitors has already led to the production of specific drugs used for treating patients. Moreover, it appears that many epigenetic regulators are mutated in various diseases, particularly in the haematopoietic compartment. I discuss here the accessible models used to study erythropoiesis and megakaryopoiesis and their associated transcription and epigenetic programme. Finally, I will describe the current approaches used for epigenetic therapy in myeloid malignancies and haemoglobinopathies such as thalassaemia.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Aigner B, Renner S, Kessler B, Klymiuk N, Kurome M, Wunsch A, Wolf E (2010) Transgenic pigs as models for translational biomedical research. J Mol Med (Berl) 88:653–664

    Google Scholar 

  • Allfrey VG, Mirsky AE (1964) Structural modifications of histones and their possible role in the regulation of RNA synthesis. Science 144:559

    CAS  PubMed  Google Scholar 

  • Allfrey VG, Faulkner R, Mirsky AE (1964) Acetylation and methylation of histones and their possible role in the regulation of Rna synthesis. Proc Natl Acad Sci USA 51:786–794

    CAS  PubMed Central  PubMed  Google Scholar 

  • Anguita E, Hughes J, Heyworth C, Blobel GA, Wood WG, Higgs DR (2004) Globin gene activation during haemopoiesis is driven by protein complexes nucleated by GATA-1 and GATA-2. EMBO J 23:2841–2852

    CAS  PubMed Central  PubMed  Google Scholar 

  • Atallah E, Verstovsek S (2009) Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms. Expert Rev Anticancer Ther 9:663–670

    CAS  PubMed  Google Scholar 

  • Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, Jaenisch R, Wagschal A, Feil R, Schreiber SL, Lander ES (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315–326

    CAS  PubMed  Google Scholar 

  • Bianchi N, Zuccato C, Lampronti I, Borgatti M, Gambari R (2009) Fetal hemoglobin inducers from the natural world: a novel approach for identification of drugs for the treatment of {beta}-thalassemia and sickle-cell anemia. Evid Based Complement Alternat Med 6:141–151

    PubMed Central  PubMed  Google Scholar 

  • Binda C, Valente S, Romanenghi M, Pilotto S, Cirilli R, Karytinos A, Ciossani G, Botrugno OA, Forneris F, Tardugno M, Edmondson DE, Minucci S, Mattevi A, Mai A (2010) Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J Am Chem Soc 132:6827–6833

    CAS  PubMed  Google Scholar 

  • Black JC, Van Rechem C, Whetstine JR (2012) Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell 48:491–507

    CAS  PubMed  Google Scholar 

  • Bottardi S, Ross J, Bourgoin V, Fotouhi-Ardakani N, el Affar B, Trudel M, Milot E (2009) Ikaros and GATA-1 combinatorial effect is required for silencing of human gamma-globin genes. Mol Cell Biol 29:1526–1537

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cantor AB, Orkin SH (2002) Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene 21:3368–3376

    CAS  PubMed  Google Scholar 

  • Caravaca JM, Donahue G, Becker JS, He X, Vinson C, Zaret KS (2013) Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes. Genes Dev 27:251–260

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chagraoui H, Porcher C (2012) Establishment of an ES cell-derived murine megakaryocytic cell line, MKD1, with features of primary megakaryocyte progenitors. PLoS One 7:e32981

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen AT, Prchal JT (2010) JAK2 kinase inhibitors and myeloproliferative disorders. Curr Opin Hematol 17:110–116

    CAS  PubMed  Google Scholar 

  • Chen Q, Lu Z, Jin Y, Wu Y, Pan J (2010) Triptolide inhibits Jak2 transcription and induces apoptosis in human myeloproliferative disorder cells bearing Jak2V617F through caspase-3-mediated cleavage of Mcl-1. Cancer Lett 291:246–255

    CAS  PubMed  Google Scholar 

  • Cimmino L, Abdel-Wahab O, Levine RL, Aifantis I (2011) TET family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell 9:193–204

    CAS  PubMed Central  PubMed  Google Scholar 

  • Clouaire T, Webb S, Skene P, Illingworth R, Kerr A, Andrews R, Lee JH, Skalnik D, Bird A (2012) Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells. Genes Dev 26:1714–1728

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cortin V, Garnier A, Pineault N, Lemieux R, Boyer L, Proulx C (2005) Efficient in vitro megakaryocyte maturation using cytokine cocktails optimized by statistical experimental design. Exp Hematol 33:1182–1191

    CAS  PubMed  Google Scholar 

  • Craddock CF, Vyas P, Sharpe JA, Ayyub H, Wood WG, Higgs DR (1995) Contrasting effects of alpha and beta globin regulatory elements on chromatin structure may be related to their different chromosomal environments. EMBO J 14:1718–1726

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150:12–27

    CAS  PubMed  Google Scholar 

  • Dawson MA, Bannister AJ, Gottgens B, Foster SD, Bartke T, Green AR, Kouzarides T (2009) JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 461:819–822

    CAS  PubMed Central  PubMed  Google Scholar 

  • De Gobbi M, Viprakasit V, Hughes JR, Fisher C, Buckle VJ, Ayyub H, Gibbons RJ, Vernimmen D, Yoshinaga Y, de Jong P, Cheng JF, Rubin EM, Wood WG, Bowden D, Higgs DR (2006) A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science 312:1215–1217

    PubMed  Google Scholar 

  • De Gobbi M, Anguita E, Hughes J, Sloane-Stanley JA, Sharpe JA, Koch CM, Dunham I, Gibbons RJ, Wood WG, Higgs DR (2007) Tissue-specific histone modification and transcription factor binding in alpha globin gene expression. Blood 110:4503–4510

    PubMed  Google Scholar 

  • De Gobbi M, Garrick D, Lynch M, Vernimmen D, Hughes JR, Goardon N, Luc S, Lower KM, Sloane-Stanley JA, Pina C, Soneji S, Renella R, Enver T, Taylor S, Jacobsen SE, Vyas P, Gibbons RJ, Higgs DR (2011) Generation of bivalent chromatin domains during cell fate decisions. Epigenetics Chromatin 4:9

    PubMed Central  PubMed  Google Scholar 

  • Deisseroth A, Hendrick D (1978) Human alpha-globin gene expression following chromosomal dependent gene transfer into mouse erythroleukemia cells. Cell 15:55–63

    CAS  PubMed  Google Scholar 

  • Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lecluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguie F, Fontenay M, Vainchenker W, Bernard OA (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301

    PubMed  Google Scholar 

  • Deneberg S, Guardiola P, Lennartsson A, Qu Y, Gaidzik V, Blanchet O, Karimi M, Bengtzen S, Nahi H, Uggla B, Tidefelt U, Hoglund M, Paul C, Ekwall K, Dohner K, Lehmann S (2011) Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks. Blood 118:5573–5582

    CAS  PubMed  Google Scholar 

  • Dey A, Seshasayee D, Noubade R, French DM, Liu J, Chaurushiya MS, Kirkpatrick DS, Pham VC, Lill JR, Bakalarski CE, Wu J, Phu L, Katavolos P, LaFave LM, Abdel-Wahab O, Modrusan Z, Seshagiri S, Dong K, Lin Z, Balazs M, Suriben R, Newton K, Hymowitz S, Garcia-Manero G, Martin F, Levine RL, Dixit VM (2012) Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 337:1541–1546

    CAS  PubMed  Google Scholar 

  • Dolznig H, Boulme F, Stangl K, Deiner EM, Mikulits W, Beug H, Mullner EW (2001) Establishment of normal, terminally differentiating mouse erythroid progenitors: molecular characterization by cDNA arrays. FASEB J 15:1442–1444

    CAS  PubMed  Google Scholar 

  • Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, Epstein CB, Frietze S, Harrow J, Kaul R, Khatun J, Lajoie BR, Landt SG, Lee BK, Pauli F, Rosenbloom KR, Sabo P, Safi A, Sanyal A, Shoresh N, Simon JM, Song L, Trinklein ND, Altshuler RC, Birney E, Brown JB, Cheng C, Djebali S, Dong X, Ernst J, Furey TS, Gerstein M, Giardine B, Greven M, Hardison RC, Harris RS, Herrero J, Hoffman MM, Iyer S, Kelllis M, Kheradpour P, Lassmann T, Li Q, Lin X, Marinov GK, Merkel A, Mortazavi A, Parker SC, Reddy TE, Rozowsky J, Schlesinger F, Thurman RE, Wang J, Ward LD, Whitfield TW, Wilder SP, Wu W, Xi HS, Yip KY, Zhuang J, Bernstein BE, Green ED, Gunter C, Snyder M, Pazin MJ, Lowdon RF, Dillon LA, Adams LB, Kelly CJ, Zhang J, Wexler JR, Good PJ, Feingold EA, Crawford GE, Dekker J, Elinitski L, Farnham PJ, Giddings MC, Gingeras TR, Guigo R, Hubbard TJ, Kellis M, Kent WJ, Lieb JD, Margulies EH, Myers RM, Starnatoyannopoulos JA, Tennebaum SA, Weng Z, White KP, Wold B, Yu Y, Wrobel J, Risk BA, Gunawardena HP, Kuiper HC, Maier CW, Xie L, Chen X, Mikkelsen TS et al (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74

    CAS  PubMed  Google Scholar 

  • Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10:223–232

    CAS  PubMed  Google Scholar 

  • Forget BG (1998) Molecular basis of hereditary persistence of fetal hemoglobin. Ann N Y Acad Sci 850:38–44

    CAS  PubMed  Google Scholar 

  • Forrester WC, Epner E, Driscoll MC, Enver T, Brice M, Papayannopoulou T, Groudine M (1990) A deletion of the human beta-globin locus activation region causes a major alteration in chromatin structure and replication across the entire beta-globin locus. Genes Dev 4:1637–1649

    CAS  PubMed  Google Scholar 

  • Fucharoen S, Viprakasit V (2009) Hb H disease: clinical course and disease modifiers. Hematology Am Soc Hematol Educ Program 26–34

    Google Scholar 

  • Fugman DA, Witte DP, Jones CL, Aronow BJ, Lieberman MA (1990) In vitro establishment and characterization of a human megakaryoblastic cell line. Blood 75:1252–1261

    CAS  PubMed  Google Scholar 

  • Fujimoto TT, Kohata S, Suzuki H, Miyazaki H, Fujimura K (2003) Production of functional platelets by differentiated embryonic stem (ES) cells in vitro. Blood 102:4044–4051

    CAS  PubMed  Google Scholar 

  • Garrick D, De Gobbi M, Samara V, Rugless M, Holland M, Ayyub H, Lower K, Sloane-Stanley J, Gray N, Koch C, Dunham I, Higgs DR (2008) The role of the polycomb complex in silencing alpha-globin gene expression in nonerythroid cells. Blood 112:3889–3899

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gaur M, Kamata T, Wang S, Moran B, Shattil SJ, Leavitt AD (2006) Megakaryocytes derived from human embryonic stem cells: a genetically tractable system to study megakaryocytopoiesis and integrin function. J Thromb Haemost 4:436–442

    CAS  PubMed  Google Scholar 

  • Gieger C, Radhakrishnan A, Cvejic A, Tang W, Porcu E, Pistis G, Serbanovic-Canic J, Elling U, Goodall AH, Labrune Y, Lopez LM, Magi R, Meacham S, Okada Y, Pirastu N, Sorice R, Teumer A, Voss K, Zhang W, Ramirez-Solis R, Bis JC, Ellinghaus D, Gogele M, Hottenga JJ, Langenberg C, Kovacs P, O’Reilly PF, Shin SY, Esko T, Hartiala J, Kanoni S, Murgia F, Parsa A, Stephens J, van der Harst P, Ellen van der Schoot C, Allayee H, Attwood A, Balkau B, Bastardot F, Basu S, Baumeister SE, Biino G, Bomba L, Bonnefond A, Cambien F, Chambers JC, Cucca F, D’Adamo P, Davies G, de Boer RA, de Geus EJ, Doring A, Elliott P, Erdmann J, Evans DM, Falchi M, Feng W, Folsom AR, Frazer IH, Gibson QD, Glazer NL, Hammond C, Hartikainen AL, Heckbert SR, Hengstenberg C, Hersch M, Illig T, Loos RJ, Jolley J, Khaw KT, Kuhnel B, Kyrtsonis MC, Lagou V, Lloyd-Jones H, Lumley T, Mangino M, Maschio A, Mateo Leach I, McKnight B, Memari Y, Mitchell BD, Montgomery GW, Nakamura Y, Nauck M, Navis G, Nothlings U, Nolte IM, Porteous DJ, Pouta A, Pramstaller PP, Pullat J, Ring SM, Rotter JI, Ruggiero D, Ruokonen A, Sala C, Samani NJ, Sambrook J, Schlessinger D et al (2011) New gene functions in megakaryopoiesis and platelet formation. Nature 480:201–208

    CAS  PubMed Central  PubMed  Google Scholar 

  • Goldstein AM (2011) Germline BAP1 mutations and tumor susceptibility. Nat Genet 43:925–926

    CAS  PubMed  Google Scholar 

  • Gore SD (2011) New ways to use DNA methyltransferase inhibitors for the treatment of myelodysplastic syndrome. Hematology Am Soc Hematol Educ Program 2011:550–555

    PubMed Central  PubMed  Google Scholar 

  • Grass JA, Boyer ME, Pal S, Wu J, Weiss MJ, Bresnick EH (2003) GATA-1-dependent transcriptional repression of GATA-2 via disruption of positive autoregulation and domain-wide chromatin remodeling. Proc Natl Acad Sci U S A 100:8811–8816

    CAS  PubMed Central  PubMed  Google Scholar 

  • Higgs DR, Garrick D, Anguita E, De Gobbi M, Hughes J, Muers M, Vernimmen D, Lower K, Law M, Argentaro A, Deville MA, Gibbons R (2005) Understanding alpha-globin gene regulation: aiming to improve the management of thalassemia. Ann N Y Acad Sci 1054:92–102

    CAS  PubMed  Google Scholar 

  • Higgs DR, Vernimmen D, Wood B (2008) Long-range regulation of alpha-globin gene expression. Adv Genet 61:143–173

    CAS  PubMed  Google Scholar 

  • Higgs DR, Engel JD, Stamatoyannopoulos G (2012) Thalassaemia. Lancet 379:373–383

    CAS  PubMed  Google Scholar 

  • Houston IB, Huang KJ, Jennings SR, DeKoter RP (2007) PU.1 immortalizes hematopoietic progenitors in a GM-CSF-dependent manner. Exp Hematol 35:374–384

    CAS  PubMed  Google Scholar 

  • Hu M, Krause D, Greaves M, Sharkis S, Dexter M, Heyworth C, Enver T (1997) Multilineage gene expression precedes commitment in the hemopoietic system. Genes Dev 11:774–785

    CAS  PubMed  Google Scholar 

  • Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N, Rowan R, Amaral S, Curley D, Williams IR, Akashi K, Gilliland DG (2004) MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6:587–596

    CAS  PubMed  Google Scholar 

  • Iliou MS, Lujambio A, Portela A, Brustle O, Koch P, Andersson-Vincent PH, Sundstrom E, Hovatta O, Esteller M (2011) Bivalent histone modifications in stem cells poise miRNA loci for CpG island hypermethylation in human cancer. Epigenetics 6:1344–1353

    CAS  PubMed  Google Scholar 

  • Ishida Y, Levin J, Baker G, Stenberg PE, Yamada Y, Sasaki H, Inoue T (1993) Biological and biochemical characteristics of murine megakaryoblastic cell line L8057. Exp Hematol 21:289–298

    CAS  PubMed  Google Scholar 

  • Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, Minna J, Borodovsky A, Schultz DC, Wilkinson KD, Maul GG, Barlev N, Berger SL, Prendergast GC, Rauscher FJ 3rd (1998) BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16:1097–1112

    CAS  PubMed  Google Scholar 

  • Kadauke S, Blobel GA (2013) Mitotic bookmarking by transcription factors. Epigenetics Chromatin 6:6

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kadauke S, Udugama MI, Pawlicki JM, Achtman JC, Jain DP, Cheng Y, Hardison RC, Blobel GA (2012) Tissue-specific mitotic bookmarking by hematopoietic transcription factor GATA1. Cell 150:725–737

    CAS  PubMed Central  PubMed  Google Scholar 

  • Khandros E, Thom CS, D’Souza J, Weiss MJ (2012) Integrated protein quality-control pathways regulate free alpha-globin in murine beta-thalassemia. Blood 119:5265–5275

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ko M, Rao A (2011) TET2: epigenetic safeguard for HSC. Blood 118:4501–4503

    CAS  PubMed  Google Scholar 

  • Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, Tsangaratou A, Rajewsky K, Koralov SB, Rao A (2011) Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci USA 108:14566–14571

    CAS  PubMed Central  PubMed  Google Scholar 

  • Komatsu N, Yamamoto M, Fujita H, Miwa A, Hatake K, Endo T, Okano H, Katsube T, Fukumaki Y, Sassa S et al (1993) Establishment and characterization of an erythropoietin-dependent subline, UT-7/Epo, derived from human leukemia cell line, UT-7. Blood 82:456–464

    CAS  PubMed  Google Scholar 

  • Komatsu N, Kunitama M, Yamada M, Hagiwara T, Kato T, Miyazaki H, Eguchi M, Yamamoto M, Miura Y (1996) Establishment and characterization of the thrombopoietin-dependent megakaryocytic cell line, UT-7/TPO. Blood 87:4552–4560

    CAS  PubMed  Google Scholar 

  • Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, Bantscheff M, Bountra C, Bridges A, Diallo H, Eberhard D, Hutchinson S, Jones E, Katso R, Leveridge M, Mander PK, Mosley J, Ramirez-Molina C, Rowland P, Schofield CJ, Sheppard RJ, Smith JE, Swales C, Tanner R, Thomas P, Tumber A, Drewes G, Oppermann U, Patel DJ, Lee K, Wilson DM (2012) A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488:404–408

    CAS  PubMed  Google Scholar 

  • Kutlar A (2007) Sickle cell disease: a multigenic perspective of a single gene disorder. Hemoglobin 31:209–224

    CAS  PubMed  Google Scholar 

  • Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH (2009) Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41:838–842

    CAS  PubMed  Google Scholar 

  • Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O’Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, Swift GW, Reed JP, Alldredge PA, Wylie T, Walker J, Kalicki J, Watson MA, Heath S, Shannon WD, Varghese N, Nagarajan R, Westervelt P, Tomasson MH, Link DC, Graubert TA, DiPersio JF, Mardis ER, Wilson RK (2010) DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363:2424–2433

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR (2003) TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 17:637–641

    CAS  PubMed  Google Scholar 

  • Lozzio CB, Lozzio BB (1975) Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood 45:321–334

    CAS  PubMed  Google Scholar 

  • Lynch MD, Smith AJ, De Gobbi M, Flenley M, Hughes JR, Vernimmen D, Ayyub H, Sharpe JA, Sloane-Stanley JA, Sutherland L, Meek S, Burdon T, Gibbons RJ, Garrick D, Higgs DR (2012) An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO J 31(2):317–329

    CAS  PubMed Central  PubMed  Google Scholar 

  • Marks PA, Sheffery M, Rifkind RA (1987) Induction of transformed cells to terminal differentiation and the modulation of gene expression. Cancer Res 47:659–666

    CAS  PubMed  Google Scholar 

  • McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra A 3rd, Diaz E, LaFrance LV, Mellinger M, Duquenne C, Tian X, Kruger RG, McHugh CF, Brandt M, Miller WH, Dhanak D, Verma SK, Tummino PJ, Creasy CL (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492:108–112

    CAS  PubMed  Google Scholar 

  • Mendenhall EM, Koche RP, Truong T, Zhou VW, Issac B, Chi AS, Ku M, Bernstein BE (2010) GC-rich sequence elements recruit PRC2 in mammalian ES cells. PLoS Genet 6:e1001244

    PubMed Central  PubMed  Google Scholar 

  • Miyamoto T, Iwasaki H, Reizis B, Ye M, Graf T, Weissman IL, Akashi K (2002) Myeloid or lymphoid promiscuity as a critical step in hematopoietic lineage commitment. Dev Cell 3:137–147

    CAS  PubMed  Google Scholar 

  • Musallam KM, Taher AT, Cappellini MD, Sankaran VG (2013) Clinical experience with fetal hemoglobin induction therapy in patients with beta-thalassemia. Blood 121:2199–2212, quiz 2372

    CAS  PubMed  Google Scholar 

  • Ney PA, D’Andrea AD (2000) Friend erythroleukemia revisited. Blood 96:3675–3680

    CAS  PubMed  Google Scholar 

  • Noguchi CT, Rodgers GP, Serjeant G, Schechter AN (1988) Levels of fetal hemoglobin necessary for treatment of sickle cell disease. N Engl J Med 318:96–99

    CAS  PubMed  Google Scholar 

  • Oakley K, Han Y, Vishwakarma BA, Chu S, Bhatia R, Gudmundsson KO, Keller J, Chen X, Vasko V, Jenkins NA, Copeland NG, Du Y (2012) Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10. Blood 119:6099–6108

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ono Y, Wang Y, Suzuki H, Okamoto S, Ikeda Y, Murata M, Poncz M, Matsubara Y (2012) Induction of functional platelets from mouse and human fibroblasts by p45NF-E2/Maf. Blood 120:3812–3821

    CAS  PubMed Central  PubMed  Google Scholar 

  • Orkin SH (2000) Diversification of haematopoietic stem cells to specific lineages. Nat Rev Genet 1:57–64

    CAS  PubMed  Google Scholar 

  • Palis J (2008) Ontogeny of erythropoiesis. Curr Opin Hematol 15:155–161

    PubMed  Google Scholar 

  • Palstra RJ, Tolhuis B, Splinter E, Nijmeijer R, Grosveld F, de Laat W (2003) The beta-globin nuclear compartment in development and erythroid differentiation. Nat Genet 35:190–194

    CAS  PubMed  Google Scholar 

  • Pencovich N, Jaschek R, Tanay A, Groner Y (2011) Dynamic combinatorial interactions of RUNX1 and cooperating partners regulates megakaryocytic differentiation in cell line models. Blood 117:e1–e14

    CAS  PubMed  Google Scholar 

  • Pope SH, Fibach E, Sun J, Chin K, Rodgers GP (2000) Two-phase liquid culture system models normal human adult erythropoiesis at the molecular level. Eur J Haematol 64:292–303

    CAS  PubMed  Google Scholar 

  • Prather RS (2013) Pig genomics for biomedicine. Nat Biotechnol 31:122–124

    CAS  PubMed  Google Scholar 

  • Pronk CJ, Rossi DJ, Mansson R, Attema JL, Norddahl GL, Chan CK, Sigvardsson M, Weissman IL, Bryder D (2007) Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell 1:428–442

    CAS  PubMed  Google Scholar 

  • Rada-Iglesias A (2013) Pioneering barren land: mitotic bookmarking by transcription factors. Dev Cell 24:342–344

    CAS  PubMed  Google Scholar 

  • Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, Beyan H, Whittaker P, McCann OT, Finer S, Valdes AM, Leslie RD, Deloukas P, Spector TD (2010) Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 20:434–439

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rank G, Cerruti L, Simpson RJ, Moritz RL, Jane SM, Zhao Q (2010) Identification of a PRMT5-dependent repressor complex linked to silencing of human fetal globin gene expression. Blood 116:1585–1592

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rodriguez J, Munoz M, Vives L, Frangou CG, Groudine M, Peinado MA (2008) Bivalent domains enforce transcriptional memory of DNA methylated genes in cancer cells. Proc Natl Acad Sci U S A 105:19809–19814

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rutherford T, Clegg JB, Higgs DR, Jones RW, Thompson J, Weatherall DJ (1981) Embryonic erythroid differentiation in the human leukemic cell line K562. Proc Natl Acad Sci USA 78:348–352

    CAS  PubMed Central  PubMed  Google Scholar 

  • Saito H (1997) Megakaryocytic cell lines. Baillieres Clin Haematol 10:47–63

    CAS  PubMed  Google Scholar 

  • Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, Mikkola HK, Hirschhorn JN, Cantor AB, Orkin SH (2008) Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 322:1839–1842

    CAS  PubMed  Google Scholar 

  • Sankaran VG, Xu J, Orkin SH (2010) Advances in the understanding of haemoglobin switching. Br J Haematol 149:181–194

    CAS  PubMed  Google Scholar 

  • Sankaran VG, Xu J, Byron R, Greisman HA, Fisher C, Weatherall DJ, Sabath DE, Groudine M, Orkin SH, Premawardhena A, Bender MA (2011) A functional element necessary for fetal hemoglobin silencing. N Engl J Med 365:807–814

    CAS  PubMed Central  PubMed  Google Scholar 

  • Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Muller J (2010) Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 465:243–247

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shi L, Cui S, Engel JD, Tanabe O (2013) Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction. Nat Med 19:291–294

    CAS  PubMed  Google Scholar 

  • Shih AH, Abdel-Wahab O, Patel JP, Levine RL (2012) The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 12:599–612

    CAS  PubMed  Google Scholar 

  • Song CX, Szulwach KE, Dai Q, Fu Y, Mao SQ, Lin L, Street C, Li Y, Poidevin M, Wu H, Gao J, Liu P, Li L, Xu GL, Jin P, He C (2013) Genome-wide profiling of 5-formylcytosine reveals its roles in epigenetic priming. Cell 153:678–691

    CAS  PubMed  Google Scholar 

  • Spivak JL, Toretti D, Dickerman HW (1973) Effect of phenylhydrazine-induced hemolytic anemia on nuclear RNA polymerase activity of the mouse spleen. Blood 42:257–266

    CAS  PubMed  Google Scholar 

  • Spooncer E, Heyworth CM, Dunn A, Dexter TM (1986) Self-renewal and differentiation of interleukin-3-dependent multipotent stem cells are modulated by stromal cells and serum factors. Differentiation 31:111–118

    CAS  PubMed  Google Scholar 

  • Stroud H, Feng S, Morey Kinney S, Pradhan S, Jacobsen SE (2011) 5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. Genome Biol 12:R54

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, Buchou T, Cheng Z, Rousseaux S, Rajagopal N, Lu Z, Ye Z, Zhu Q, Wysocka J, Ye Y, Khochbin S, Ren B, Zhao Y (2011) Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146:1016–1028

    CAS  PubMed Central  PubMed  Google Scholar 

  • Thein SL, Menzel S (2009) Discovering the genetics underlying foetal haemoglobin production in adults. Br J Haematol 145:455–467

    CAS  PubMed  Google Scholar 

  • Thomson JP, Skene PJ, Selfridge J, Clouaire T, Guy J, Webb S, Kerr AR, Deaton A, Andrews R, James KD, Turner DJ, Illingworth R, Bird A (2010) CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature 464:1082–1086

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tijssen MR, Cvejic A, Joshi A, Hannah RL, Ferreira R, Forrai A, Bellissimo DC, Oram SH, Smethurst PA, Wilson NK, Wang X, Ottersbach K, Stemple DL, Green AR, Ouwehand WH, Gottgens B (2011) Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators. Dev Cell 20:597–609

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, Shin JJ, Harbom KM, Beaty R, Pappou E, Harris J, Yen RW, Ahuja N, Brock MV, Stearns V, Feller-Kopman D, Yarmus LB, Lin YC, Welm AL, Issa JP, Minn I, Matsui W, Jang YY, Sharkis SJ, Baylin SB, Zahnow CA (2012) Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21:430–446

    CAS  PubMed Central  PubMed  Google Scholar 

  • Vernimmen D, De Gobbi M, Sloane-Stanley JA, Wood WG, Higgs DR (2007) Long-range chromosomal interactions regulate the timing of the transition between poised and active gene expression. EMBO J 26:2041–2051

    CAS  PubMed Central  PubMed  Google Scholar 

  • Vernimmen D, Lynch MD, De Gobbi M, Garrick D, Sharpe JA, Sloane-Stanley JA, Smith AJ, Higgs DR (2011) Polycomb eviction as a new distant enhancer function. Genes Dev 25:1583–1588

    CAS  PubMed Central  PubMed  Google Scholar 

  • Verstovsek S (2009) Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program 636–42

    Google Scholar 

  • Whyte WA, Bilodeau S, Orlando DA, Hoke HA, Frampton GM, Foster CT, Cowley SM, Young RA (2012) Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482:221–225

    CAS  PubMed  Google Scholar 

  • Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J, Helin K (2011) TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473:343–348

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wu H, Zhang Y (2011) Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 25:2436–2452

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wu H, D’Alessio AC, Ito S, Xia K, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y (2011) Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473:389–393

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xu J, Bauer DE, Kerenyi MA, Vo TD, Hou S, Hsu YJ, Yao H, Trowbridge JJ, Mandel G, Orkin SH (2013) Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad Sci U S A 110:6518–6523

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zaret KS, Carroll JS (2011) Pioneer transcription factors: establishing competence for gene expression. Genes Dev 25:2227–2241

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zeitlin HC, Weatherall DJ (1983) Selective expression within the human alpha globin gene complex following chromosome-dependent transfer into diploid mouse erythroleukaemia cells. Mol Biol Med 1:489–500

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I would like to thank Mattia Frontini and Ailbhe Brazel for critically reviewing the manuscript. The Vernimmen lab benefits funding from by the British Society for Haematology (BSH), the Lady Tata Memorial Trust and the Roslin Foundation. Douglas Vernimmen is supported by a Chancellor’s Fellowship at The University of Edinburgh. The Roslin Institute receives Institute Strategic Grant funding from the BBSRC.

Author information

Authors and Affiliations

  1. The Roslin Institute, Developmental Biology Division, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK

    Douglas Vernimmen

Authors
  1. Douglas Vernimmen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas Vernimmen .

Editor information

Editors and Affiliations

  1. Institute of Biomedical Research, University of Birmingham Medical and Dental Sciences, Birmingham, United Kingdom

    Constanze Bonifer

  2. Institute of Biomedical Research, University of Birmingham Medical and Dental Sciences, Birmingham, United Kingdom

    Peter N. Cockerill

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Vernimmen, D. (2014). The Molecular Basis of Normal Erythroid/Megakaryocyte Development and Mechanisms of Epigenetic/Transcriptional Deregulation Leading to Erythroleukemia and Thalassaemia. In: Bonifer, C., Cockerill, P. (eds) Transcriptional and Epigenetic Mechanisms Regulating Normal and Aberrant Blood Cell Development. Epigenetics and Human Health. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-45198-0_10

Download citation

Publish with us

Policies and ethics

Search

Navigation