Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Differential contributions of haematopoietic stem cells to foetal and adult haematopoiesis: insights from functional analysis of transcriptional regulators

Oncogene volume 26, pages 6750–6765 (2007)Cite this article

Abstract

An increasing number of molecules have been identified as candidate regulators of stem cell fates through their involvement in leukaemia or via post-genomic gene discovery approaches. A full understanding of the function of these molecules requires (1) detailed knowledge of the gene networks in which they participate and (2) an appreciation of how these networks vary as cells progress through the haematopoietic cell hierarchy. An additional layer of complexity is added by the occurrence of different haematopoietic cell hierarchies at different stages of ontogeny. Beyond these issues of cell context dependence, it is important from a mechanistic point of view to define the particular cell fate pathway impacted by any given regulator. Herein, we advance the notion that haematopoietic stem cells (HSC), which sustain haematopoiesis throughout adult life and are specified in foetal life, have a minimal or late contribution to foetal haematopoiesis but instead largely proliferate during the foetal period. In light of this notion, we revisit published data on mouse knockouts of haematopoietically-affiliated transcription factors highlighting novel insights that may be gained from taking such a view.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM, Poznansky MC et al. (2006). Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439: 599–603.

    CAS  PubMed  Google Scholar 

  • Adolfsson J, Borge OJ, Bryder D, Theilgaard-Monch K, Astrand-Grundstrom I, Sitnicka E et al. (2001). Upregulation of Flt3 expression within the bone marrow Lin(−)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15: 659–669.

    CAS  PubMed  Google Scholar 

  • Adolfsson J, Mansson R, Buza-Vidas N, Hultquist A, Liuba K, Jensen CT et al. (2005). Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121: 295–306.

    CAS  PubMed  Google Scholar 

  • Akashi K, He X, Chen J, Iwasaki H, Niu C, Steenhard B et al. (2003). Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. Blood 101: 383–389.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Arai S, Miyazaki T . (2005). Impaired maturation of myeloid progenitors in mice lacking novel Polycomb group protein MBT-1. EMBO J 24: 1863–1873.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Begley CG, Aplan PD, Davey MP, Nakahara K, Tchorz K, Kurtzberg J et al. (1989). Chromosomal translocation in a human leukemic stem-cell line disrupts the T-cell antigen receptor delta-chain diversity region and results in a previously unreported fusion transcript. Proc Natl Acad Sci USA 86: 2031–2035.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Betschinger J, Knoblich JA . (2004). Dare to be different: asymmetric cell division in Drosophila, C. elegans and vertebrates. Curr Biol 14: R674–R685.

    CAS  PubMed  Google Scholar 

  • Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K et al. (2001). Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2: 172–180.

    CAS  PubMed  Google Scholar 

  • Boehm T, Baer R, Lavenir I, Forster A, Waters JJ, Nacheva E et al. (1988). The mechanism of chromosomal translocation t(11;14) involving the T-cell receptor C delta locus on human chromosome 14q11 and a transcribed region of chromosome 11p15. EMBO J 7: 385–394.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bowie MB, Kent DG, Dykstra B, McKnight KD, McCaffrey L, Hoodless PA et al. (2007). Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties. Proc Natl Acad Sci USA 104: 5878–5882.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bowie MB, McKnight KD, Kent DG, McCaffrey L, Hoodless PA, Eaves CJ . (2006). Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. J Clin Invest 116: 2808–2816.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brunet de la Grange P, Armstrong F, Duval V, Rouyez MC, Goardon N, Romeo PH et al. (2006). Low SCL/TAL1 expression reveals its major role in adult hematopoietic myeloid progenitors and stem cells. Blood 108: 2998–3004.

    CAS  PubMed  Google Scholar 

  • Bruno L, Hoffmann R, McBlane F, Brown J, Gupta R, Joshi C et al. (2004). Molecular signatures of self-renewal, differentiation, and lineage choice in multipotential hemopoietic progenitor cells in vitro. Mol Cell Biol 24: 741–756.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC et al. (2003). Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425: 841–846.

    CAS  PubMed  Google Scholar 

  • Christensen JL, Weissman IL . (2001). Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci USA 98: 14541–14546.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Collins EC, Rabbitts TH . (2002). The promiscuous MLL gene links chromosomal translocations to cellular differentiation and tumour tropism. Trends Mol Med 8: 436–442.

    CAS  PubMed  Google Scholar 

  • Cumano A, Ferraz JC, Klaine M, Di Santo JP, Godin I . (2001). Intraembryonic, but not yolk sac hematopoietic precursors, isolated before circulation, provide long-term multilineage reconstitution. Immunity 15: 477–485.

    CAS  PubMed  Google Scholar 

  • Curtis DJ, Hall MA, Van Stekelenburg LJ, Robb L, Jane SM, Begley CG . (2004). SCL is required for normal function of short-term repopulating hematopoietic stem cells. Blood 103: 3342–3348.

    CAS  PubMed  Google Scholar 

  • de Bruijn MF, Ma X, Robin C, Ottersbach K, Sanchez MJ, Dzierzak E . (2002). Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta. Immunity 16: 673–683.

    CAS  PubMed  Google Scholar 

  • de Bruijn MF, Speck NA . (2004). Core-binding factors in hematopoiesis and immune function. Oncogene 23: 4238–4248.

    CAS  PubMed  Google Scholar 

  • de Bruijn MF, Speck NA, Peeters MC, Dzierzak E . (2000). Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. EMBO J 19: 2465–2474.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Delassus S, Cumano A . (1996). Circulation of hematopoietic progenitors in the mouse embryo. Immunity 4: 97–106.

    CAS  PubMed  Google Scholar 

  • Delassus S, Titley I, Enver T . (1999). Functional and molecular analysis of hematopoietic progenitors derived from the aorta–gonad–mesonephros region of the mouse embryo. Blood 94: 1495–1503.

    CAS  PubMed  Google Scholar 

  • Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD et al. (1991). TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66: 649–661.

    CAS  PubMed  Google Scholar 

  • Erfurth F, Hemenway CS, de Erkenez AC, Domer PH . (2004). MLL fusion partners AF4 and AF9 interact at subnuclear foci. Leukemia 18: 92–102.

    CAS  PubMed  Google Scholar 

  • Ernst P, Fisher JK, Avery W, Wade S, Foy D, Korsmeyer SJ . (2004a). Definitive hematopoiesis requires the mixed-lineage leukemia gene. Dev Cell 6: 437–443.

    CAS  PubMed  Google Scholar 

  • Ernst P, Mabon M, Davidson AJ, Zon LI, Korsmeyer SJ . (2004b). An Mll-dependent Hox program drives hematopoietic progenitor expansion. Curr Biol 14: 2063–2069.

    CAS  PubMed  Google Scholar 

  • Forsberg EC, Prohaska SS, Katzman S, Heffner GC, Stuart JM, Weissman IL . (2005). Differential expression of novel potential regulators in hematopoietic stem cells. PLoS Genet 1: e28.

    PubMed  PubMed Central  Google Scholar 

  • Forsberg EC, Serwold T, Kogan S, Weissman IL, Passegue E . (2006). New evidence supporting megakaryocyte–erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors. Cell 126: 415–426.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gekas C, Dieterlen-Lievre F, Orkin SH, Mikkola HK . (2005). The placenta is a niche for hematopoietic stem cells. Dev Cell 8: 365–375.

    CAS  PubMed  Google Scholar 

  • Godin I, Cumano A . (2002). The hare and the tortoise: an embryonic haematopoietic race. Nat Rev Immunol 2: 593–604.

    CAS  PubMed  Google Scholar 

  • Godin I, Garcia-Porrero JA, Dieterlen-Lievre F, Cumano A . (1999). Stem cell emergence and hemopoietic activity are incompatible in mouse intraembryonic sites. J Exp Med 190: 43–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P et al. (1995). Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci USA 92: 4917–4921.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gothot A, Pyatt R, McMahel J, Rice S, Srour EF . (1997). Functional heterogeneity of human CD34(+) cells isolated in subcompartments of the G0/G1 phase of the cell cycle. Blood 90: 4384–4393.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Hess JL, Yu BD, Li B, Hanson R, Korsmeyer SJ . (1997). Defects in yolk sac hematopoiesis in Mll-null embryos. Blood 90: 1799–1806.

    CAS  PubMed  Google Scholar 

  • Heyworth C, Gale K, Dexter M, May G, Enver T . (1999). A GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal. Genes Dev 13: 1847–1860.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hock H, Orkin SH . (2006). Zinc-finger transcription factor Gfi-1: versatile regulator of lymphocytes, neutrophils and hematopoietic stem cells. Curr Opin Hematol 13: 1–6.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Ichikawa M, Asai T, Saito T, Seo S, Yamazaki I, Yamagata T 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: 299–304.

    CAS  PubMed  Google Scholar 

  • Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR . (2002). A stem cell molecular signature. Science 298: 601–604.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Iwasaki H, Mizuno S, Arinobu Y, Ozawa H, Mori Y, Shigematsu H et al. (2006). The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev 20: 3010–3021.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M . (1999). The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397: 164–168.

    CAS  PubMed  Google Scholar 

  • Kikuchi K, Kondo M . (2006). Developmental switch of mouse hematopoietic stem cells from foetal to adult type occurs in bone marrow after birth. Proc Natl Acad Sci USA 103: 17852–17857.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kingsley PD, Malik J, Fantauzzo KA, Palis J . (2004). Yolk sac-derived primitive erythroblasts enucleate during mammalian embryogenesis. Blood 104: 19–25.

    CAS  PubMed  Google Scholar 

  • Knoblich JA . (1997). Mechanisms of asymmetric cell division during animal development. Curr Opin Cell Biol 9: 833–841.

    CAS  PubMed  Google Scholar 

  • Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF et al. (2003). Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol 21: 759–806.

    CAS  PubMed  Google Scholar 

  • Kumaravelu P, Hook L, Morrison AM, Ure J, Zhao S, Zuyev S 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: 4891–4899.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Laslo P, Spooner CJ, Warmflash A, Lancki DW, Lee HJ, Sciammas R et al. (2006). Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 126: 755–766.

    CAS  PubMed  Google Scholar 

  • Leroy H, Roumier C, Huyghe P, Biggio V, Fenaux P, Preudhomme C . (2005). CEBPA point mutations in hematological malignancies. Leukemia 19: 329–334.

    CAS  PubMed  Google Scholar 

  • Lessard J, Faubert A, Sauvageau G . (2004). Genetic programs regulating HSC specification, maintenance and expansion. Oncogene 23: 7199–7209.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Lessard J, Schumacher A, Thorsteinsdottir U, van Lohuizen M, Magnuson T, Sauvageau G . (1999). Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev 13: 2691–2703.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mansson R, Hultquist A, Luc S, Yang L, Anderson K, Kharazi S et al. (2007). Molecular evidence for hierarchical transcriptional lineage priming in foetal and adult stem cells and multipotent progenitors. Immunity 26: 407–419.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Medvinsky A, Dzierzak E . (1999). Development of the hematopoietic stem cell: can we describe it? Blood 94: 3613–3614.

    CAS  PubMed  Google Scholar 

  • Medvinsky AL, Dzierzak EA . (1998). Development of the definitive hematopoietic hierarchy in the mouse. Dev Comp Immunol 22: 289–301.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Mikkola HK, Klintman J, Yang H, Hock H, Schlaeger TM, Fujiwara Y et al. (2003). Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene. Nature 421: 547–551.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y, Ohki M . (1991). t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc Natl Acad Sci USA 88: 10431–10434.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morrison SJ, Weissman IL . (1994). The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1: 661–673.

    CAS  PubMed  Google Scholar 

  • Mueller BU, Pabst T . (2006). C/EBPalpha and the pathophysiology of acute myeloid leukemia. Curr Opin Hematol 13: 7–14.

    PubMed  Google Scholar 

  • Mukouyama Y, Chiba N, Hara T, Okada H, Ito Y, Kanamaru R et al. (2000). The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta–gonad–mesonephros region. Dev Biol 220: 27–36.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Naito M, Umeda S, Yamamoto T, Moriyama H, Umezu H, Hasegawa G et al. (1996). Development, differentiation, and phenotypic heterogeneity of murine tissue macrophages. J Leukoc Biol 59: 133–138.

    CAS  PubMed  Google Scholar 

  • Niki M, Okada H, Takano H, Kuno J, Tani K, Hibino H et al. (1997). Hematopoiesis in the foetal liver is impaired by targeted mutagenesis of a gene encoding a non-DNA binding subunit of the transcription factor, polyomavirus enhancer binding protein 2/core binding factor. Proc Natl Acad Sci USA 94: 5697–5702.

    CAS  PubMed  PubMed Central  Google Scholar 

  • North T, Gu TL, Stacy T, Wang Q, Howard L, Binder M et al. (1999). Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development 126: 2563–2575.

    CAS  PubMed  Google Scholar 

  • North TE, de Bruijn MF, Stacy T, Talebian L, Lind E, Robin C et al. (2002). Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity 16: 661–672.

    CAS  PubMed  Google Scholar 

  • North TE, Stacy T, Matheny CJ, Speck NA, de Bruijn MF . (2004). Runx1 is expressed in adult mouse hematopoietic stem cells and differentiating myeloid and lymphoid cells, but not in maturing erythroid cells. Stem Cells 22: 158–168.

    CAS  PubMed  Google Scholar 

  • Oguro H, Iwama A, Morita Y, Kamijo T, van Lohuizen M, Nakauchi H . (2006). Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J Exp Med 203: 2247–2253.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ohta H, Sawada A, Kim JY, Tokimasa S, Nishiguchi S, Humphries RK et al. (2002). Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells. J Exp Med 195: 759–770.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Osada H, Grutz GG, Axelson H, Forster A, Rabbitts TH . (1997). LIM-only protein Lmo2 forms a protein complex with erythroid transcription factor GATA-1. Leukemia 11 (Suppl 3): 307–312.

    PubMed  Google Scholar 

  • Ottersbach K, Dzierzak E . (2005). The murine placenta contains hematopoietic stem cells within the vascular labyrinth region. Dev Cell 8: 377–387.

    CAS  PubMed  Google Scholar 

  • Palis J, Chan RJ, Koniski A, Patel R, Starr M, Yoder MC . (2001). Spatial and temporal emergence of high proliferative potential hematopoietic precursors during murine embryogenesis. Proc Natl Acad Sci USA 98: 4528–4533.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Park IK, He Y, Lin F, Laerum OD, Tian Q, Bumgarner R et al. (2002). Differential gene expression profiling of adult murine hematopoietic stem cells. Blood 99: 488–498.

    CAS  PubMed  Google Scholar 

  • Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL et al. (2003). Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423: 302–305.

    CAS  PubMed  Google Scholar 

  • Persons DA, Allay JA, Allay ER, Ashmun RA, Orlic D, Jane SM et al. (1999). Enforced expression of the GATA-2 transcription factor blocks normal hematopoiesis. Blood 93: 488–499.

    CAS  PubMed  Google Scholar 

  • 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: 47–57.

    CAS  PubMed  Google Scholar 

  • Porse BT, Bryder D, Theilgaard-Monch K, Hasemann MS, Anderson K, Damgaard I et al. (2005). Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage. J Exp Med 202: 85–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Porse BT, Pedersen TA, Xu X, Lindberg B, Wewer UM, Friis-Hansen L et al. (2001). E2F repression by C/EBPalpha is required for adipogenesis and granulopoiesis in vivo. Cell 107: 247–258.

    CAS  PubMed  Google Scholar 

  • Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K et al. (2003). A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423: 409–414.

    CAS  PubMed  Google Scholar 

  • Reynaud D, Ravet E, Titeux M, Mazurier F, Renia L, Dubart-Kupperschmitt A et al. (2005). SCL/TAL1 expression level regulates human hematopoietic stem cell self-renewal and engraftment. Blood 106: 2318–2328.

    CAS  PubMed  Google Scholar 

  • Ringrose L, Paro R . (2004). Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 38: 413–443.

    CAS  PubMed  Google Scholar 

  • Robb L, Elwood NJ, Elefanty AG, Kontgen F, Li R, Barnett LD et al. (1996). The scl gene product is required for the generation of all hematopoietic lineages in the adult mouse. EMBO J 15: 4123–4129.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Robb L, Lyons I, Li R, Hartley L, Kontgen F, Harvey RP et al. (1995). Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. Proc Natl Acad Sci USA 92: 7075–7079.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rodrigues NP, Janzen V, Forkert R, Dombkowski DM, Boyd AS, Orkin SH et al. (2005). Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis. Blood 106: 477–484.

    CAS  PubMed  Google Scholar 

  • Rodriguez P, Bonte E, Krijgsveld J, Kolodziej KE, Guyot B, Heck AJ et al. (2005). GATA-1 forms distinct activating and repressive complexes in erythroid cells. EMBO J 24: 2354–2366.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenbauer F, Koschmieder S, Steidl U, Tenen DG . (2005). Effect of transcription-factor concentrations on leukemic stem cells. Blood 106: 1519–1524.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Samokhvalov IM, Samokhvalova NI, Nishikawa S . (2007). Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature 446: 1056–1061.

    CAS  PubMed  Google Scholar 

  • Shivdasani RA, Mayer EL, Orkin SH . (1995). Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 373: 432–434.

    CAS  PubMed  Google Scholar 

  • Shojaei F, Trowbridge J, Gallacher L, Yuefei L, Goodale D, Karanu F et al. (2005). Hierarchical and ontogenic positions serve to define the molecular basis of human hematopoietic stem cell behavior. Dev Cell 8: 651–663.

    CAS  PubMed  Google Scholar 

  • So CW, Karsunky H, Passegue E, Cozzio A, Weissman IL, Cleary ML . (2003). MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell 3: 161–171.

    CAS  PubMed  Google Scholar 

  • Soneji S, Huang S, Loose M, Donaldson IJ, Patient R, Gottgens B et al. (2007). Inference, validation and dynamic modelling of transcription networks in multipotent hematopoietic cells. Ann NY Acad Sci 1106: 30–40.

    CAS  PubMed  Google Scholar 

  • Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D et al. (1999). Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 23: 166–175.

    CAS  PubMed  Google Scholar 

  • Sparmann A, van Lohuizen M . (2006). Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6: 846–856.

    CAS  PubMed  Google Scholar 

  • Speck NA, Gilliland DG . (2002). Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer 2: 502–513.

    CAS  PubMed  Google Scholar 

  • Stier S, Ko Y, Forkert R, Lutz C, Neuhaus T, Grunewald E et al. (2005). Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J Exp Med 201: 1781–1791.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sugiyama T, Kohara H, Noda M, Nagasawa T . (2006). Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25: 977–988.

    CAS  PubMed  Google Scholar 

  • Taoudi S, Morrison AM, Inoue H, Gribi R, Ure J, Medvinsky A . (2005). Progressive divergence of definitive haematopoietic stem cells from the endothelial compartment does not depend on contact with the foetal liver. Development 132: 4179–4191.

    CAS  PubMed  Google Scholar 

  • Tober J, Koniski A, McGrath KE, Vemishetti R, Emerson R, de Mesy-Bentley KK et al. (2007). The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis. Blood 109: 1433–1441.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M et al. (1994). An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 371: 221–226.

    CAS  PubMed  Google Scholar 

  • van der Lugt NM, Domen J, Linders K, van Roon M, Robanus-Maandag E, te Riele H et al. (1994). Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 8: 757–769.

    CAS  PubMed  Google Scholar 

  • van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A . (1991). Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell 65: 737–752.

    CAS  PubMed  Google Scholar 

  • Wadman IA, Osada H, Grutz GG, Agulnick AD, Westphal H, Forster A et al. (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: 3145–3157.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang LC, Kuo F, Fujiwara Y, Gilliland DG, Golub TR, Orkin SH . (1997). Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL. EMBO J 16: 4374–4383.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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 USA 93: 3444–3449.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Warren AJ, Colledge WH, Carlton MB, Evans MJ, Smith AJ, Rabbitts TH . (1994). The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell 78: 45–57.

    CAS  PubMed  Google Scholar 

  • Wilpshaar J, Bhatia M, Kanhai HH, Breese R, Heilman DK, Johnson CS et al. (2002). Engraftment potential of human foetal hematopoietic cells in NOD/SCID mice is not restricted to mitotically quiescent cells. Blood 100: 120–127.

    CAS  PubMed  Google Scholar 

  • Wilpshaar J, Frederik Falkenburg JH, Tong X, Noort WA, Breese R, Heilman D et al. (2000). Similar repopulating capacity of mitotically active and resting umbilical cord blood CD34+ cells in NOD/SCID mice. Blood 96: 2100–2107.

    CAS  PubMed  Google Scholar 

  • Wilson A, Trumpp A . (2006). Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6: 93–106.

    CAS  PubMed  Google Scholar 

  • Yagi H, Deguchi K, Aono A, Tani Y, Kishimoto T, Komori T . (1998). Growth disturbance in foetal liver hematopoiesis of Mll-mutant mice. Blood 92: 108–117.

    CAS  PubMed  Google Scholar 

  • Yamada Y, Warren AJ, Dobson C, Forster A, Pannell R, Rabbitts TH . (1998). The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis. Proc Natl Acad Sci USA 95: 3890–3895.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yoder MC, Hiatt K . (1997). Engraftment of embryonic hematopoietic cells in conditioned newborn recipients. Blood 89: 2176–2183.

    CAS  PubMed  Google Scholar 

  • Yu BD, Hanson RD, Hess JL, Horning SE, Korsmeyer SJ . (1998). MLL, a mammalian trithorax-group gene, functions as a transcriptional maintenance factor in morphogenesis. Proc Natl Acad Sci USA 95: 10632–10636.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zelent A, Greaves M, Enver T . (2004). Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia. Oncogene 23: 4275–4283.

    CAS  PubMed  Google Scholar 

  • Zeng H, Yucel R, Kosan C, Klein-Hitpass L, Moroy T . (2004). Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cells. EMBO J 23: 4116–4125.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG . (1997). Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci USA 94: 569–574.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML, Dayaram T, Owens BM 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: 853–863.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Marella de Bruijn, Aldo Ciau-Uitz and Catherine Porcher for their critical reading of this manuscript and helpful comments and suggestions; we also thank Alexander Medvinsky for helpful discussions. Cristina Pina is a student of the Gulbenkian PhD programme in Biomedicine and is funded by Fundação para a Ciência e Tecnologia, Portugal (SFRH/BD/11812/2003). Work in Tariq Enver's laboratory is funded by the Leukaemia Research Fund and the Medical Research Council, United Kingdom.

Author information

Authors and Affiliations

  1. MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    C Pina & T Enver

Authors
  1. C Pina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Enver
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Pina.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pina, C., Enver, T. Differential contributions of haematopoietic stem cells to foetal and adult haematopoiesis: insights from functional analysis of transcriptional regulators. Oncogene 26, 6750–6765 (2007). https://doi.org/10.1038/sj.onc.1210759

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210759

Keywords

This article is cited by

Search

Advanced search

Quick links