Advertisement

Megakaryocytic Transcription Factors in Disease and Leukemia

  • Alan B. CantorEmail author
Chapter

Abstract

An understanding of the transcriptional regulation of megakaryopoiesis has lagged behind that of other hematopoietic lineages due to the rarity of these cells and the relatively recent development of systems to culture large numbers of megakaryocytes. However, significant progress has been made over the past few decades resulting in the identification of many key transcription factors involved in megakaryocyte specification and maturation. A number of important principles have emerged including physical and functional interactions among a core set of transcription factors including GATA, ETS, and RUNX family members, cross antagonistic network interactions with key erythroid-specific factors in cell fate determination of bipotential erythroid-megakaryocytic progenitor cells, and a surprising overlap with hematopoietic stem cell transcriptional regulators. A high proportion of genes encoding megakaryocytic transcription factors are mutated in human thrombopoiesis disorders, and a number of these are associated with leukemia predisposition. This chapter reviews the current knowledge about transcription factors involved in megakaryopoiesis, how they interact, and how their activities are influenced by cell signaling events. It also highlights the important role that dysregulation of these factors play in certain human platelet biogenesis disorders and leukemogenesis.

Keywords

Down Syndrome Megakaryocytic Cell Transient Myeloproliferative Disorder Congenital Erythropoietic Porphyria Proplatelet Formation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The author would like to thank the many colleagues in the field and members of the laboratory who have contributed ideas and insights to the material discussed in this chapter. I apologize for any work from others that was omitted due to space limitations. A.B.C. is supported by grants from the NIH (R01 DK098448 and R01 HL130793).

References

  1. 1.
    Ahmed M, Sternberg A, Hall G, Thomas A, Smith O, O’Marcaigh A, Wynn R, Stevens R, Addison M, King D, Stewart B, Gibson B, Roberts I, Vyas P (2004) Natural history of GATA1 mutations in Down syndrome. Blood 103(7):2480–2489PubMedCrossRefGoogle Scholar
  2. 2.
    Alford KA, Reinhardt K, Garnett C, Norton A, Bohmer K, von Neuhoff C, Kolenova A, Marchi E, Klusmann JH, Roberts I, Hasle H, Reinhardt D, Vyas P (2011) Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia. Blood 118(8):2222–2238. doi: 10.1182/blood-2011-03-342774 PubMedCrossRefGoogle Scholar
  3. 3.
    Aminkeng F (2014) GFI1B mutation causes autosomal dominant gray platelet syndrome. Clin Genet 85(6):534–535. doi: 10.1111/cge.12380 PubMedCrossRefGoogle Scholar
  4. 4.
    Antony-Debre I, Bluteau D, Itzykson R, Baccini V, Renneville A, Boehlen F, Morabito M, Droin N, Deswarte C, Chang Y, Leverger G, Solary E, Vainchenker W, Favier R, Raslova H (2012) MYH10 protein expression in platelets as a biomarker of RUNX1 and FLI1 alterations. Blood 120(13):2719–2722. doi: 10.1182/blood-2012-04-422352 PubMedCrossRefGoogle Scholar
  5. 5.
    Antony-Debre I, Manchev VT, Balayn N, Bluteau D, Tomowiak C, Legrand C, Langlois T, Bawa O, Tosca L, Tachdjian G, Leheup B, Debili N, Plo I, Mills JA, French DL, Weiss MJ, Solary E, Favier R, Vainchenker W, Raslova H (2015) Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia. Blood 125(6):930–940. doi: 10.1182/blood-2014-06-585513 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Avecilla ST, Hattori K, Heissig B, Tejada R, Liao F, Shido K, Jin DK, Dias S, Zhang F, Hartman TE, Hackett NR, Crystal RG, Witte L, Hicklin DJ, Bohlen P, Eaton D, Lyden D, de Sauvage F, Rafii S (2004) Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med 10(1):64–71PubMedCrossRefGoogle Scholar
  7. 7.
    Azcoitia V, Aracil M, Martinez AC, Torres M (2005) The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev Biol 280(2):307–320PubMedCrossRefGoogle Scholar
  8. 8.
    Balduini CL, Pecci A, Loffredo G, Izzo P, Noris P, Grosso M, Bergamaschi G, Rosti V, Magrini U, Ceresa IF, Conti V, Poggi V, Savoia A (2004) Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost 91(1):129–140. doi: 10.1267/THRO04010129 PubMedGoogle Scholar
  9. 9.
    Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, Kantarjian H, Raza A, Levine RL, Neuberg D, Ebert BL (2011) Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 364(26):2496–2506. doi: 10.1056/NEJMoa1013343 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Ben-David Y, Giddens EB, Bernstein A (1990) Identification and mapping of a common proviral integration site Fli-1 in erythroleukemia cells induced by Friend murine leukemia virus. Proc Natl Acad Sci U S A 87(4):1332–1336PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Ben-David Y, Giddens EB, Letwin K, Bernstein A (1991) Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1. Genes Dev 5(6):908–918PubMedCrossRefGoogle Scholar
  12. 12.
    Blink M, Buitenkamp TD, van den Heuvel-Eibrink MM, Danen-van Oorschot AA, de Haas V, Reinhardt D, Klusmann JH, Zimmermann M, Devidas M, Carroll AJ, Basso G, Pession A, Hasle H, Pieters R, Rabin KR, Izraeli S, Zwaan CM (2011) Frequency and prognostic implications of JAK 1–3 aberrations in Down syndrome acute lymphoblastic and myeloid leukemia. Leukemia 25(8):1365–1368. doi: 10.1038/leu.2011.86 PubMedCrossRefGoogle Scholar
  13. 13.
    Blink M, van den Heuvel-Eibrink MM, Aalbers AM, Balgobind BV, Hollink IH, Meijerink JP, van der Velden VH, Beverloo BH, de Haas V, Hasle H, Reinhardt D, Klusmann JH, Pieters R, Calado RT, Zwaan CM (2012) High frequency of copy number alterations in myeloid leukaemia of Down syndrome. Br J Haematol 158(6):800–803. doi: 10.1111/j.1365-2141.2012.09224.x PubMedCrossRefGoogle Scholar
  14. 14.
    Bluteau D, Gilles L, Hilpert M, Antony-Debre I, James C, Debili N, Camara-Clayette V, Wagner-Ballon O, Cordette-Lagarde V, Robert T, Ripoche H, Gonin P, Swierczek S, Prchal J, Vainchenker W, Favier R, Raslova H (2011) Down-regulation of the RUNX1-target gene NR4A3 contributes to hematopoiesis deregulation in familial platelet disorder/acute myelogenous leukemia. Blood 118(24):6310–6320. doi: 10.1182/blood-2010-12-325555 PubMedCrossRefGoogle Scholar
  15. 15.
    Bluteau D, Glembotsky AC, Raimbault A, Balayn N, Gilles L, Rameau P, Nurden P, Alessi MC, Debili N, Vainchenker W, Heller PG, Favier R, Raslova H (2012) Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression. Blood 120(13):2708–2718. doi: 10.1182/blood-2012-04-422337 PubMedCrossRefGoogle Scholar
  16. 16.
    Bresnick EH, Lee HY, Fujiwara T, Johnson KD, Keles S (2010) GATA switches as developmental drivers. J Biol Chem 285:31087–31093PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Breton-Gorius J, Favier R, Guichard J, Cherif D, Berger R, Debili N, Vainchenker W, Douay L (1995) A new congenital dysmegakaryopoietic thrombocytopenia (Paris-Trousseau) associated with giant platelet alpha-granules and chromosome 11 deletion at 11q23. Blood 85(7):1805–1814PubMedGoogle Scholar
  18. 18.
    Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, Seandel M, Shido K, White IA, Kobayashi M, Witte L, May C, Shawber C, Kimura Y, Kitajewski J, Rosenwaks Z, Bernstein ID, Rafii S (2010) Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell 6(3):251–264. doi: 10.1016/j.stem.2010.02.001 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Cai X, Gao L, Teng L, Ge J, Oo ZM, Kumar AR, Gilliland DG, Mason PJ, Tan K, Speck NA (2015) Runx1 deficiency decreases ribosome biogenesis and confers stress resistance to hematopoietic stem and progenitor cells. Cell Stem Cell 17(2):165–177. doi: 10.1016/j.stem.2015.06.002 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Cai X, Gaudet JJ, Mangan JK, Chen MJ, De Obaldia ME, Oo Z, Ernst P, Speck NA (2011) Runx1 loss minimally impacts long-term hematopoietic stem cells. PLoS ONE 6(12), e28430. doi: 10.1371/journal.pone.0028430 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Calligaris R, Bottardi S, Cogoi S, Apezteguia I, Santoro C (1995) Alternative translation initiation site usage results in two functionally distinct forms of the GATA-1 transcription factor. Proc Natl Acad Sci U S A 92(25):11598–11602PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Cantor AB (2015) Myeloid proliferations associated with Down syndrome. J Hematop 8:169–176PubMedCrossRefGoogle Scholar
  23. 23.
    Cantor AB, Iwasaki H, Arinobu Y, Moran TB, Shigematsu H, Sullivan MR, Akashi K, Orkin SH (2008) Antagonism of FOG-1 and GATA factors in fate choice for the mast cell lineage. J Exp Med 205(3):611–624PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Cantor AB, Katz SG, Orkin SH (2002) Distinct domains of the GATA-1 cofactor FOG-1 differentially influence erythroid versus megakaryocytic maturation. Mol Cell Biol 22(12):4268–4279PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Cantor AB, Orkin SH (2005) Coregulation of GATA factors by the Friend of GATA (FOG) family of multitype zinc finger proteins. Semin Cell Dev Biol 16(1):117–128PubMedCrossRefGoogle Scholar
  26. 26.
    Carpinelli MR, Hilton DJ, Metcalf D, Antonchuk JL, Hyland CD, Mifsud SL, Di Rago L, Hilton AA, Willson TA, Roberts AW, Ramsay RG, Nicola NA, Alexander WS (2004) Suppressor screen in Mpl-/- mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling. Proc Natl Acad Sci U S A 101(17):6553–6558. doi: 10.1073/pnas.0401496101 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Chagraoui H, Kassouf M, Banerjee S, Goardon N, Clark K, Atzberger A, Pearce AC, Skoda RC, Ferguson DJ, Watson SP, Vyas P, Porcher C (2011) SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis. Blood 118(3):723–735. doi: 10.1182/blood-2011-01-328765 PubMedCrossRefGoogle Scholar
  28. 28.
    Chang AN, Cantor AB, Fujiwara Y, Lodish MB, Droho S, Crispino JD, Orkin SH (2002) GATA-factor dependence of the multitype zinc-finger protein FOG-1 for its essential role in megakaryopoiesis. Proc Natl Acad Sci U S A 99(14):9237–9242PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Chen MJ, Yokomizo T, Zeigler BM, Dzierzak E, Speck NA (2009) Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457(7231):887–891PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Chou ST, Kacena MA, Weiss MJ, Rasking WH (2014) GATA1-related X-linked cytopenia. http://www.ncbi.nlm.nih.gov/books/NBK1364/
  31. 31.
    Chou ST, Opalinska JB, Yao Y, Fernandes MA, Kalota A, Brooks JS, Choi JK, Gewirtz AM, Danet-Desnoyers GA, Nemiroff RL, Weiss MJ (2008) Trisomy 21 enhances human fetal erythro-megakaryocytic development. Blood 112(12):4503–4506PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Christiansen DH, Andersen MK, Pedersen-Bjergaard J (2004) Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation. Blood 104(5):1474–1481PubMedCrossRefGoogle Scholar
  33. 33.
    Crispino JD, Lodish MB, MacKay JP, Orkin SH (1999) Use of altered specificity mutants to probe a specific protein-protein interaction in differentiation: the GATA-1:FOG complex. Mol Cell 3(2):219–228PubMedCrossRefGoogle Scholar
  34. 34.
    Deveaux S, Filipe A, Lemarchandel V, Ghysdael J, Romeo PH, Mignotte V (1996) Analysis of the thrombopoietin receptor (MPL) promoter implicates GATA and Ets proteins in the coregulation of megakaryocyte-specific genes. Blood 87(11):4678–4685PubMedGoogle Scholar
  35. 35.
    Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M, Lakey JH, Rahman T, Wang XN, McGovern N, Pagan S, Cookson S, McDonald D, Chua I, Wallis J, Cant A, Wright M, Keavney B, Chinnery PF, Loughlin J, Hambleton S, Santibanez-Koref M, Collin M (2011) Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood 118(10):2656–2658. doi: 10.1182/blood-2011-06-360313 PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Dore LC, Chlon TM, Brown CD, White KP, Crispino JD (2012) Chromatin occupancy analysis reveals genome-wide GATA factor switching during hematopoiesis. Blood 119(16):3724–3733. doi: 10.1182/blood-2011-09-380634 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Eisbacher M, Holmes ML, Newton A, Hogg PJ, Khachigian LM, Crossley M, Chong BH (2003) Protein-protein interaction between Fli-1 and GATA-1 mediates synergistic expression of megakaryocyte-specific genes through cooperative DNA binding. Mol Cell Biol 23(10):3427–3441PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Elagib KE, Racke FK, Mogass M, Khetawat R, Delehanty LL, Goldfarb AN (2003) RUNX1 and GATA-1 coexpression and cooperation in megakaryocytic differentiation. Blood 101(11):4333–4341PubMedCrossRefGoogle Scholar
  39. 39.
    Emambokus N, Vegiopoulos A, Harman B, Jenkinson E, Anderson G, Frampton J (2003) Progression through key stages of haemopoiesis is dependent on distinct threshold levels of c-Myb. EMBO J 22(17):4478–4488. doi: 10.1093/emboj/cdg434 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Evans T, Reitman M, Felsenfeld G (1988) An erythrocyte-specific DNA-binding factor recognizes a regulatory sequence common to all chicken globin genes. Proc Natl Acad Sci U S A 85(16):5976–5980PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Ford AM, Bennett CA, Price CM, Bruin MC, Van Wering ER, Greaves M (1998) Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia. Proc Natl Acad Sci U S A 95(8):4584–4588PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Fox AH, Liew C, Holmes M, Kowalski K, Mackay J, Crossley M (1999) Transcriptional cofactors of the FOG family interact with GATA proteins by means of multiple zinc fingers. Embo J 18(10):2812–2822PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Freson K, Devriendt K, Matthijs G, Van Hoof A, De Vos R, Thys C, Minner K, Hoylaerts MF, Vermylen J, Van Geet C (2001) Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood 98(1):85–92PubMedCrossRefGoogle Scholar
  44. 44.
    Freson K, Matthijs G, Thys C, Marien P, Hoylaerts MF, Vermylen J, Van Geet C (2002) Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. Hum Mol Genet 11(2):147–152PubMedCrossRefGoogle Scholar
  45. 45.
    Fujiwara Y, Browne CP, Cunniff K, Goff SC, Orkin SH (1996) Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc Natl Acad Sci U S A 93(22):12355–12358PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Gamis AS, Alonzo TA, Gerbing RB, Hilden JM, Sorrell AD, Sharma M, Loew TW, Arceci RJ, Barnard D, Doyle J, Massey G, Perentesis J, Ravindranath Y, Taub J, Smith FO (2011) Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children’s Oncology Group Study A2971. Blood 118(26):6752–6759. doi: 10.1182/blood-2011-04-350017; quiz 6996PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Ge Y, LaFiura KM, Dombkowski AA, Chen Q, Payton SG, Buck SA, Salagrama S, Diakiw AE, Matherly LH, Taub JW (2008) The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia 22(3):521–529. doi: 10.1038/sj.leu.2405066 PubMedCrossRefGoogle Scholar
  48. 48.
    Greene ME, Mundschau G, Wechsler J, McDevitt M, Gamis A, Karp J, Gurbuxani S, Arceci R, Crispino JD (2003) Mutations in GATA1 in both transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome. Blood Cells Mol Dis 31(3):351–356PubMedCrossRefGoogle Scholar
  49. 49.
    Growney JD, Shigematsu H, Li Z, Lee BH, Adelsperger J, Rowan R, Curley DP, Kutok JL, Akashi K, Williams IR, Speck NA, Gilliland DG (2005) Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood 106(2):494–504PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC, Babic M, Lin M, Carmagnac A, Lee YK, Kok CH, Gagliardi L, Friend KL, Ekert PG, Butcher CM, Brown AL, Lewis ID, To LB, Timms AE, Storek J, Moore S, Altree M, Escher R, Bardy PG, Suthers GK, D’Andrea RJ, Horwitz MS, Scott HS (2011) Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 43(10):1012–1017. doi: 10.1038/ng.913 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Harada H, Harada Y, Tanaka H, Kimura A, Inaba T (2003) Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood 101(2):673–680PubMedCrossRefGoogle Scholar
  52. 52.
    Hart A, Melet F, Grossfeld P, Chien K, Jones C, Tunnacliffe A, Favier R, Bernstein A (2000) Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia. Immunity 13(2):167–177PubMedCrossRefGoogle Scholar
  53. 53.
    Heller PG, Glembotsky AC, Gandhi MJ, Cummings CL, Pirola CJ, Marta RF, Kornblihtt LI, Drachman JG, Molinas FC (2005) Low Mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel AML1 mutation. Blood 105(12):4664–4670PubMedCrossRefGoogle Scholar
  54. 54.
    Hisa T, Spence SE, Rachel RA, Fujita M, Nakamura T, Ward JM, Devor-Henneman DE, Saiki Y, Kutsuna H, Tessarollo L, Jenkins NA, Copeland NG (2004) Hematopoietic, angiogenic and eye defects in Meis1 mutant animals. Embo J 23(2):450–459PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Hitzler JK, Cheung J, Li Y, Scherer SW, Zipursky A (2003) GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101(11):4301–4304PubMedCrossRefGoogle Scholar
  56. 56.
    Hock H, Meade E, Medeiros S, Schindler JW, Valk PJ, Fujiwara Y, Orkin SH (2004) Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev 18(19):2336–2341PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Hollanda LM, Lima CS, Cunha AF, Albuquerque DM, Vassallo J, Ozelo MC, Joazeiro PP, Saad ST, Costa FF (2006) An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. Nat Genet 38(7):807–812PubMedCrossRefGoogle Scholar
  58. 58.
    Hong W, Nakazawa M, Chen YY, Kori R, Vakoc CR, Rakowski C, Blobel GA (2005) FOG-1 recruits the NuRD repressor complex to mediate transcriptional repression by GATA-1. EMBO J 24(13):2367–2378. doi: 10.1038/sj.emboj.7600703 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Horvat-Switzer RD, Thompson AA (2006) HOXA11 mutation in amegakaryocytic thrombocytopenia with radio-ulnar synostosis syndrome inhibits megakaryocytic differentiation in vitro. Blood Cells Mol Dis 37(1):55–63. doi: 10.1016/j.bcmd.2006.04.001 PubMedCrossRefGoogle Scholar
  60. 60.
    Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY, Frucht DM, Vinh DC, Auth RD, Freeman AF, Olivier KN, Uzel G, Zerbe CS, Spalding C, Pittaluga S, Raffeld M, Kuhns DB, Ding L, Paulson ML, Marciano BE, Gea-Banacloche JC, Orange JS, Cuellar-Rodriguez J, Hickstein DD, Holland SM (2011) Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118(10):2653–2655. doi: 10.1182/blood-2011-05-356352 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Huang H, Cantor AB (2009) Common features of megakaryocytes and hematopoietic stem cells: what’s the connection? J Cell Biochem 107(5):857–864PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Huang H, Woo AJ, Waldon Z, Schindler Y, Moran TB, Zhu HH, Feng G, Steen H, Cantor AB (2012) A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T lymphocyte differentiation. Genes Dev 26:1587–1601, Jul 3. [Epub ahead of print] PMID: 22759635PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Huang H, Yu M, Akie TE, Moran TB, Woo AJ, Tu N, Waldon Z, Lin YY, Steen H, Cantor AB (2009) Differentiation-dependent interactions between RUNX-1 and FLI-1 during megakaryocyte development. Mol Cell Biol 29(15):4103–4115. doi: 10.1128/MCB.00090-09, doi:MCB.00090-09 [pii]PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Huang X, Peng JW, Speck NA, Bushweller JH (1999) Solution structure of core binding factor beta and map of the CBF alpha binding site. Nat Struct Biol 6(7):624–627PubMedCrossRefGoogle Scholar
  65. 65.
    Ichikawa M, Asai T, Saito T, Yamamoto G, Seo S, Yamazaki I, Yamagata T, Mitani K, Chiba S, Hirai H, Ogawa S, Kurokawa M (2004) AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med 10(3):299–304PubMedCrossRefGoogle Scholar
  66. 66.
    Ito Y, Bae SC, Chuang LS (2015) The RUNX family: developmental regulators in cancer. Nat Rev Cancer 15(2):81–95. doi: 10.1038/nrc3877 PubMedCrossRefGoogle Scholar
  67. 67.
    Jacob B, Osato M, Yamashita N, Wang CQ, Taniuchi I, Littman DR, Asou N, Ito Y (2010) Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis. Blood 115(8):1610–1620PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Junt T, Schulze H, Chen Z, Massberg S, Goerge T, Krueger A, Wagner DD, Graf T, Italiano JE Jr, Shivdasani RA, von Andrian UH (2007) Dynamic visualization of thrombopoiesis within bone marrow. Science 317(5845):1767–1770PubMedCrossRefGoogle Scholar
  69. 69.
    Katsumura KR, Yang C, Boyer ME, Li L, Bresnick EH (2014) Molecular basis of crosstalk between oncogenic Ras and the master regulator of hematopoiesis GATA-2. EMBO Rep 15(9):938–947. doi: 10.15252/embr.201438808 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Kaur G, Jalagadugula G, Mao G, Rao AK (2010) RUNX1/core binding factor A2 regulates platelet 12-lipoxygenase gene (ALOX12): studies in human RUNX1 haplodeficiency. Blood 115(15):3128–3135PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Kazenwadel J, Secker GA, Liu YJ, Rosenfeld JA, Wildin RS, Cuellar-Rodriguez J, Hsu AP, Dyack S, Fernandez CV, Chong CE, Babic M, Bardy PG, Shimamura A, Zhang MY, Walsh T, Holland SM, Hickstein DD, Horwitz MS, Hahn CN, Scott HS, Harvey NL (2012) Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood 119(5):1283–1291. doi: 10.1182/blood-2011-08-374363 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Kirito K, Fox N, Kaushansky K (2004) Thrombopoietin induces HOXA9 nuclear transport in immature hematopoietic cells: potential mechanism by which the hormone favorably affects hematopoietic stem cells. Mol Cell Biol 24(15):6751–6762PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Klusmann JH, Creutzig U, Zimmermann M, Dworzak M, Jorch N, Langebrake C, Pekrun A, Macakova-Reinhardt K, Reinhardt D (2008) Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 111(6):2991–2998PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Klusmann JH, Godinho FJ, Heitmann K, Maroz A, Koch ML, Reinhardt D, Orkin SH, Li Z (2010) Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis. Genes Dev 24(15):1659–1672. doi: 10.1101/gad.1903410 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Klusmann JH, Li Z, Bohmer K, Maroz A, Koch ML, Emmrich S, Godinho FJ, Orkin SH, Reinhardt D (2010) miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia. Genes Dev 24(5):478–490. doi: 10.1101/gad.1856210 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Kruse EA, Loughran SJ, Baldwin TM, Josefsson EC, Ellis S, Watson DK, Nurden P, Metcalf D, Hilton DJ, Alexander WS, Kile BT (2009) Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage. Proc Natl Acad Sci U S A 106(33):13814–13819. doi: 10.1073/pnas.0906556106 PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Kuvardina ON, Herglotz J, Kolodziej S, Kohrs N, Herkt S, Wojcik B, Oellerich T, Corso J, Behrens K, Kumar A, Hussong H, Urlaub H, Koch J, Serve H, Bonig H, Stocking C, Rieger MA, Lausen J (2015) RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation. Blood 125(23):3570–3579. doi: 10.1182/blood-2014-11-610519 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kwiatkowski BA, Bastian LS, Bauer TR Jr, Tsai S, Zielinska-Kwiatkowska AG, Hickstein DD (1998) The ets family member Tel binds to the Fli-1 oncoprotein and inhibits its transcriptional activity. J Biol Chem 273(28):17525–17530PubMedCrossRefGoogle Scholar
  79. 79.
    Kwiatkowski BA, Zielinska-Kwiatkowska AG, Bauer TR Jr, Hickstein DD (2000) The ETS family member Tel antagonizes the Fli-1 phenotype in hematopoietic cells. Blood Cells Mol Dis 26(1):84–90. doi: 10.1006/bcmd.2000.0282 PubMedCrossRefGoogle Scholar
  80. 80.
    Lancrin C, Sroczynska P, Stephenson C, Allen T, Kouskoff V, Lacaud G (2009) The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature 457(7231):892–895PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Lange B (2000) The management of neoplastic disorders of haematopoiesis in children with Down’s syndrome. Br J Haematol 110(3):512–524PubMedCrossRefGoogle Scholar
  82. 82.
    Lemarchandel V, Ghysdael J, Mignotte V, Rahuel C, Romeo PH (1993) GATA and Ets cis-acting sequences mediate megakaryocyte-specific expression. Mol Cell Biol 13(1):668–676PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Letting DL, Chen YY, Rakowski C, Reedy S, Blobel GA (2004) Context-dependent regulation of GATA-1 by friend of GATA-1. Proc Natl Acad Sci U S A 101(2):476–481PubMedCrossRefGoogle Scholar
  84. 84.
    Li Z, Godinho FJ, Klusmann JH, Garriga-Canut M, Yu C, Orkin SH (2005) Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet 37(6):613–619PubMedCrossRefGoogle Scholar
  85. 85.
    Lu J, Guo S, Ebert BL, Zhang H, Peng X, Bosco J, Pretz J, Schlanger R, Wang JY, Mak RH, Dombkowski DM, Preffer FI, Scadden DT, Golub TR (2008) MicroRNA-mediated control of cell fate in megakaryocyte-erythrocyte progenitors. Dev Cell 14(6):843–853. doi: 10.1016/j.devcel.2008.03.012 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Lu J, Pazin MJ, Ravid K (2004) Properties of ets-1 binding to chromatin and its effect on platelet factor 4 gene expression. Mol Cell Biol 24(1):428–441PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Ludlow LB, Schick BP, Budarf ML, Driscoll DA, Zackai EH, Cohen A, Konkle BA (1996) Identification of a mutation in a GATA binding site of the platelet glycoprotein Ibbeta promoter resulting in the Bernard-Soulier syndrome. J Biol Chem 271(36):22076–22080PubMedCrossRefGoogle Scholar
  88. 88.
    Ludwig LS, Gazda HT, Eng JC, Eichhorn SW, Thiru P, Ghazvinian R, George TI, Gotlib JR, Beggs AH, Sieff CA, Lodish HF, Lander ES, Sankaran VG (2014) Altered translation of GATA1 in Diamond-Blackfan anemia. Nat Med 20(7):748–753. doi: 10.1038/nm.3557 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Lulli V, Romania P, Morsilli O, Gabbianelli M, Pagliuca A, Mazzeo S, Testa U, Peschle C, Marziali G (2006) Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation. Cell Death Differ 13(7):1064–1074. doi: 10.1038/sj.cdd.4401811 PubMedCrossRefGoogle Scholar
  90. 90.
    Maclean GA, Menne TF, Guo G, Sanchez DJ, Park IH, Daley GQ, Orkin SH (2012) Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells. Proc Natl Acad Sci U S A 109(43):17567–17572. doi: 10.1073/pnas.1215468109 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Malinge S, Izraeli S, Crispino JD (2009) Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 113(12):2619–2628PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Malinge S, Ragu C, Della-Valle V, Pisani D, Constantinescu SN, Perez C, Villeval JL, Reinhardt D, Landman-Parker J, Michaux L, Dastugue N, Baruchel A, Vainchenker W, Bourquin JP, Penard-Lacronique V, Bernard OA (2008) Activating mutations in human acute megakaryoblastic leukemia. Blood 112(10):4220–4226. doi: 10.1182/blood-2008-01-136366 PubMedCrossRefGoogle Scholar
  93. 93.
    Malkin D, Brown EJ, Zipursky A (2000) The role of p53 in megakaryocyte differentiation and the megakaryocytic leukemias of Down syndrome. Cancer Genet Cytogenet 116(1):1–5PubMedCrossRefGoogle Scholar
  94. 94.
    Massey GV, Zipursky A, Chang MN, Doyle JJ, Nasim S, Taub JW, Ravindranath Y, Dahl G, Weinstein HJ (2006) A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children’s Oncology Group (COG) study POG-9481. Blood 107(12):4606–4613PubMedCrossRefGoogle Scholar
  95. 95.
    Mehaffey MG, Newton AL, Gandhi MJ, Crossley M, Drachman JG (2001) X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood 98(9):2681–2688PubMedCrossRefGoogle Scholar
  96. 96.
    Mercher T, Cornejo MG, Sears C, Kindler T, Moore SA, Maillard I, Pear WS, Aster JC, Gilliland DG (2008) Notch signaling specifies megakaryocyte development from hematopoietic stem cells. Cell Stem Cell 3(3):314–326PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Miccio A, Wang Y, Hong W, Gregory GD, Wang H, Yu X, Choi JK, Shelat S, Tong W, Poncz M, Blobel GA (2010) NuRD mediates activating and repressive functions of GATA-1 and FOG-1 during blood development. Embo J 29(2):442–456PubMedCrossRefGoogle Scholar
  98. 98.
    Miller CA, Wilson RK, Ley TJ (2013) Genomic landscapes and clonality of de novo AML. N Engl J Med 369:1473PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Monteferrario D, Bolar NA, Marneth AE, Hebeda KM, Bergevoet SM, Veenstra H, Laros-van Gorkom BA, MacKenzie MA, Khandanpour C, Botezatu L, Fransen E, Van Camp G, Duijnhouwer AL, Salemink S, Willemsen B, Huls G, Preijers F, Van Heerde W, Jansen JH, Kempers MJ, Loeys BL, Van Laer L, Van der Reijden BA (2014) A dominant-negative GFI1B mutation in the gray platelet syndrome. N Engl J Med 370(3):245–253. doi: 10.1056/NEJMoa1308130 PubMedCrossRefGoogle Scholar
  100. 100.
    Mukai HY, Motohashi H, Ohneda O, Suzuki N, Nagano M, Yamamoto M (2006) Transgene insertion in proximity to the c-myb gene disrupts erythroid-megakaryocytic lineage bifurcation. Mol Cell Biol 26(21):7953–7965. doi: 10.1128/MCB.00718-06 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Mundschau G, Gurbuxani S, Gamis AS, Greene ME, Arceci RJ, Crispino JD (2003) Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101(11):4298–4300PubMedCrossRefGoogle Scholar
  102. 102.
    Muramatsu H, Kato K, Watanabe N, Matsumoto K, Nakamura T, Horikoshi Y, Mimaya J, Suzuki C, Hayakawa M, Kojima S (2008) Risk factors for early death in neonates with Down syndrome and transient leukaemia. Br J Haematol 142(4):610–615. doi: 10.1111/j.1365-2141.2008.07231.x PubMedCrossRefGoogle Scholar
  103. 103.
    Nakao M, Horiike S, Fukushima-Nakase Y, Nishimura M, Fujita Y, Taniwaki M, Okuda T (2004) Novel loss-of-function mutations of the haematopoiesis-related transcription factor, acute myeloid leukaemia 1/runt-related transcription factor 1, detected in acute myeloblastic leukaemia and myelodysplastic syndrome. Br J Haematol 125(6):709–719PubMedCrossRefGoogle Scholar
  104. 104.
    Ng AP, Hu Y, Metcalf D, Hyland CD, Ierino H, Phipson B, Wu D, Baldwin TM, Kauppi M, Kiu H, Di Rago L, Hilton DJ, Smyth GK, Alexander WS (2015) Early lineage priming by trisomy of erg leads to myeloproliferation in a down syndrome model. PLoS Genet 11(5), e1005211. doi: 10.1371/journal.pgen.1005211 PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Ng AP, Hyland CD, Metcalf D, Carmichael CL, Loughran SJ, Di Rago L, Kile BT, Alexander WS (2010) Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome. Blood 115(19):3966–3969. doi: 10.1182/blood-2009-09-242107 PubMedCrossRefGoogle Scholar
  106. 106.
    Nichols KE, Crispino JD, Poncz M, White JG, Orkin SH, Maris JM, Weiss MJ (2000) Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet 24(3):266–270PubMedCrossRefGoogle Scholar
  107. 107.
    Noetzli L, Lo RW, Lee-Sherick AB, Callaghan M, Noris P, Savoia A, Rajpurkar M, Jones K, Gowan K, Balduini CL, Pecci A, Gnan C, De Rocco D, Doubek M, Li L, Lu L, Leung R, Landolt-Marticorena C, Hunger S, Heller P, Gutierrez-Hartmann A, Xiayuan L, Pluthero FG, Rowley JW, Weyrich AS, Kahr WH, Porter CC, Di Paola J (2015) Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. doi: 10.1038/ng.3253 PubMedPubMedCentralGoogle Scholar
  108. 108.
    O’Neil J, Look AT (2007) Mechanisms of transcription factor deregulation in lymphoid cell transformation. Oncogene 26(47):6838–6849. doi: 10.1038/sj.onc.1210766 PubMedCrossRefGoogle Scholar
  109. 109.
    Okada Y, Nagai R, Sato T, Matsuura E, Minami T, Morita I, Doi T (2003) Homeodomain proteins MEIS1 and PBXs regulate the lineage-specific transcription of the platelet factor 4 gene. Blood 101(12):4748–4756. doi: 10.1182/blood-2002-02-0380 PubMedCrossRefGoogle Scholar
  110. 110.
    Onodera K, Shavit JA, Motohashi H, Yamamoto M, Engel JD (2000) Perinatal synthetic lethality and hematopoietic defects in compound mafG::mafK mutant mice. Embo J 19(6):1335–1345PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ, Dafou D, Kilo T, Smithson S, Lunt P, Murday VA, Hodgson S, Keenan R, Pilz DT, Martinez-Corral I, Makinen T, Mortimer PS, Jeffery S, Trembath RC, Mansour S (2011) Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet 43(10):929–931. doi: 10.1038/ng.923 PubMedCrossRefGoogle Scholar
  112. 112.
    Owen CJ, Toze CL, Koochin A, Forrest DL, Smith CA, Stevens JM, Jackson SC, Poon MC, Sinclair GD, Leber B, Johnson PR, Macheta A, Yin JA, Barnett MJ, Lister TA, Fitzgibbon J (2008) Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy (FPD/AML). Blood 112:4639–4645PubMedCrossRefGoogle Scholar
  113. 113.
    Ozaki T, Nakagawara A, Nagase H (2013) RUNX family participates in the regulation of p53-dependent DNA damage response. Int J Genom 2013:271347. doi: 10.1155/2013/271347 Google Scholar
  114. 114.
    Ozaki T, Wu D, Sugimoto H, Nagase H, Nakagawara A (2013) Runt-related transcription factor 2 (RUNX2) inhibits p53-dependent apoptosis through the collaboration with HDAC6 in response to DNA damage. Cell Death Dis 4, e610. doi: 10.1038/cddis.2013.127 PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Pal S, Cantor AB, Johnson KD, Moran TB, Boyer ME, Orkin SH, Bresnick EH (2004) Coregulator-dependent facilitation of chromatin occupancy by GATA-1. Proc Natl Acad Sci U S A 101(4):980–985PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Pang L, Xue HH, Szalai G, Wang X, Wang Y, Watson DK, Leonard WJ, Blobel GA, Poncz M (2006) Maturation stage-specific regulation of megakaryopoiesis by pointed-domain Ets proteins. Blood 108(7):2198–2206PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP (2007) Congenital erythropoietic porphyria due to a mutation in GATA-1: the first trans-acting mutation causative for a human porphyria. Blood 109(6):2618–2621Google Scholar
  118. 118.
    Porcher C, Swat W, Rockwell K, Fujiwara Y, Alt FW, Orkin SH (1996) The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell 86(1):47–57PubMedCrossRefGoogle Scholar
  119. 119.
    Qin X, Jiang Q, Matsuo Y, Kawane T, Komori H, Moriishi T, Taniuchi I, Ito K, Kawai Y, Rokutanda S, Izumi S, Komori T (2015) Cbfb regulates bone development by stabilizing Runx family proteins. J Bone Miner Res 30(4):706–714. doi: 10.1002/jbmr.2379 PubMedCrossRefGoogle Scholar
  120. 120.
    Rainis L, Bercovich D, Strehl S, Teigler-Schlegel A, Stark B, Trka J, Amariglio N, Biondi A, Muler I, Rechavi G, Kempski H, Haas OA, Izraeli S (2003) Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 102(3):981–986PubMedCrossRefGoogle Scholar
  121. 121.
    Raskind WH, Niakan KK, Wolff J, Matsushita M, Vaughan T, Stamatoyannopoulos G, Watanabe C, Rios J, Ochs HD (2000) Mapping of a syndrome of X-linked thrombocytopenia with Thalassemia to band Xp11-12: further evidence of genetic heterogeneity of X-linked thrombocytopenia. Blood 95(7):2262–2268PubMedGoogle Scholar
  122. 122.
    Raslova H, Komura E, Le Couedic JP, Larbret F, Debili N, Feunteun J, Danos O, Albagli O, Vainchenker W, Favier R (2004) FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia. J Clin Invest 114(1):77–84PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Robert-Moreno A, Espinosa L, de la Pompa JL, Bigas A (2005) RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells. Development 132(5):1117–1126PubMedCrossRefGoogle Scholar
  124. 124.
    Roberts I, Alford K, Hall G, Juban G, Richmond H, Norton A, Vallance G, Perkins K, Marchi E, McGowan S, Roy A, Cowan G, Anthony M, Gupta A, Ho J, Uthaya S, Curley A, Rasiah SV, Watts T, Nicholl R, Bedford-Russell A, Blumberg R, Thomas A, Gibson B, Halsey C, Lee PW, Godambe S, Sweeney C, Bhatnagar N, Goriely A, Campbell P, Vyas P (2013) GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. Blood 122(24):3908–3917. doi: 10.1182/blood-2013-07-515148 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Roberts I, O’Connor D, Roy A, Cowan G, Vyas P (2013) The impact of trisomy 21 on foetal haematopoiesis. Blood Cells Mol Dis 51(4):277–281. doi: 10.1016/j.bcmd.2013.07.008 PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Roy A, Cowan G, Mead AJ, Filippi S, Bohn G, Chaidos A, Tunstall O, Chan JK, Choolani M, Bennett P, Kumar S, Atkinson D, Wyatt-Ashmead J, Hu M, Stumpf MP, Goudevenou K, O’Connor D, Chou ST, Weiss MJ, Karadimitris A, Jacobsen SE, Vyas P, Roberts I (2012) Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21. Proc Natl Acad Sci U S A 109(43):17579–17584. doi: 10.1073/pnas.1211405109 PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Saleque S, Cameron S, Orkin SH (2002) The zinc-finger proto-oncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages. Genes Dev 16(3):301–306PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Saleque S, Kim J, Rooke HM, Orkin SH (2007) Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Mol Cell 27(4):562–572PubMedCrossRefGoogle Scholar
  129. 129.
    Sandberg ML, Sutton SE, Pletcher MT, Wiltshire T, Tarantino LM, Hogenesch JB, Cooke MP (2005) c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. Dev Cell 8(2):153–166. doi: 10.1016/j.devcel.2004.12.015 PubMedCrossRefGoogle Scholar
  130. 130.
    Satoh Y, Matsumura I, Tanaka H, Harada H, Harada Y, Matsui K, Shibata M, Mizuki M, Kanakura Y (2012) C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells. Leukemia 26(2):303–311. doi: 10.1038/leu.2011.202 PubMedCrossRefGoogle Scholar
  131. 131.
    Schuh AH, Tipping AJ, Clark AJ, Hamlett I, Guyot B, Iborra FJ, Rodriguez P, Strouboulis J, Enver T, Vyas P, Porcher C (2005) ETO-2 associates with SCL in erythroid cells and megakaryocytes and provides repressor functions in erythropoiesis. Mol Cell Biol 25(23):10235–10250. doi: 10.1128/MCB.25.23.10235-10250.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Shivdasani RA, Fujiwara Y, McDevitt MA, Orkin SH (1997) A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. Embo J 16(13):3965–3973PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Shivdasani RA, Rosenblatt MF, Zucker-Franklin D, Jackson CW, Hunt P, Saris CJ, Orkin SH (1995) Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 81(5):695–704PubMedCrossRefGoogle Scholar
  134. 134.
    Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D, Ratajczak J, Resende IC, Haworth C, Hock R, Loh M, Felix C, Roy DC, Busque L, Kurnit D, Willman C, Gewirtz AM, Speck NA, Bushweller JH, Li FP, Gardiner K, Poncz M, Maris JM, Gilliland DG (1999) Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 23(2):166–175PubMedCrossRefGoogle Scholar
  135. 135.
    Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, Arthur DC, Gu W, Gould CM, Brewer CC, Cowen EW, Freeman AF, Olivier KN, Uzel G, Zelazny AM, Daub JR, Spalding CD, Claypool RJ, Giri NK, Alter BP, Mace EM, Orange JS, Cuellar-Rodriguez J, Hickstein DD, Holland SM (2014) GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123(6):809–821. doi: 10.1182/blood-2013-07-515528 PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Stankiewicz MJ, Crispino JD (2009) ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells. Blood 113(14):3337–3347. doi: 10.1182/blood-2008-08-174813 PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Stankiewicz MJ, Crispino JD (2013) AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL. Leukemia 27(6):1339–1347. doi: 10.1038/leu.2013.33 PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Starck J, Cohet N, Gonnet C, Sarrazin S, Doubeikovskaia Z, Doubeikovski A, Verger A, Duterque-Coquillaud M, Morle F (2003) Functional cross-antagonism between transcription factors FLI-1 and EKLF. Mol Cell Biol 23(4):1390–1402PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Starck J, Weiss-Gayet M, Gonnet C, Guyot B, Vicat JM, Morle F (2010) Inducible Fli-1 gene deletion in adult mice modifies several myeloid lineage commitment decisions and accelerates proliferation arrest and terminal erythrocytic differentiation. Blood 116(23):4795–4805. doi: 10.1182/blood-2010-02-270405 PubMedCrossRefGoogle Scholar
  140. 140.
    Stevenson WS, Morel-Kopp MC, Chen Q, Liang HP, Bromhead CJ, Wright S, Turakulov R, Ng AP, Roberts AW, Bahlo M, Ward CM (2013) GFI1B mutation causes a bleeding disorder with abnormal platelet function. J Thromb Haemost JTH 11(11):2039–2047. doi: 10.1111/jth.12368 PubMedCrossRefGoogle Scholar
  141. 141.
    Stevenson WS, Rabbolini DJ, Beutler L, Chen Q, Gabrielli S, Mackay JP, Brighton TA, Ward CM, Morel-Kopp MC (2015) Paris-Trousseau thrombocytopenia is phenocopied by the autosomal recessive inheritance of a DNA-binding domain mutation in FLI1. Blood 126(17):2027–2030. doi: 10.1182/blood-2015-06-650887 PubMedCrossRefGoogle Scholar
  142. 142.
    Stockley J, Morgan NV, Bem D, Lowe GC, Lordkipanidze M, Dawood B, Simpson MA, Macfarlane K, Horner K, Leo VC, Talks K, Motwani J, Wilde JT, Collins PW, Makris M, Watson SP, Daly ME (2013) Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects. Blood 122(25):4090–4093. doi: 10.1182/blood-2013-06-506873 PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Sun L, Gorospe JR, Hoffman EP, Rao AK (2007) Decreased platelet expression of myosin regulatory light chain polypeptide (MYL9) and other genes with platelet dysfunction and CBFA2/RUNX1 mutation: insights from platelet expression profiling. J Thromb Haemost 5(1):146–154PubMedCrossRefGoogle Scholar
  144. 144.
    Sun L, Mao G, Rao AK (2004) Association of CBFA2 mutation with decreased platelet PKC-theta and impaired receptor-mediated activation of GPIIb-IIIa and pleckstrin phosphorylation: proteins regulated by CBFA2 play a role in GPIIb-IIIa activation. Blood 103(3):948–954PubMedCrossRefGoogle Scholar
  145. 145.
    Talebian L, Li Z, Guo Y, Gaudet J, Speck ME, Sugiyama D, Kaur P, Pear WS, Maillard I, Speck NA (2007) T-lymphoid, megakaryocyte, and granulocyte development are sensitive to decreases in CBFbeta dosage. Blood 109(1):11–21PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Tanaka T, Kurokawa M, Ueki K, Tanaka K, Imai Y, Mitani K, Okazaki K, Sagata N, Yazaki Y, Shibata Y, Kadowaki T, Hirai H (1996) The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability. Mol Cell Biol 16(7):3967–3979PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Tang JL, Hou HA, Chen CY, Liu CY, Chou WC, Tseng MH, Huang CF, Lee FY, Liu MC, Yao M, Huang SY, Ko BS, Hsu SC, Wu SJ, Tsay W, Chen YC, Lin LI, Tien HF (2009) AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 114:5352–5361PubMedCrossRefGoogle Scholar
  148. 148.
    Taub JW, Mundschau G, Ge Y, Poulik JM, Qureshi F, Jensen T, James SJ, Matherly LH, Wechsler J, Crispino JD (2004) Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome. Blood 104(5):1588–1589. doi: 10.1182/blood-2004-04-1563 PubMedCrossRefGoogle Scholar
  149. 149.
    Thompson AA, Nguyen LT (2000) Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet 26(4):397–398. doi: 10.1038/82511 PubMedCrossRefGoogle Scholar
  150. 150.
    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(5):597–609. doi: 10.1016/j.devcel.2011.04.008 PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Topka S, Vijai J, Walsh MF, Jacobs L, Maria A, Villano D, Gaddam P, Wu G, McGee RB, Quinn E, Inaba H, Hartford C, Pui CH, Pappo A, Edmonson M, Zhang MY, Stepensky P, Steinherz P, Schrader K, Lincoln A, Bussel J, Lipkin SM, Goldgur Y, Harit M, Stadler ZK, Mullighan C, Weintraub M, Shimamura A, Zhang J, Downing JR, Nichols KE, Offit K (2015) Germline ETV6 mutations confer susceptibility to acute lymphoblastic leukemia and thrombocytopenia. PLoS Genet 11(6), e1005262. doi: 10.1371/journal.pgen.1005262 PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M, Alt FW, Orkin SH (1994) An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 371(6494):221–226PubMedCrossRefGoogle Scholar
  153. 153.
    Tsai SF, Martin DI, Zon LI, D’Andrea AD, Wong GG, Orkin SH (1989) Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells. Nature 339(6224):446–451PubMedCrossRefGoogle Scholar
  154. 154.
    Tsang AP, Fujiwara Y, Hom DB, Orkin SH (1998) Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA-1 transcriptional cofactor FOG. Genes Dev 12(8):1176–1188PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Tsang AP, Visvader JE, Turner CA, Fujiwara Y, Yu C, Weiss MJ, Crossley M, Orkin SH (1997) FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell 90(1):109–119PubMedCrossRefGoogle Scholar
  156. 156.
    Tubman VN, Levine JE, Campagna DR, Monahan-Earley R, Dvorak AM, Neufeld EJ, Fleming MD (2007) X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation. Blood 109(8):3297–3299. doi: 10.1182/blood-2006-02-004101 PubMedCrossRefGoogle Scholar
  157. 157.
    Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, Bennett P, Norton A, Vyas P, Roberts I (2008) Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 112(12):4507–4511PubMedCrossRefGoogle Scholar
  158. 158.
    Vannucchi AM, Bianchi L, Cellai C, Paoletti F, Rana RA, Lorenzini R, Migliaccio G, Migliaccio AR (2002) Development of myelofibrosis in mice genetically impaired for GATA-1 expression (GATA-1(low) mice). Blood 100(4):1123–1132PubMedCrossRefGoogle Scholar
  159. 159.
    Visvader JE, Fujiwara Y, Orkin SH (1998) Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development. Genes Dev 12(4):473–479PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Vyas P, Ault K, Jackson CW, Orkin SH, Shivdasani RA (1999) Consequences of GATA-1 deficiency in megakaryocytes and platelets. Blood 93(9):2867–2875PubMedGoogle Scholar
  161. 161.
    Wadman IA, Osada H, Grutz GG, Agulnick AD, Westphal H, Forster A, Rabbitts TH (1997) The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. Embo J 16(11):3145–3157PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Walters DK, Mercher T, Gu TL, O’Hare T, Tyner JW, Loriaux M, Goss VL, Lee KA, Eide CA, Wong MJ, Stoffregen EP, McGreevey L, Nardone J, Moore SA, Crispino J, Boggon TJ, Heinrich MC, Deininger MW, Polakiewicz RD, Gilliland DG, Druker BJ (2006) Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10(1):65–75. doi: 10.1016/j.ccr.2006.06.002 PubMedCrossRefGoogle Scholar
  163. 163.
    Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH, Speck NA (1996) Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc Natl Acad Sci U S A 93(8):3444–3449PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Wang X, Crispino JD, Letting DL, Nakazawa M, Poncz M, Blobel GA (2002) Control of megakaryocyte-specific gene expression by GATA-1 and FOG-1: role of Ets transcription factors. Embo J 21(19):5225–5234PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD (2002) Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32(1):148–152PubMedCrossRefGoogle Scholar
  166. 166.
    Weiss MJ, Yu C, Orkin SH (1997) Erythroid-cell-specific properties of transcription factor GATA-1 revealed by phenotypic rescue of a gene-targeted cell line. Mol Cell Biol 17(3):1642–1651PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    White JG, Nichols WL, Steensma DP (2007) Platelet pathology in sex-linked GATA-1 dyserythropoietic macrothrombocytopenia I ultrastructure. Platelets 18(4):273–283. doi: 10.1080/09537100601065825 PubMedCrossRefGoogle Scholar
  168. 168.
    White JG, Nichols WL, Steensma DP (2007) Platelet pathology in sex-linked GATA-1 dyserythropoietic macrothrombocytopenia II. Cytochemistry. Platelets 18(6):436–450. doi: 10.1080/09537100701280662 PubMedCrossRefGoogle Scholar
  169. 169.
    Wilson NK, Foster SD, Wang X, Knezevic K, Schutte J, Kaimakis P, Chilarska PM, Kinston S, Ouwehand WH, Dzierzak E, Pimanda JE, de Bruijn MF, Gottgens B (2010) Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell 7(4):532–544. doi: 10.1016/j.stem.2010.07.016 PubMedCrossRefGoogle Scholar
  170. 170.
    Woo AJ, Wieland K, Huang H, Akie TE, Piers T, Kim J, Cantor AB (2013) Developmental differences in IFN signaling affect GATA1s-induced megakaryocyte hyperproliferation. J Clin Invest 123:3292–3304. doi: 10.1172/JCI40609 PubMedCentralCrossRefGoogle Scholar
  171. 171.
    Wu D, Ozaki T, Yoshihara Y, Kubo N, Nakagawara A (2013) Runt-related transcription factor 1 (RUNX1) stimulates tumor suppressor p53 protein in response to DNA damage through complex formation and acetylation. J Biol Chem 288(2):1353–1364. doi: 10.1074/jbc.M112.402594 PubMedCrossRefGoogle Scholar
  172. 172.
    Xu G, Nagano M, Kanezaki R, Toki T, Hayashi Y, Taketani T, Taki T, Mitui T, Koike K, Kato K, Imaizumi M, Sekine I, Ikeda Y, Hanada R, Sako M, Kudo K, Kojima S, Ohneda O, Yamamoto M, Ito E (2003) Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome. Blood 102(8):2960–2968PubMedCrossRefGoogle Scholar
  173. 173.
    Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A, Sanada M, Park MJ, Terui K, Suzuki H, Kon A, Nagata Y, Sato Y, Wang R, Shiba N, Chiba K, Tanaka H, Hama A, Muramatsu H, Hasegawa D, Nakamura K, Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Kato K, Nishimura R, Izraeli S, Hayashi Y, Miyano S, Kojima S, Ito E, Ogawa S (2013) The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet 45(11):1293–1299. doi: 10.1038/ng.2759 PubMedCrossRefGoogle Scholar
  174. 174.
    Yoshimi A, Toya T, Kawazu M, Ueno T, Tsukamoto A, Iizuka H, Nakagawa M, Nannya Y, Arai S, Harada H, Usuki K, Hayashi Y, Ito E, Kirito K, Nakajima H, Ichikawa M, Mano H, Kurokawa M (2014) Recurrent CDC25C mutations drive malignant transformation in FPD/AML. Nat Commun 5:4770. doi: 10.1038/ncomms5770 PubMedCrossRefGoogle Scholar
  175. 175.
    Yu C, Niakan KK, Matsushita M, Stamatoyannopoulos G, Orkin SH, Raskind WH (2002) X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood 100(6):2040–2045PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Zhang L, Fried FB, Guo H, Friedman AD (2008) Cyclin-dependent kinase phosphorylation of RUNX1/AML1 on 3 sites increases transactivation potency and stimulates cell proliferation. Blood 111(3):1193–1200. doi: 10.1182/blood-2007-08-109702 PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Zhang MY, Churpek JE, Keel SB, Walsh T, Lee MK, Loeb KR, Gulsuner S, Pritchard CC, Sanchez-Bonilla M, Delrow JJ, Basom RS, Forouhar M, Gyurkocza B, Schwartz BS, Neistadt B, Marquez R, Mariani CJ, Coats SA, Hofmann I, Lindsley RC, Williams DA, Abkowitz JL, Horwitz MS, King MC, Godley LA, Shimamura A (2015) Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet 47(2):180–185. doi: 10.1038/ng.3177 PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Zhang SJ, Ma LY, Huang QH, Li G, Gu BW, Gao XD, Shi JY, Wang YY, Gao L, Cai X, Ren RB, Zhu J, Chen Z, Chen SJ (2008) Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia. Proc Natl Acad Sci U S A 105(6):2076–2081. doi: 10.1073/pnas.0711824105 PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Zhao X, Jankovic V, Gural A, Huang G, Pardanani A, Menendez S, Zhang J, Dunne R, Xiao A, Erdjument-Bromage H, Allis CD, Tempst P, Nimer SD (2008) Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity. Genes Dev 22(5):640–653PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Zharlyganova D, Harada H, Harada Y, Shinkarev S, Zhumadilov Z, Zhunusova A, Tchaizhunusova NJ, Apsalikov KN, Kemaikin V, Zhumadilov K, Kawano N, Kimura A, Hoshi M (2008) High frequency of AML1/RUNX1 point mutations in radiation-associated myelodysplastic syndrome around Semipalatinsk nuclear test site. J Radiat Res 49(5):549–555PubMedCrossRefGoogle Scholar
  181. 181.
    Zipursky A (2003) Transient leukaemia – a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 120(6):930–938PubMedCrossRefGoogle Scholar
  182. 182.
    Zon LI, Yamaguchi Y, Yee K, Albee EA, Kimura A, Bennett JC, Orkin SH, Ackerman SJ (1993) Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: potential role in gene transcription. Blood 81(12):3234–3241PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Pediatric Hematology-OncologyBoston Children’s Hospital/Dana-Farber Cancer Institute, Harvard Medical SchoolBostonUSA
  2. 2.Harvard Stem Cell InstituteCambridgeUSA

Personalised recommendations