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Transcriptional Regulation of Haematopoietic Stem Cells

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Transcriptional and Translational Regulation of Stem Cells

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 786))

Abstract

Haematopoietic stem cells (HSCs) are a rare cell population found in the bone marrow of adult mammals and are responsible for maintaining the entire haematopoietic system. Definitive HSCs are produced from mesoderm during embryonic development, from embryonic day 10 in the mouse. HSCs seed the foetal liver before migrating to the bone marrow around the time of birth. In the adult, HSCs are largely quiescent but have the ability to divide to self-renew and expand, or to proliferate and differentiate into any mature haematopoietic cell type. Both the specification of HSCs during development and their cellular choices once formed are tightly controlled at the level of transcription. Numerous transcriptional regulators of HSC specification, expansion, homeostasis and differentiation have been identified, primarily from analysis of mouse gene knockout experiments and transplantation assays. These include transcription factors, epigenetic modifiers and signalling pathway effectors. This chapter reviews the current knowledge of these HSC transcriptional regulators, predominantly focusing on the transcriptional regulation of mouse HSCs, although transcriptional regulation of human HSCs is also mentioned where relevant. Due to the breadth and maturity of this field, we have prioritised recently identified examples of HSC transcriptional regulators. We go on to highlight additional layers of control that regulate expression and activity of HSC transcriptional regulators and discuss how chromosomal translocations that result in fusion proteins of these HSC transcriptional regulators commonly drive leukaemias through transcriptional dysregulation.

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References

  1. Krause DS, Theise ND, Collector MI, Henegariu O et al (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105(3):369–377

    PubMed  CAS  Google Scholar 

  2. Keller G (2005) Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev 19(10):1129–1155

    PubMed  CAS  Google Scholar 

  3. Medvinsky A, Rybtsov S, Taoudi S (2011) Embryonic origin of the adult hematopoietic system: advances and questions. Development 138(6):1017–1031

    PubMed  CAS  Google Scholar 

  4. Silver L, Palis J (1997) Initiation of murine embryonic erythropoiesis: a spatial analysis. Blood 89(4):1154–1164

    PubMed  CAS  Google Scholar 

  5. Medvinsky AL, Samoylina NL, Muller AM, Dzierzak EA (1993) An early pre-liver intraembryonic source of CFU-S in the developing mouse. Nature 364(6432):64–67

    PubMed  CAS  Google Scholar 

  6. Muller AM, Medvinsky A, Strouboulis J, Grosveld F et al (1994) Development of hematopoietic stem cell activity in the mouse embryo. Immunity 1(4):291–301

    PubMed  CAS  Google Scholar 

  7. Medvinsky A, Dzierzak E (1996) Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86(6):897–906

    PubMed  CAS  Google Scholar 

  8. Lancrin C, Sroczynska P, Stephenson C, Allen T et al (2009) The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature 457(7231):892–895

    PubMed  CAS  Google Scholar 

  9. Kataoka H, Hayashi M, Nakagawa R, Tanaka Y et al (2011) Etv2/ER71 induces vascular mesoderm from Flk1 + PDGFR{alpha} + primitive mesoderm. Blood 118:6975–6986

    PubMed  CAS  Google Scholar 

  10. Lee D, Park C, Lee H, Lugus JJ et al (2008) ER71 acts downstream of BMP, notch, and Wnt signaling in blood and vessel progenitor specification. Cell Stem Cell 2(5):497–507

    PubMed  CAS  Google Scholar 

  11. Liu F, Kang I, Park C, Chang LW et al (2012) ER71 specifies Flk-1+ hemangiogenic mesoderm by inhibiting cardiac mesoderm and Wnt signaling. Blood 119(14):3295–3305

    PubMed  CAS  Google Scholar 

  12. Kallianpur AR, Jordan JE, Brandt SJ (1994) The SCL/TAL-1 gene is expressed in progenitors of both the hematopoietic and vascular systems during embryogenesis. Blood 83(5):1200–1208

    PubMed  CAS  Google Scholar 

  13. Gottgens B, Broccardo C, Sanchez MJ, Deveaux S et al (2004) The scl +18/19 stem cell enhancer is not required for hematopoiesis: identification of a 5 bifunctional hematopoietic-endothelial enhancer bound by Fli-1 and Elf-1. Mol Cell Biol 24(5):1870–1883

    PubMed  Google Scholar 

  14. Gottgens B, Nastos A, Kinston S, Piltz S et al (2002) Establishing the transcriptional programme for blood: the SCL stem cell enhancer is regulated by a multiprotein complex containing Ets and GATA factors. EMBO J 21(12):3039–3050

    PubMed  CAS  Google Scholar 

  15. Ogilvy S, Ferreira R, Piltz SG, Bowen JM et al (2007) The SCL +40 enhancer targets the midbrain together with primitive and definitive hematopoiesis and is regulated by SCL and GATA proteins. Mol Cell Biol 27(20):7206–7219

    PubMed  CAS  Google Scholar 

  16. Delabesse E, Ogilvy S, Chapman MA, Piltz SG et al (2005) Transcriptional regulation of the SCL locus: identification of an enhancer that targets the primitive erythroid lineage in vivo. Mol Cell Biol 25(12):5215–5225

    PubMed  CAS  Google Scholar 

  17. Okuda T, van Deursen J, Hiebert SW, Grosveld G et al (1996) AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84(2):321–330

    PubMed  CAS  Google Scholar 

  18. Wang Q, Stacy T, Miller JD, Lewis AF et al (1996) The CBF subunit is essential for CBF2 (AML1) function in vivo. Cell 87(4):697–708

    PubMed  CAS  Google Scholar 

  19. Sasaki K, Yagi H, Bronson RT, Tominaga K et al (1996) Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta. Proc Natl Acad Sci U S A 93(22):12359–12363

    PubMed  CAS  Google Scholar 

  20. Chen MJ, Yokomizo T, Zeigler BM, Dzierzak E et al (2009) Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457(7231):887–891

    PubMed  CAS  Google Scholar 

  21. Nottingham WT, Jarratt A, Burgess M, Speck CL et al (2007) Runx1-mediated hematopoietic stem-cell emergence is controlled by a gata/Ets/SCL-regulated enhancer. Blood 110(13):4188–4197

    PubMed  CAS  Google Scholar 

  22. Ernst P, Fisher JK, Avery W, Wade S et al (2004) Definitive hematopoiesis requires the mixed-lineage leukemia gene. Dev Cell 6(3):437–443

    PubMed  CAS  Google Scholar 

  23. McMahon KA, Hiew SYL, Hadjur S, Veiga-Fernandes H et al (2007) Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal. Cell Stem Cell 1(3):338–345

    PubMed  CAS  Google Scholar 

  24. Schuettengruber B, Martinez AM, Iovino N, Cavalli G (2011) Trithorax group proteins: switching genes on and keeping them active. Nat Rev Mol Cell Biol 12(12):799–814

    PubMed  CAS  Google Scholar 

  25. Bertani S, Sauer S, Bolotin E, Sauer F (2011) The noncoding RNA mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin. Mol Cell 43(6):1040–1046

    PubMed  CAS  Google Scholar 

  26. Kim J, Guermah M, Roeder RG (2010) The human PAF1 complex acts in chromatin transcription elongation both independently and cooperatively with SII/TFIIS. Cell 140(4):491–503

    PubMed  CAS  Google Scholar 

  27. Ito T, Arimitsu N, Takeuchi M, Kawamura N et al (2006) Transcription elongation factor S-II is required for definitive hematopoiesis. Mol Cell Biol 26(8):3194–3203

    PubMed  CAS  Google Scholar 

  28. Huang G, Zhao X, Wang L, Elf S et al (2011) The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations. Blood 118(25):6544–6552

    PubMed  CAS  Google Scholar 

  29. Minegishi N, Ohta J, Yamagiwa H, Suzuki N et al (1999) The mouse GATA-2 gene is expressed in the para-aortic splanchnopleura and aorta-gonads and mesonephros region. Blood 93(12):4196–4207

    PubMed  CAS  Google Scholar 

  30. Minegishi N, Suzuki N, Yokomizo T, Pan X et al (2003) Expression and domain-specific function of GATA-2 during differentiation of the hematopoietic precursor cells in midgestation mouse embryos. Blood 102(3):896–905

    PubMed  CAS  Google Scholar 

  31. Pimanda JE, Ottersbach K, Knezevic K, Kinston S et al (2007) Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hemat­opoietic development. Proc Natl Acad Sci U S A 104(45):17692–17697

    PubMed  CAS  Google Scholar 

  32. Kobayashi-Osaki M, Ohneda O, Suzuki N, Minegishi N et al (2005) GATA motifs regulate early hematopoietic lineage-specific expression of the Gata2 gene. Mol Cell Biol 25(16):7005–7020

    PubMed  CAS  Google Scholar 

  33. Wilson NK, Foster SD, Wang X, Knezevic K et al (2010) Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. Cell Stem Cell 7(4):532–544

    PubMed  CAS  Google Scholar 

  34. Taoudi S, Bee T, Hilton A, Knezevic K et al (2011) ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification. Genes Dev 25(3):251–262

    PubMed  CAS  Google Scholar 

  35. Pajcini KV, Speck NA, Pear WS (2011) Notch signaling in mammalian hematopoietic stem cells. Leukemia 25(10):1525–1532

    PubMed  CAS  Google Scholar 

  36. Kumano K, Chiba S, Kunisato A, Sata M et al (2003) Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity 18(5):699–711

    PubMed  CAS  Google Scholar 

  37. Hadland BK, Huppert SS, Kanungo J, Xue Y et al (2004) A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development. Blood 104(10):3097–3105

    PubMed  CAS  Google Scholar 

  38. Burns CE, Traver D, Mayhall E, Shepard JL et al (2005) Hematopoietic stem cell fate is established by the notch-runx pathway. Genes Dev 19(19):2331–2342

    PubMed  CAS  Google Scholar 

  39. Nakagawa M, Ichikawa M, Kumano K, Goyama S et al (2006) AML1/Runx1 rescues Notch1-null mutation-induced deficiency of para-aortic splanchnopleural hematopoiesis. Blood 108(10):3329–3334

    PubMed  CAS  Google Scholar 

  40. Azcoitia V, Aracil M, Martínez-A C, Torres M (2005) The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev Biol 280(2):307–320

    PubMed  CAS  Google Scholar 

  41. Hisa T, Spence SE, Rachel RA, Fujita M et al (2004) Hematopoietic, angiogenic and eye defects in Meis1 mutant animals. EMBO J 23(2):450–459

    PubMed  CAS  Google Scholar 

  42. Iacovino M, Chong D, Szatmari I, Hartweck L et al (2011) HoxA3 is an apical regulator of haemogenic endothelium. Nat Cell Biol 13(1):72–U165

    PubMed  CAS  Google Scholar 

  43. Dzierzak E, Speck NA (2008) Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol 9(2):129–136

    PubMed  CAS  Google Scholar 

  44. Kumaravelu P, Hook L, Morrison AM, Ure J et al (2002) Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the ­aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver. Development 129(21):4891–4899

    PubMed  CAS  Google Scholar 

  45. Kim I, Saunders TL, Morrison SJ (2007) Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130(3):470–483

    PubMed  CAS  Google Scholar 

  46. Wilson A, Laurenti E, Oser G, van der Wath RC et al (2008) Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135(6):1118–1129

    PubMed  CAS  Google Scholar 

  47. van der Wath RC, Wilson A, Laurenti E, Trumpp A et al (2009) Estimating dormant and active hematopoietic stem cell kinetics through extensive modeling of bromodeoxyuridine label-retaining cell dynamics. PLoS One 4(9):e6972

    PubMed  Google Scholar 

  48. Morrison SJ, Kimble J (2006) Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441(7097):1068–1074

    PubMed  CAS  Google Scholar 

  49. Mansson R, Zandi S, Bryder D, Sigvardsson M (2009) The road to commitment: lineage restriction events in hematopoiesis. In: Wickrema A, Kee B (eds) Molecular basis of hematopoiesis. Springer, New York, pp 23–46

    Google Scholar 

  50. Stoffel R, Ziegler S, Ghilardi N, Ledermann B et al (1999) Permissive role of thrombopoietin and granulocyte colony-stimulating factor receptors in hematopoietic cell fate decisions in vivo. Proc Natl Acad Sci U S A 96(2):698–702

    PubMed  CAS  Google Scholar 

  51. Rieger MA, Hoppe PS, Smejkal BM, Eitelhuber AC et al (2009) Hematopoietic cytokines can instruct lineage choice. Science 325(5937):217–218

    PubMed  CAS  Google Scholar 

  52. Pimanda JE, Gottgens B (2010) Gene regulatory networks governing haematopoietic stem cell development and identity. Int J Dev Biol 54(6–7):1201–1211

    PubMed  CAS  Google Scholar 

  53. Novershtern N, Subramanian A, Lawton LN, Mak RH et al (2011) Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 144(2):296–309

    PubMed  CAS  Google Scholar 

  54. Lacombe J, Herblot S, Rojas-Sutterlin S, Haman A et al (2010) Scl regulates the quiescence and the long-term competence of hematopoietic stem cells. Blood 115(4):792–803

    PubMed  CAS  Google Scholar 

  55. Capron C, Lécluse Y, Kaushik AL, Foudi A et al (2006) The SCL relative LYL-1 is required for fetal and adult hematopoietic stem cell function and B-cell differentiation. Blood 107(12):4678–4686

    PubMed  CAS  Google Scholar 

  56. Souroullas GP, Salmon JM, Sablitzky F, Curtis DJ et al (2009) Adult hematopoietic stem and progenitor cells require either Lyl1 or Scl for survival. Cell Stem Cell 4(2):180–186

    PubMed  CAS  Google Scholar 

  57. Li L, Jothi R, Cui K, Lee JY et al (2011) Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells. Nat Immunol 12(2):129–136

    PubMed  CAS  Google Scholar 

  58. Yamada Y, Warren AJ, Dobson C, Forster A et al (1998) The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis. Proc Natl Acad Sci U S A 95(7):3890–3895

    PubMed  CAS  Google Scholar 

  59. Soler E, Andrieu-Soler C, de Boer E, Bryne JC et al (2010) The genome-wide dynamics of the binding of Ldb1 complexes during erythroid differentiation. Genes Dev 24(3):277–289

    PubMed  CAS  Google Scholar 

  60. Goardon N, Lambert JA, Rodriguez P, Nissaire P et al (2006) ETO2 coordinates cellular proliferation and differentiation during erythropoiesis. EMBO J 25(2):357–366

    PubMed  CAS  Google Scholar 

  61. Fujiwara T, Lee HY, Sanalkumar R, Bresnick EH (2010) Building multifunctionality into a complex containing master regulators of hematopoiesis. Proc Natl Acad Sci U S A 107(47):20429–20434

    PubMed  CAS  Google Scholar 

  62. Song SH, Hou CH, Dean A (2007) A positive role for NLI/Ldb1 in long-range beta-globin locus control region function. Mol Cell 28(5):810–822

    PubMed  CAS  Google Scholar 

  63. Semerad CL, Mercer EM, Inlay MA, Weissman IL et al (2009) E2A proteins maintain the hematopoietic stem cell pool and promote the maturation of myelolymphoid and myeloerythroid progenitors. Proc Natl Acad Sci U S A 106(6):1930–1935

    PubMed  CAS  Google Scholar 

  64. Yang Q, Kardava L, St. Leger A, Martincic K et al (2008) E47 controls the developmental integrity and cell cycle quiescence of multipotential hematopoietic progenitors. J Immunol 181(9):5885–5894

    PubMed  CAS  Google Scholar 

  65. Jankovic V, Ciarrocchi A, Boccuni P, DeBlasio T et al (2007) Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cells. Proc Natl Acad Sci U S A 104(4):1260–1265

    PubMed  CAS  Google Scholar 

  66. Perry SS, Zhao Y, Nie L, Cochrane SW et al (2007) Id1, but not Id3, directs long-term repopulating hematopoietic stem-cell maintenance. Blood 110(7):2351–2360

    PubMed  CAS  Google Scholar 

  67. Ji M, Li H, Suh HC, Klarmann KD et al (2008) Id2 intrinsically regulates lymphoid and erythroid development via interaction with different target proteins. Blood 112(4):1068–1077

    PubMed  CAS  Google Scholar 

  68. Deed RW, Jasiok M, Norton JD (1998) Lymphoid-specific expression of the Id3 gene in hematopoietic cells—selective antagonism of E2A basic helix-loop-helix protein associated with Id3-induced differentiation of erythroleukemia cells. J Biol Chem 273(14):8278–8286

    PubMed  CAS  Google Scholar 

  69. Miyazaki M, Rivera RR, Miyazaki K, Lin YC et al (2011) The opposing roles of the transcription factor E2A and its antagonist Id3 that orchestrate and enforce the naive fate of T cells. Nat Immunol 12(10):992–103

    PubMed  CAS  Google Scholar 

  70. Wilson A, Murphy MJ, Oskarsson T, Kaloulis K et al (2004) c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev 18(22):2747–2763

    PubMed  CAS  Google Scholar 

  71. Laurenti E, Varnum-Finney B, Wilson A, Ferrero I et al (2008) Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity. Cell Stem Cell 3(6):611–624

    PubMed  CAS  Google Scholar 

  72. Baena E, Ortiz M, Martínez-A C, de Alborán IM (2007) c-Myc is essential for hematopoietic stem cell differentiation and regulates Lin(−)Sca-1(+)c-Kit(−) cell generation through p21. Exp Hematol 35(9):1333–1343

    PubMed  CAS  Google Scholar 

  73. Pearson JC, Lemons D, McGinnis W (2005) Modulating Hox gene functions during animal body patterning. Nat Rev Genet 6(12):893–904

    PubMed  CAS  Google Scholar 

  74. Moens CB, Selleri L (2006) Hox cofactors in vertebrate development. Dev Biol 291(2):193–206

    PubMed  CAS  Google Scholar 

  75. Argiropoulos B, Humphries RK (2007) Hox genes in hematopoiesis and leukemogenesis. Oncogene 26(47):6766–6776

    PubMed  CAS  Google Scholar 

  76. Thorsteinsdottir U, Mamo A, Kroon E, Jerome L et al (2002) Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Blood 99(1):121–129

    PubMed  CAS  Google Scholar 

  77. Magnusson M, Brun ACM, Miyake N, Larsson J et al (2007) HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development. Blood 109(9):3687–3696

    PubMed  CAS  Google Scholar 

  78. Antonchuk J, Sauvageau G, Humphries RK (2002) HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell 109(1):39–45

    PubMed  CAS  Google Scholar 

  79. Auvray C, Delahaye A, Pflumio F, Haddad R et al (2012) HOXC4 homeoprotein efficiently expands human hematopoietic stem cells and triggers similar molecular alterations as HOXB4. Haematologica 97(2):168–178

    PubMed  CAS  Google Scholar 

  80. Fischbach NA, Rozenfeld S, Shen W, Fong S et al (2005) HOXB6 overexpression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo. Blood 105(4):1456–1466

    PubMed  CAS  Google Scholar 

  81. Bjornsson JM, Larsson N, Brun ACM, Magnusson M et al (2003) Reduced proliferative capacity of hematopoietic stem cells deficient in Hoxb3 and Hoxb4. Mol Cell Biol 23(11):3872–3883

    PubMed  CAS  Google Scholar 

  82. Lawrence HJ, Christensen J, Fong S, Hu YL et al (2005) Loss of expression of the hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells. Blood 106(12):3988–3994

    PubMed  CAS  Google Scholar 

  83. Magnusson M, Brun ACM, Lawrence HJ, Karlsson S (2007) Hoxa9/hoxb3/hoxb4 compound null mice display severe hematopoietic defects. Exp Hematol 35(9):1421–1428

    PubMed  CAS  Google Scholar 

  84. Chang CP, Jacobs Y, Nakamura T, Jenkins NA et al (1997) Meis proteins are major in vivo DNA binding partners for wild-type but not chimeric Pbx proteins. Mol Cell Biol 17(10):5679–5687

    PubMed  CAS  Google Scholar 

  85. Mann RS, Lelli KM, Joshi R (2009) Hox specificity: unique roles for cofactors and collaborators. Curr Top Dev Biol 88:63–101

    PubMed  CAS  Google Scholar 

  86. DiMartino JF (2001) The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver. Blood 98(3):618–626

    PubMed  CAS  Google Scholar 

  87. Ficara F, Murphy MJ, Lin M, Cleary ML (2008) Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence. Cell Stem Cell 2(5):484–496

    PubMed  CAS  Google Scholar 

  88. Loughran SJ, Kruse EA, Hacking DF, de Graaf CA et al (2008) The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells. Nat Immunol 9(7):810–819

    PubMed  CAS  Google Scholar 

  89. Ng AP, Loughran SJ, Metcalf D, Hyland CD et al (2011) Erg is required for self-renewal of hematopoietic stem cells during stress hematopoiesis in mice. Blood 118(9):2454–2461

    PubMed  CAS  Google Scholar 

  90. Kruse EA, Loughran SJ, Baldwin TM, Josefsson EC et al (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

    PubMed  CAS  Google Scholar 

  91. Yu S, Cui K, Jothi R, Zhao D-M et al (2011) GABP controls a critical transcription regulatory module that is essential for maintenance and differentiation of hematopoietic stem/progenitor cells. Blood 117(7):2166–2178

    PubMed  CAS  Google Scholar 

  92. Iwasaki H, Somoza C, Shigematsu H, Duprez EA et al (2005) Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 106(5):1590–1600

    PubMed  CAS  Google Scholar 

  93. Hock H, Meade E, Medeiros S, Schindler JW et al (2004) Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes Dev 18(19):2336–2341

    PubMed  CAS  Google Scholar 

  94. Lacorazza HD, Yamada T, Liu Y, Miyata Y et al (2006) The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells. Cancer Cell 9(3):175–187

    PubMed  CAS  Google Scholar 

  95. Wang LC, Swat W, Fujiwara Y, Davidson L et al (1998) The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow. Genes Dev 12(15):2392–2402

    PubMed  CAS  Google Scholar 

  96. Ristevski S, O’Leary DA, Thornell AP, Owen MJ et al (2004) The ETS transcription factor GABPalpha is essential for early embryogenesis. Mol Cell Biol 24(13):5844–5849

    PubMed  CAS  Google Scholar 

  97. Alder JK, Georgantas RW, Yu X, Civin CI (2004) KLF4 as a mediator of quiescence in hematopo­ietic stem/progenitor cells. Blood 104(11, Part 2):123B–123B

    Google Scholar 

  98. Yang J, Aguila JR, Alipio Z, Lai R et al (2011) Enhanced self-renewal of hematopoietic stem/progenitor cells mediated by the stem cell gene Sall4. J Hematol Oncol 4(1):38–38

    PubMed  CAS  Google Scholar 

  99. Aguila JR, Liao W, Yang J, Avila C et al (2011) SALL4 is a robust stimulator for the expansion of hematopoietic stem cells. Blood 118(3):576–585

    PubMed  CAS  Google Scholar 

  100. Galan-Caridad JM, Harel S, Arenzana TL, Hou ZE et al (2007) Zfx controls the self-renewal of embryonic and hematopoietic stem cells. Cell 129(2):345–357

    PubMed  CAS  Google Scholar 

  101. Ku CJ, Hosoya T, Maillard I, Engel JD (2012) GATA-3 regulates hematopoietic stem cell maintenance and cell cycle entry. Blood 119(10):2242–2251

    PubMed  CAS  Google Scholar 

  102. Rodrigues NP, Tipping AJ, Wang Z, Enver T (2012) GATA-2 mediated regulation of normal hematopoietic stem/progenitor cell function, myelodysplasia and myeloid leukemia. Int J Biochem Cell Biol 44(3):457–460

    PubMed  CAS  Google Scholar 

  103. Zeng H, Yücel R, Kosan C, Klein-Hitpass L et al (2004) Transcription factor Gfi1 regulates ­self-renewal and engraftment of hematopoietic stem cells. EMBO J 23(20):4116–4125

    PubMed  CAS  Google Scholar 

  104. Hock H, Hamblen MJ, Rooke HM, Schindler JW et al (2004) Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431(7011):1002–1007

    PubMed  CAS  Google Scholar 

  105. Khandanpour C, Sharif-Askari E, Vassen L, Gaudreau M-C et al (2010) Evidence that growth factor independence 1b regulates dormancy and peripheral blood mobilization of hematopoietic stem cells. Blood 116(24):5149–5161

    PubMed  CAS  Google Scholar 

  106. Ng SY-M, Yoshida T, Zhang J, Georgopoulos K (2009) Genome-wide lineage-specific transcriptional networks underscore ikaros-dependent lymphoid priming in hematopoietic stem cells. Immunity 30(4):493–507

    PubMed  CAS  Google Scholar 

  107. Goyama S, Yamamoto G, Shimabe M, Sato T et al (2008) Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. Cell Stem Cell 3(2):207–220

    PubMed  CAS  Google Scholar 

  108. Zhang Y, Stehling-Sun S, Lezon-Geyda K, Juneja SC et al (2011) PR-domain-containing Mds1-Evi1 is critical for long-term hematopoietic stem cell function. Blood 118(14):3853–3861

    PubMed  CAS  Google Scholar 

  109. Jiang J, Chan YS, Loh YH, Cai J et al (2008) A core Klf circuitry regulates self-renewal of embryonic stem cells. Nat Cell Biol 10(3):353–360

    PubMed  Google Scholar 

  110. Zhang J, Tam WL, Tong GQ, Wu Q et al (2006) Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 8(10):1114–1123

    PubMed  CAS  Google Scholar 

  111. Ling K-W, Ottersbach K, van Hamburg JP, Oziemlak A et al (2004) GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells. J Exp Med 200(7):871–882

    PubMed  CAS  Google Scholar 

  112. Tipping AJ, Pina C, Castor A, Hong D et al (2009) High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. Blood 113(12):2661–2672

    PubMed  CAS  Google Scholar 

  113. John LB, Ward AC (2011) The ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol 48(9–10):1272–1278

    PubMed  CAS  Google Scholar 

  114. Klug CA (1998) Hematopoietic stem cells and lymphoid progenitors express different ikaros isoforms, and ikaros is localized to heterochromatin in immature lymphocytes. Proc Natl Acad Sci 95(2):657–662

    PubMed  CAS  Google Scholar 

  115. Nichogiannopoulou A (1999) Defects in hemopoietic stem cell activity in ikaros mutant mice. J Exp Med 190(9):1201–1214

    PubMed  CAS  Google Scholar 

  116. Kumano K, Kurokawa M (2010) The role of Runx1/AML1 and Evi-1 in the regulation of hematopoietic stem cells. J Cell Physiol 222(2):282–285

    PubMed  CAS  Google Scholar 

  117. Kataoka K, Sato T, Yoshimi A, Goyama S et al (2011) Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks ­hematopoietic cells with long-term multilineage repopulating activity. J Exp Med 208(12):2403–2416, jem.20110447-jem.20110447-

    PubMed  CAS  Google Scholar 

  118. Aguilo F, Avagyan S, Labar A, Sevilla A et al (2011) Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood 117(19):5057–5066

    PubMed  CAS  Google Scholar 

  119. Deneault E, Cellot S, Faubert A, Laverdure JP et al (2009) A functional screen to identify novel effectors of hematopoietic stem cell activity. Cell 137(2):369–379

    PubMed  CAS  Google Scholar 

  120. Chuikov S, Levi BP, Smith ML, Morrison SJ (2010) Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol 12(10):999–1006

    PubMed  CAS  Google Scholar 

  121. Lieu YK, Reddy EP (2009) Conditional c-myb knockout in adult hematopoietic stem cells leads to loss of self-renewal due to impaired proliferation and accelerated differentiation. Proc Natl Acad Sci U S A 106(51):21689–21694

    PubMed  CAS  Google Scholar 

  122. Sandberg ML, Sutton SE, Pletcher MT, Wiltshire T et al (2005) c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation. Dev Cell 8(2):153–166

    PubMed  CAS  Google Scholar 

  123. Kobayashi M, Srour EF (2011) Regulation of murine hematopoietic stem cell quiescence by Dmtf1. Blood 118(25):6562–6571

    PubMed  CAS  Google Scholar 

  124. Growney JD, Shigematsu H, Li Z, Lee BH et al (2005) Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood 106(2):494–504

    PubMed  CAS  Google Scholar 

  125. Ichikawa M, Asai T, Saito T, Seo S et al (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):299–304

    PubMed  CAS  Google Scholar 

  126. Ichikawa M, Goyama S, Asai T, Kawazu M et al (2008) AML1/Runx1 negatively regulates quiescent hematopoietic stem cells in adult hematopoiesis. J Immunol 180(7):4402–4408

    PubMed  CAS  Google Scholar 

  127. Motoda L, Osato M, Yamashita N, Jacob B et al (2007) Runx1 protects hematopoietic stem/progenitor cells from oncogenic insult. Stem Cells 25(12):2976–2986

    PubMed  CAS  Google Scholar 

  128. Jacob B, Osato M, Yamashita N, Wang CQ et al (2010) Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis. Blood 115(8):1610–1620

    PubMed  CAS  Google Scholar 

  129. Cai X, Gaudet JJ, Mangan JK, Chen MJ et al (2011) Runx1 loss minimally impacts long-term hematopoietic stem cells. PLoS One 6(12):e28430–e28430

    PubMed  CAS  Google Scholar 

  130. Tsuzuki S, Hong DL, Gupta R, Matsuo K et al (2007) Isoform-specific potentiation of stem and progenitor cell engraftment by AML1/RUNX1. PLoS Med 4(5):880–896

    CAS  Google Scholar 

  131. Challen GA, Goodell MA (2010) Runx1 isoforms show differential expression patterns during hematopoietic development but have similar functional effects in adult hematopoietic stem cells. Exp Hematol 38(5):403–416

    PubMed  CAS  Google Scholar 

  132. Tsuzuki S, Seto M (2012) Expansion of functionally defined mouse hematopoietic stem and progenitor cells by a short isoform of RUNX1/AML1. Blood 119(3):727–735

    PubMed  CAS  Google Scholar 

  133. Talebian L, Li Z, Guo YL, Gaudet J et al (2007) T-lymphoid, megakaryocyte, and granulocyte development are sensitive to decreases in CBF beta dosage. Blood 109(1):11–21

    PubMed  CAS  Google Scholar 

  134. Miller J, Horner A, Stacy T, Lowrey C et al (2002) The core-binding factor beta subunit is required for bone formation and hematopoietic maturation. Nat Genet 32(4):645–649

    PubMed  CAS  Google Scholar 

  135. Link KA, Chou FS, Mulloy JC (2010) Core binding factor at the crossroads: determining the fate of the HSC. J Cell Physiol 222(1):50–56

    PubMed  CAS  Google Scholar 

  136. Deguchi K, Yagi H, Inada M, Yoshizaki K et al (1999) Excessive extramedullary hematopoiesis in Cbfa1-deficient mice with a congenital lack of bone marrow. Biochem Biophys Res Commun 255(2):352–359

    PubMed  CAS  Google Scholar 

  137. Komori T, Yagi H, Nomura S, Yamaguchi A et al (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89(5):755–764

    PubMed  CAS  Google Scholar 

  138. Viatour P, Somervaille TC, Venkatasubrahmanyam S, Kogan S et al (2008) Hematopoietic stem cell quiescence is maintained by compound contributions of the retinoblastoma gene family. Cell Stem Cell 3(4):416–428

    PubMed  CAS  Google Scholar 

  139. Asai T, Liu Y, Bae N, Nimer SD (2011) The p53 tumor suppressor protein regulates hematopoietic stem cell fate. J Cell Physiol 226(9):2215–2221

    PubMed  CAS  Google Scholar 

  140. Liu Y, Elf SE, Asai T, Miyata Y et al (2009) The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior. Cell Cycle 8(19):3120–3124

    PubMed  CAS  Google Scholar 

  141. Liu Y, Elf SE, Miyata Y, Sashida G et al (2009) p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell 4(1):37–48

    PubMed  CAS  Google Scholar 

  142. Walkley CR, Shea JM, Sims NA, Purton LE et al (2007) Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 129(6):1081–1095

    PubMed  CAS  Google Scholar 

  143. Kubota Y, Osawa M, Jakt LM, Yoshikawa K et al (2009) Necdin restricts proliferation of hematopoietic stem cells during hematopoietic regeneration. Blood 114(20):4383–4392

    PubMed  CAS  Google Scholar 

  144. Mantovani R (1999) The molecular biology of the CCAAT-binding factor NF-Y. Gene 239(1):15–27

    PubMed  CAS  Google Scholar 

  145. Bhattacharya A, Deng JM, Zhang Z, Behringer R et al (2003) The B subunit of the CCAAT box binding transcription factor complex (CBF/NF-Y) is essential for early mouse development and cell proliferation. Cancer Res 63(23):8167–8172

    PubMed  CAS  Google Scholar 

  146. Zhu J, Zhang Y, Joe GJ, Pompetti R et al (2005) NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal. Proc Natl Acad Sci U S A 102(33):11728–11733

    PubMed  CAS  Google Scholar 

  147. Bungartz G, Land H, Scadden DT, Emerson SG (2012) NF-Y is necessary for hematopoietic stem cell proliferation and survival. Blood 119(6):1380–1389

    PubMed  CAS  Google Scholar 

  148. Santaguida M, Schepers K, King B, Sabnis AJ et al (2009) JunB protects against myeloid malignancies by limiting hematopoietic stem cell proliferation and differentiation without affecting self-renewal. Cancer Cell 15(4):341–352

    PubMed  CAS  Google Scholar 

  149. Verrecchia F, Tacheau C, Schorpp-Kistner M, Angel P et al (2001) Induction of the AP-1 members c-Jun and JunB by TGF-beta/smad suppresses early smad-driven gene activation. Oncogene 20(18):2205–2211

    PubMed  CAS  Google Scholar 

  150. Min IM, Pietramaggiori G, Kim FS, Passegué E et al (2008) The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. Cell Stem Cell 2(4):380–391

    PubMed  CAS  Google Scholar 

  151. Rebel VI, Kung AL, Tanner EA, Yang H et al (2002) Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal. Proc Natl Acad Sci U S A 99(23):14789–14794

    PubMed  CAS  Google Scholar 

  152. Katsumoto T, Aikawa Y, Iwama A, Ueda S et al (2006) MOZ is essential for maintenance of hematopoietic stem cells. Genes Dev 20(10):1321–1330

    PubMed  CAS  Google Scholar 

  153. Chan WI, Hannah RL, Dawson MA, Pridans C et al (2011) The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells. Mol Cell Biol 31(24):5046–5060

    PubMed  CAS  Google Scholar 

  154. Nguyen AT, He J, Taranova O, Zhang Y (2011) Essential role of DOT1L in maintaining normal adult hematopoiesis. Cell Res 21(9):1370–1373

    PubMed  CAS  Google Scholar 

  155. Jo SY, Granowicz EM, Maillard I, Thomas D et al (2011) Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation. Blood 117(18):4759–4768

    PubMed  CAS  Google Scholar 

  156. Maillard I, Hess JL (2009) The role of menin in hematopoiesis. Adv Exp Med Biol 668:51–57

    PubMed  CAS  Google Scholar 

  157. Jude CD, Climer L, Xu D, Artinger E et al (2007) Unique and independent roles for MLL in adult hematopoietic stem cells and progenitors. Cell Stem Cell 1(3):324–337

    PubMed  CAS  Google Scholar 

  158. Gan T, Jude CD, Zaffuto K, Ernst P (2010) Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis. Leukemia 24(10):1732–1741

    PubMed  CAS  Google Scholar 

  159. Heuser M, Yap DB, Leung M, de Algara TR et al (2009) Loss of MLL5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation. Blood 113(7):1432–1443

    PubMed  CAS  Google Scholar 

  160. Madan V, Madan B, Brykczynska U, Zilbermann F et al (2009) Impaired function of primitive hema­topoietic cells in mice lacking the mixed-lineage-leukemia homolog MLL5. Blood 113(7):1444–1454

    PubMed  CAS  Google Scholar 

  161. Zhang Y, Wong J, Klinger M, Tran MT et al (2009) MLL5 contributes to hematopoietic stem cell fitness and homeostasis. Blood 113(7):1455–1463

    PubMed  CAS  Google Scholar 

  162. Konuma T, Oguro H, Iwama A (2010) Role of the polycomb group proteins in hematopoietic stem cells. Dev Growth Differ 52(6):505–516

    PubMed  CAS  Google Scholar 

  163. Majewski IJ, Ritchie ME, Phipson B, Corbin J et al (2010) Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood 116(5):731–739

    PubMed  CAS  Google Scholar 

  164. Iwama A, Oguro H, Negishi M, Kato Y et al (2005) Epigenetic regulation of hematopoietic stem cell self-renewal by polycomb group genes. Int J Hematol 81(4):294–300

    PubMed  CAS  Google Scholar 

  165. Lessard J, Schumacher A, Thorsteinsdottir U, van Lohuizen M et al (1999) Functional antagonism of the polycomb-group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev 13(20):2691–2703

    PubMed  CAS  Google Scholar 

  166. Majewski IJ, Blewitt ME, de Graaf CA, McManus EJ et al (2008) Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity. PLoS Biol 6(4):e93

    PubMed  Google Scholar 

  167. Su IH, Basavaraj A, Krutchinsky AN, Hobert O et al (2003) Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol 4(2):124–131

    PubMed  CAS  Google Scholar 

  168. Mochizuki-Kashio M, Mishima Y, Miyagi S, Negishi M et al (2011) Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood 118(25):6553–6561

    PubMed  CAS  Google Scholar 

  169. Calés C, Román-Trufero M, Pavón L, Serrano I et al (2008) Inactivation of the polycomb group protein Ring1B unveils an antiproliferative role in hematopoietic cell expansion and cooperation with tumorigenesis associated with Ink4a deletion. Mol Cell Biol 28(3):1018–1028

    PubMed  Google Scholar 

  170. Iwama A, Oguro H, Negishi M, Kato Y et al (2004) Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21(6):843–851

    PubMed  CAS  Google Scholar 

  171. Kim JY, Sawada A, Tokimasa S, Endo H et al (2004) Defective long-term repopulating ability in hematopoietic stem cells lacking the polycomb-group gene rae28. Eur J Haematol 73(2):75–84

    PubMed  CAS  Google Scholar 

  172. Lessard J, Sauvageau G (2003) Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423(6937):255–260

    PubMed  CAS  Google Scholar 

  173. Ohta H (2002) Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells. J Exp Med 195(6):759–770

    PubMed  CAS  Google Scholar 

  174. Rizo A, Dontje B, Vellenga E, de Haan G et al (2008) Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1. Blood 111(5):2621–2630

    PubMed  CAS  Google Scholar 

  175. Elderkin S, Maertens GN, Endoh M, Mallery DL et al (2007) A phosphorylated form of Mel-18 targets the Ring1B histone H2A ubiquitin ligase to chromatin. Mol Cell 28(1):107–120

    PubMed  CAS  Google Scholar 

  176. Kajiume T, Ninomiya Y, Ishihara H, Kanno R et al (2004) Polycomb group gene mel-18 modulates the self-renewal activity and cell cycle status of hematopoietic stem cells. Exp Hematol 32(6):571–578

    PubMed  CAS  Google Scholar 

  177. Smith L-L, Yeung J, Zeisig BB, Popov N et al (2011) Functional crosstalk between Bmi1 and MLL/Hoxa9 axis in establishment of normal hematopoietic and leukemic stem cells. Cell Stem Cell 8(6):649–662

    PubMed  CAS  Google Scholar 

  178. Challen GA, Sun D, Jeong M, Luo M et al (2011) Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44(1):23–31

    PubMed  Google Scholar 

  179. Tadokoro Y, Ema H, Okano M, Li E et al (2007) De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J Exp Med 204(4):715–722

    PubMed  CAS  Google Scholar 

  180. Trowbridge JJ, Snow JW, Kim J, Orkin SH (2009) DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell 5(4):442–449

    PubMed  CAS  Google Scholar 

  181. Ko M, Bandukwala HS, An J, Lamperti ED et al (2011) Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci 108(35):14566–14571

    PubMed  CAS  Google Scholar 

  182. Li Z, Cai X, Cai C, Wang J et al (2011) Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118(17):4509–4518

    PubMed  CAS  Google Scholar 

  183. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O et al (2011) Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20(1):11–24

    PubMed  CAS  Google Scholar 

  184. Yoshida T, Hazan I, Zhang J, Ng SY et al (2008) The role of the chromatin remodeler Mi-2beta in hematopoietic stem cell self-renewal and multilineage differentiation. Genes Dev 22(9):1174–1189

    PubMed  CAS  Google Scholar 

  185. Staal FJT, Clevers HC (2005) WNT signalling and haematopoiesis: a WNT-WNT situation. Nat Rev Immunol 5(1):21–30

    PubMed  CAS  Google Scholar 

  186. Staal FJT, Luis TC (2010) Wnt signaling in hematopoiesis: crucial factors for self-renewal, proliferation, and cell fate decisions. J Cell Biochem 109(5):844–849

    PubMed  CAS  Google Scholar 

  187. Blank U, Karlsson G, Karlsson S (2008) Signaling pathways governing stem-cell fate. Blood 111(2):492–503

    PubMed  CAS  Google Scholar 

  188. Blank U, Karlsson S (2011) The role of smad signaling in hematopoiesis and translational hematology. Leukemia 25(9):1379–1388

    PubMed  CAS  Google Scholar 

  189. Purton LE, Dworkin S, Olsen GH, Walkley CR et al (2006) RARgamma is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation. J Exp Med 203(5):1283–1293

    PubMed  CAS  Google Scholar 

  190. Kent D, Copley M, Benz C, Dykstra B et al (2008) Regulation of hematopoietic stem cells by the steel factor/KIT signaling pathway. Clin Cancer Res 14(7):1926–1930

    PubMed  CAS  Google Scholar 

  191. de Graaf CA, Metcalf D (2011) Thrombopoietin and hematopoietic stem cells. Cell Cycle 10(10):1582–1589

    PubMed  Google Scholar 

  192. Arai F, Hirao A, Ohmura M, Sato H et al (2004) Tie2/Angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118(2):149–161

    PubMed  CAS  Google Scholar 

  193. Tothova Z, Gilliland DG (2007) FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell 1(2):140–152

    PubMed  CAS  Google Scholar 

  194. Tothova Z, Kollipara R, Huntly BJ, Lee BH et al (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128(2):325–339

    PubMed  CAS  Google Scholar 

  195. Miyamoto K, Araki KY, Naka K, Arai F et al (2007) Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1(1):101–112

    PubMed  CAS  Google Scholar 

  196. Takubo K, Goda N, Yamada W, Iriuchishima H et al (2010) Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7(3):391–402

    PubMed  CAS  Google Scholar 

  197. Orkin SH, Zon LI (2008) Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132(4):631–644

    PubMed  CAS  Google Scholar 

  198. Kiritoa K, Kaushansky K (2006) Transcriptional regulation of megakaryopoiesis: thrombopoietin signaling and nuclear factors. Curr Opin Hematol 13(3):151–156

    Google Scholar 

  199. Dore LC, Crispino JD (2011) Transcription factor networks in erythroid cell and megakaryocyte development. Blood 118(2):231–239

    PubMed  CAS  Google Scholar 

  200. Goldfarb AN (2007) Transcriptional control of megakaryocyte development. Oncogene 26(47):6795–6802

    PubMed  CAS  Google Scholar 

  201. Kim SI, Bresnick EH (2007) Transcriptional control of erythropoiesis: emerging mechanisms and principles. Oncogene 26(47):6777–6794

    PubMed  CAS  Google Scholar 

  202. Dias S, Xu W, McGregor S, Kee B (2008) Transcriptional regulation of lymphocyte development. Curr Opin Genet Dev 18(5):441–448

    PubMed  CAS  Google Scholar 

  203. Friedman AD (2007) Transcriptional control of granulocyte and monocyte development. Oncogene 26(47):6816–6828

    PubMed  CAS  Google Scholar 

  204. Friedman AD, Keefer JR, Kummalue T, Liu HT et al (2003) Regulation of granulocyte and monocyte differentiation by CCAAT/enhancer binding protein alpha. Blood Cells Mol Dis 31(3):338–341

    PubMed  CAS  Google Scholar 

  205. Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML et al (2004) Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity 21(6):853–863

    PubMed  CAS  Google Scholar 

  206. Suh HC, Gooya J, Renn K, Friedman AD et al (2006) C/EBP alpha determines hematopoietic cell fate in multipotential progenitor cells by inhibiting erythroid differentiation and inducing myeloid differentiation. Blood 107(11):4308–4316

    PubMed  CAS  Google Scholar 

  207. Nemeth MJ, Kirby MR, Bodine DM (2006) Hmgb3 regulates the balance between hematopoietic stem cell self-renewal and differentiation. Proc Natl Acad Sci U S A 103(37):13783–13788

    PubMed  CAS  Google Scholar 

  208. Nemeth MJ, Cline AP, Anderson SM, Garrett-Beal LJ et al (2005) Hmgb3 deficiency deregulates proliferation and differentiation of common lymphoid and myeloid progenitors. Blood 105(2):627–634

    PubMed  CAS  Google Scholar 

  209. Bee T, Swiers G, Muroi S, Pozner A et al (2010) Nonredundant roles for Runx1 alternative promoters reflect their activity at discrete stages of developmental hematopoiesis. Blood 115(15):3042–3050

    PubMed  CAS  Google Scholar 

  210. Levanon D, Glusman C, Bangsow T, Ben-Asher E et al (2001) Architecture and anatomy of the genomic locus encoding the human leukemia-associated transcription factor RUNX1/AML1. Gene 262(1–2):23–33

    PubMed  CAS  Google Scholar 

  211. Ben-Ami O, Pencovich N, Lotem J, Levanon D et al (2009) A regulatory interplay between miR-27a and Runx1 during megakaryopoiesis. Proc Natl Acad Sci U S A 106(1):238–243

    PubMed  CAS  Google Scholar 

  212. Feng J, Iwama A, Satake M, Kohu K (2009) MicroRNA-27 enhances differentiation of myeloblasts into granulocytes by post-transcriptionally downregulating Runx1. Br J Haematol 145(3):412–423

    PubMed  CAS  Google Scholar 

  213. Pozner A, Goldenberg D, Negreanu V, Le SY et al (2000) Transcription-coupled translation control of AML1/RUNX1 is mediated by cap- and internal ribosome entry site-dependent mechanisms. Mol Cell Biol 20(7):2297–2307

    PubMed  CAS  Google Scholar 

  214. Pillai RS, Bhattacharyya SN, Artus CG, Zoller T et al (2005) Inhibition of translational initiation by Let-7 microRNA in human cells. Science 309(5740):1573–1576

    PubMed  CAS  Google Scholar 

  215. Humphreys DT, Westman BJ, Martin DIK, Preiss T (2005) MicroRNAs control translation initiation by inhibiting eukaryotic initiation factor 4E/cap and poly(a) tail function. Proc Natl Acad Sci U S A 102(47):16961–16966

    PubMed  CAS  Google Scholar 

  216. Biggs JR, Peterson LF, Zhang Y, Kraft AS et al (2006) AML1/RUNX1 phosphorylation by cyclin-dependent kinases regulates the degradation of AML1/RUNX1 by the anaphase-promoting complex. Mol Cell Biol 26(20):7420–7429

    PubMed  CAS  Google Scholar 

  217. Guo H, Friedman AD (2011) Phosphorylation of RUNX1 by cyclin-dependent kinase reduces direct interaction with HDAC1 and HDAC3. J Biol Chem 286(1):208–215

    PubMed  CAS  Google Scholar 

  218. 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

    PubMed  CAS  Google Scholar 

  219. Yamaguchi Y, Kurokawa M, Imai Y, Izutsu K et al (2004) AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues. J Biol Chem 279(15):15630–15638

    PubMed  CAS  Google Scholar 

  220. Yoshida H, Kitabayashi I (2008) Chromatin regulation by AML1 complex. Int J Hematol 87(1):19–24

    PubMed  CAS  Google Scholar 

  221. Zhao X, Jankovic V, Gural A, Huang G et al (2008) Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity. Genes Dev 22(5):640–653

    PubMed  CAS  Google Scholar 

  222. Chakraborty S, Sinha KK, Senyuk V, Nucifora G (2003) SUV39H1 interacts with AML1 and abrogates AML1 transactivity. AML1 is methylated in vivo. Oncogene 22(34):5229–5237

    PubMed  CAS  Google Scholar 

  223. Wang L, Gural A, Sun XJ, Zhao XY et al (2011) The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation. Science 333(6043):765–769

    PubMed  CAS  Google Scholar 

  224. Pimanda JE, Donaldson IJ, de Bruijn MF, Kinston S et al (2007) The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity. Proc Natl Acad Sci U S A 104(3):840–845

    PubMed  CAS  Google Scholar 

  225. Shen R, Chen M, Wang YJ, Kaneki H et al (2006) Smad6 interacts with Runx2 and mediates smad ubiquitin regulatory factor 1-induced Runx2 degradation. J Biol Chem 281(6):3569–3576

    PubMed  CAS  Google Scholar 

  226. Knezevic K, Bee T, Wilson NK, Janes ME et al (2011) A Runx1-Smad6 rheostat controls Runx1 activity during embryonic hematopoiesis. Mol Cell Biol 31(14):2817–2826

    PubMed  CAS  Google Scholar 

  227. Mitelman F, Johansson B, Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7(4):233–245

    PubMed  CAS  Google Scholar 

  228. Crans HN, Sakamoto KM (2001) Transcription factors and translocations in lymphoid and myeloid leukemia. Leukemia 15(3):313–331

    PubMed  CAS  Google Scholar 

  229. Hess JL (2004) MLL: a histone methyltransferase disrupted in leukemia. Trends Mol Med 10(10):500–507

    PubMed  CAS  Google Scholar 

  230. Marschalek R (2010) Mixed lineage leukemia: roles in human malignancies and potential therapy. FEBS J 277(8):1822–1831

    PubMed  CAS  Google Scholar 

  231. Meyer C, Kowarz E, Hofmann J, Renneville A et al (2009) New insights to the MLL recombinome of acute leukemias. Leukemia 23(8):1490–1499

    PubMed  CAS  Google Scholar 

  232. Thomas M, Gessner A, Vornlocher HP, Hadwiger P et al (2005) Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells. Blood 106(10):3559–3566

    PubMed  CAS  Google Scholar 

  233. Thiel AT, Blessington P, Zou T, Feather D et al (2010) MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell 17(2):148–159

    PubMed  CAS  Google Scholar 

  234. Yokoyama A, Somervaille TCP, Smith KS, Rozenblatt-Rosen O et al (2005) The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123(2):207–218

    PubMed  CAS  Google Scholar 

  235. Grembecka J, He S, Shi A, Purohit T et al (2012) Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat Chem Biol 8(3):277–284

    PubMed  CAS  Google Scholar 

  236. Tan JY, Jones M, Koseki H, Nakayama M et al (2011) CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell 20(5):563–575

    PubMed  CAS  Google Scholar 

  237. Yokoyama A, Lin M, Naresh A, Kitabayashi I et al (2010) A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell 17(2):198–212

    PubMed  CAS  Google Scholar 

  238. Biswas D, Milne TA, Basrur V, Kim J et al (2011) Function of leukemogenic mixed lineage leukemia 1 (MLL) fusion proteins through distinct partner protein complexes. Proc Natl Acad Sci U S A 108(38):15751–15756

    PubMed  CAS  Google Scholar 

  239. Okada Y, Feng Q, Lin YH, Jiang Q et al (2005) hDOT1L links histone methylation to leukemogenesis. Cell 121(2):167–178

    PubMed  CAS  Google Scholar 

  240. Milne TA, Kim J, Wang GG, Stadler SC et al (2010) Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. Mol Cell 38(6):853–863

    PubMed  CAS  Google Scholar 

  241. Jang MK, Mochizuki K, Zhou MS, Jeong HS et al (2005) The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell 19(4):523–534

    PubMed  CAS  Google Scholar 

  242. Krivtsov AV, Feng Z, Lemieux ME, Faber J et al (2008) H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 14(5):355–368

    PubMed  CAS  Google Scholar 

  243. Daigle SR, Olhava EJ, Therkelsen CA, Majer CR et al (2011) Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20(1):53–65

    PubMed  CAS  Google Scholar 

  244. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G et al (2011) Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478(7370):529–533

    PubMed  CAS  Google Scholar 

  245. Wang QF, Wu G, Mi SL, He FH et al (2011) MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome. Blood 117(25):6895–6905

    PubMed  CAS  Google Scholar 

  246. Orlovsky K, Kalinkovich A, Rozovskaia T, Shezen E et al (2011) Down-regulation of homeobox genes MEIS1 and HOXA in MLL-rearranged acute leukemia impairs engraftment and reduces proliferation. Proc Natl Acad Sci U S A 108(19):7956–7961

    PubMed  CAS  Google Scholar 

  247. Arai S, Yoshimi A, Shimabe M, Ichikawa M et al (2011) Evi-1 is a transcriptional target of mixed-lineage leukemia oncoproteins in hematopoietic stem cells. Blood 117(23):6304–6314

    PubMed  CAS  Google Scholar 

  248. Zeisig BB, Milne T, Garcia-Cuellar MP, Schreiner S et al (2004) Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Mol Cell Biol 24(2):617–628

    PubMed  CAS  Google Scholar 

  249. Zuber J, Rappaport AR, Luo WJ, Wang E et al (2011) An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance. Genes Dev 25(18):1628

    PubMed  CAS  Google Scholar 

  250. Bernt KM, Zhu N, Sinha AU, Vempati S et al (2011) MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20(1):66–78

    PubMed  CAS  Google Scholar 

  251. Puente XS, Pinyol M, Quesada V, Conde L et al (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475(7354):101–105

    PubMed  CAS  Google Scholar 

  252. Ding L, Ley TJ, Larson DE, Miller CA et al (2012) Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481(7382):506–510

    PubMed  CAS  Google Scholar 

  253. Amsellem S, Pflumio F, Bardinet D, Izac B et al (2003) Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein. Nat Med 9(11):1423–1427

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

    Adam C. Wilkinson & Berthold Göttgens

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  1. Adam C. Wilkinson
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  2. Berthold Göttgens
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Correspondence to Berthold Göttgens .

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  1. , Anatomy and Neuroscience, University of Melbourne, VIC Grattan Street, Parkville, 3010, Victoria, Australia

    Gary Hime

  2. , Anatomy and Developmental Biology, Monash University, Monash University, Clayton, 3800, Victoria, Australia

    Helen Abud

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Wilkinson, A.C., Göttgens, B. (2013). Transcriptional Regulation of Haematopoietic Stem Cells. In: Hime, G., Abud, H. (eds) Transcriptional and Translational Regulation of Stem Cells. Advances in Experimental Medicine and Biology, vol 786. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6621-1_11

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