Experimental Hematology
Volume 38, Issue 11 , Pages 1074-1086.e5 , November 2010

HoxA cluster is haploinsufficient for activity of hematopoietic stem and progenitor cells

  • Charles-Etienne Lebert-Ghali

      Affiliations

    • Centre de Recherche de Hôpital Maisonneuve-Rosemont (HMR), HMR, Montréal, Canada
    • ,
  • Marilaine Fournier

      Affiliations

    • Centre de Recherche de Hôpital Maisonneuve-Rosemont (HMR), HMR, Montréal, Canada
    • ,
  • Glenda J. Dickson

      Affiliations

    • Centre for Cancer Research and Cell Biology, Queen’s University, Belfast, UK
    • ,
  • Alexander Thompson

      Affiliations

    • Centre for Cancer Research and Cell Biology, Queen’s University, Belfast, UK
    • ,
  • Guy Sauvageau

      Affiliations

    • Institute for Research in Immunology and Cancer, Montréal, Canada
    • Department of Medicine, Université de Montréal, Montréal, Canada
    • ,
  • Janet J. Bijl

      Affiliations

    • Centre de Recherche de Hôpital Maisonneuve-Rosemont (HMR), HMR, Montréal, Canada
    • Department of Medicine, Université de Montréal, Montréal, Canada
    • Corresponding Author InformationOffprint requests to: Janet Bijl, Ph.D., Centre de Recherche Hôpital Maisonneuve-Rosemont 5415 Boul. De l’Assomption, Montréal, QC H1T 2M4, Canada

Received 4 May 2010 ,Revised 5 July 2010 ,Accepted 14 July 2010.

References 

  1. Scott MP. A rational nomenclature for vertebrate homeobox (HOX) genes. Nucleic Acids Res. 1993;21:1687–1688
  2. Sauvageau G, Lansdorp PM, Eaves CJ, et al. Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells. Proc Natl Acad Sci USA. 1994;91:12223–12227
  3. Magli MC, Barba P, Celetti A, De Vita G, Cillo C, Boncinelli E. Coordinate regulation of HOX genes in human hematopoietic cells. Proc Natl Acad Sci U S A. 1991;88:6348–6352
  4. Magli MC, Largman C, Lawrence HJ. Effects of HOX homeobox genes in blood cell differentiation. J Cell Physiol. 1997;173:168–177
  5. Shen WF, Detmer K, Mathews CH, et al. Modulation of homeobox gene expression alters the phenotype of human hematopoietic cell lines. EMBO J. 1992;11:983–989
  6. Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 1998;17:3714–3725
  7. Sauvageau G, Thorsteinsdottir U, Hough MR, et al. Overexpression of HOXB3 in hematopoietic cells causes defective lymphoid development and progressive myeloproliferation. Immunity. 1997;6:13–22
  8. Thorsteinsdottir U, Sauvageau G, Hough MR, et al. Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia. Mol Cell Biol. 1997;17:495–505
  9. Fischbach NA, Rozenfeld S, Shen W, et al. 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. 2005;105:1456–1466
  10. Perkins AC, Cory S. Conditional immortalization of mouse myelomonocytic, megakaryocytic and mast cell progenitors by the Hox-2.4 homeobox gene. EMBO J. 1993;12:3835–3846
  11. Thorsteinsdottir U, Kroon E, Jerome L, Blasi F, Sauvageau G. Defining roles for HOX and MEIS1 genes in induction of acute myeloid leukemia. Mol Cell Biol. 2001;21:224–234
  12. Bach C, Buhl S, Mueller D, Garcia-Cuellar MP, Maethner E, Slany RK. Leukemogenic transformation by HOXA cluster genes. Blood. 2010;115:2910–2918
  13. Sauvageau G, Thorsteinsdottir U, Eaves CJ, et al. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev. 1995;9:1753–1765
  14. Krosl J, Beslu N, Mayotte N, Humphries RK, Sauvageau G. The competitive nature of HOXB4-transduced HSC is limited by PBX1: the generation of ultra-competitive stem cells retaining full differentiation potential. Immunity. 2003;18:561–571
  15. Chen F, Capecchi MR. Targeted mutations in hoxa-9 and hoxb-9 reveal synergistic interactions. Dev Biol. 1997;181:186–196
  16. Horan GS, Ramirez-Solis R, Featherstone MS, Wolgemuth DJ, Bradley A, Behringer RR. Compound mutants for the paralogous hoxa-4, hoxb-4, and hoxd-4 genes show more complete homeotic transformations and a dose-dependent increase in the number of vertebrae transformed. Genes Dev. 1995;9:1667–1677
  17. Kappen C. Disruption of the homeobox gene Hoxb-6 in mice results in increased numbers of early erythrocyte progenitors. Am J Hematol. 2000;65:111–118
  18. Shimamoto T, Tang Y, Naot Y, et al. Hematopoietic progenitor cell abnormalities in Hoxc-8 null mutant mice. J Exp Zool. 1999;283:186–193
  19. Brun AC, Bjornsson JM, Magnusson M, et al. Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells. Blood. 2004;103:4126–4133
  20. Lawrence HJ, Helgason CD, Sauvageau G, et al. Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis. Blood. 1997;89:1922–1930
  21. Bijl J, Thompson A, Ramirez-Solis R, et al. Analysis of HSC activity and compensatory Hox gene expression profile in Hoxb cluster mutant fetal liver cells. Blood. 2006;108:116–122
  22. Akashi K, He X, Chen J, et al. Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. Blood. 2003;101:383–389
  23. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR. A stem cell molecular signature. Science. 2002;298:601–604
  24. Pineault N, Helgason CD, Lawrence HJ, Humphries RK. Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol. 2002;30:49–57
  25. Kmita M, Tarchini B, Zakany J, Logan M, Tabin CJ, Duboule D. Early developmental arrest of mammalian limbs lacking HoxA/HoxD gene function. Nature. 2005;435:1113–1116
  26. Di-Poi N, Koch U, Radtke F, Duboule D. Additive and global functions of HoxA cluster genes in mesoderm derivatives. Dev Biol. 2010;341:488–498
  27. Rebel VI, Miller CL, Thornbury GR, Dragowska WH, Eaves CJ, Lansdorp PM. A comparison of long-term repopulating hematopoietic stem cells in fetal liver and adult bone marrow from the mouse. Exp Hematol. 1996;24:638–648
  28. Bowie MB, Kent DG, Dykstra B, et al. Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties. Proc Natl Acad Sci U S A. 2007;104:5878–5882
  29. Lakso M, Pichel JG, Gorman JR, et al. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc Natl Acad Sci U S A. 1996;93:5860–5865
  30. Humphries RK, Eaves AC, Eaves CJ. Self-renewal of hemopoietic stem cells during mixed colony formation in vitro. Proc Natl Acad Sci U S A. 1981;78:3629–3633
  31. Kondo M, Weissman IL, Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell. 1997;91:661–672
  32. Akashi K, Traver D, Miyamoto T, Weissman IL. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature. 2000;404:193–197
  33. Goodell MA, McKinney-Freeman S, Camargo FD. Isolation and characterization of side population cells. Methods Mol Biol. 2005;290:343–352
  34. Mamo A, Krosl J, Kroon E, et al. Molecular dissection of Meis1 reveals two domains required for leukemia induction and a key role for Hoxa gene activation. Blood. 2006;108:622–629
  35. Dickson GJ, Lappin TR, Thompson A. Complete array of HOX gene expression by RQ-PCR. Methods Mol Biol. 2009;538:369–393
  36. Thompson A, Quinn MF, Grimwade D, et al. Global down-regulation of HOX gene expression in PML-RARalpha + acute promyelocytic leukemia identified by small-array real-time PCR. Blood. 2003;101:1558–1565
  37. Miller CL, Rebel VI, Helgason CD, Lansdorp PM, Eaves CJ. Impaired steel factor responsiveness differentially affects the detection and long-term maintenance of fetal liver hematopoietic stem cells in vivo. Blood. 1997;89:1214–1223
  38. Amsellem S, Pflumio F, Bardinet D, et al. Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein. Nat Med. 2003;9:1423–1427
  39. Thorsteinsdottir U, Mamo A, Kroon E, et al. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Blood. 2002;99:121–129
  40. Taghon T, Stolz F, De Smedt M, et al. HOX-A10 regulates hematopoietic lineage commitment: evidence for a monocyte-specific transcription factor. Blood. 2002;99:1197–1204
  41. Magnusson M, Brun AC, Miyake N, et al. HOXA10 is a critical regulator for hematopoietic stem cells and erythroid/megakaryocyte development. Blood. 2007;109:3687–3696
  42. Lawrence HJ, Sauvageau G, Ahmadi N, et al. Stage- and lineage-specific expression of the HOXA10 homeobox gene in normal and leukemic hematopoietic cells. Exp Hematol. 1995;23:1160–1166
  43. van Oostveen J, Bijl J, Raaphorst F, Walboomers J, Meijer C. The role of homeobox genes in normal hematopoiesis and hematological malignancies. Leukemia. 1999;13:1675–1690
  44. Bijl J, van Oostveen JW, Kreike M, et al. Expression of HOXC4, HOXC5, and HOXC6 in human lymphoid cell lines, leukemias, and benign and malignant lymphoid tissue. Blood. 1996;87:1737–1745
  45. Lawrence HJ, Stage KM, Mathews CH, et al. Expression of HOX C homeobox genes in lymphoid cells. Cell Growth Differ. 1993;4:665–669
  46. Payne KJ, Crooks GM. Human hematopoietic lineage commitment. Immunol Rev. 2002;187:48–64
  47. Vieille-Grosjean I, Roullot V, Courtois G. Lineage and stage specific expression of HOX 1 genes in the human hematopoietic system. Biochem Biophys Res Commun. 1992;183:1124–1130
  48. Sieburg HB, Cho RH, Dykstra B, Uchida N, Eaves CJ, Muller-Sieburg CE. The hematopoietic stem compartment consists of a limited number of discrete stem cell subsets. Blood. 2006;107:2311–2316
  49. Challen GA, Boles NC, Chambers SM, Goodell MA. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell. 2010;6:265–278
  50. Muller-Sieburg CE, Cho RH, Karlsson L, Huang JF, Sieburg HB. Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood. 2004;103:4111–4118

PII: S0301-472X(10)00287-0

doi: 10.1016/j.exphem.2010.07.006

Experimental Hematology
Volume 38, Issue 11 , Pages 1074-1086.e5 , November 2010

Article Tools

* Image Usage & Resolution