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:

Hox genes in hematopoiesis and leukemogenesis

Oncogene volume 26, pages 6766–6776 (2007)Cite this article

Abstract

Gene expression analyses, gene targeting experiments and retroviral overexpression studies in the murine bone marrow transplantation model have provided strong correlative evidence for the involvement of clustered Hox genes in normal hematopoiesis. The data strongly support the hypothesis that the role of Hox genes in normal hematopoiesis is primarily at the level of hematopoietic stem cell function. A large body of evidence now links Hox genes to leukemic transformation including dysregulated HOX expression in leukemic patient samples, their involvement as oncogenic fusion proteins with NUP98 and their requirement for the oncogenicity of Mll fusions. In recent years, much attention has been devoted to the identification and characterization of leukemic stem cells. Given the documented role of Hox genes in hematopoiesis and leukemogenesis, we propose that Hox-dependent pathways are closely linked to the self-renewal program crucial to the origin and function of leukemic stem cells.

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

Similar content being viewed by others

References

  • Afonja O, Smith Jr JE, Cheng DM, Goldenberg AS, Amorosi E, Shimamoto T et al. (2000). MEIS1 and HOXA7 genes in human acute myeloid leukemia. Leuk Res 24: 849–855.

    CAS  PubMed  Google Scholar 

  • Alcalay M, Tiacci E, Bergomas R, Bigerna B, Venturini E, Minardi SP et al. (2005). Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. Blood 106: 899–902.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Antonchuk J, Sauvageau G, Humphries RK . (2001). HOXB4 overexpression mediates very rapid stem cell regeneration and competitive hematopoietic repopulation. Exp Hematol 29: 1125–1134.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD et al. (2002). MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 30: 41–47.

    Article  CAS  PubMed  Google Scholar 

  • Ayton PM, Cleary ML . (2003). Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev 17: 2298–2307.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bai XT, Gu BW, Yin T, Niu C, Xi XD, Zhang J et al. (2006). Trans-repressive effect of NUP98-PMX1 on PMX1-regulated c-FOS gene through recruitment of histone deacetylase 1 by FG repeats. Cancer Res 66: 4584–4590.

    CAS  PubMed  Google Scholar 

  • Bansal D, Scholl C, Frohling S, McDowell E, Lee BH, Dohner K et al. (2006). Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model. Proc Natl Acad Sci USA 103: 16924–16929.

    PubMed  PubMed Central  Google Scholar 

  • Bergeron J, Clappier E, Cauwelier B, Dastugue N, Millien C, Delabesse E et al. (2006). HOXA cluster deregulation in T-ALL associated with both a TCRD-HOXA and a CALM-AF10 chromosomal translocation. Leukemia 20: 1184–1187.

    CAS  PubMed  Google Scholar 

  • Beslu N, Krosl J, Laurin M, Mayotte N, Humphries KR, Sauvageau G . (2004). Molecular interactions involved in HOXB4-induced activation of HSC self-renewal. Blood 104: 2307–2314.

    Article  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 

  • Bijl J, Thompson A, Ramirez-Solis R, Krosl J, Grier DG, Lawrence HJ et al. (2006). Analysis of HSC activity and compensatory Hox gene expression profile in Hoxb cluster mutant fetal liver cells. Blood 108: 116–122.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bjornsson JM, Larsson N, Brun AC, Magnusson M, Andersson E, Lundstrom P et al. (2003). Reduced proliferative capacity of hematopoietic stem cells deficient in Hoxb3 and Hoxb4. Mol Cell Biol 23: 3872–3883.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Blair A, Hogge DE, Sutherland HJ . (1998). Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(−)/HLA-DR. Blood 92: 4325–4335.

    CAS  PubMed  Google Scholar 

  • Bonnet D, Dick JE . (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3: 730–737.

    CAS  PubMed  Google Scholar 

  • Brun AC, Bjornsson JM, Magnusson M, Larsson N, Leveen P, Ehinger M et al. (2004). Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells. Blood 103: 4126–4133.

    CAS  PubMed  Google Scholar 

  • Buske C, Feuring-Buske M, Abramovich C, Spiekermann K, Eaves CJ, Coulombel L et al. (2002). Deregulated expression of HOXB4 enhances the primitive growth activity of human hematopoietic cells. Blood 100: 862–868.

    CAS  PubMed  Google Scholar 

  • Calvo KR, Sykes DB, Pasillas MP, Kamps MP . (2002). Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1. Oncogene 21: 4247–4256.

    CAS  PubMed  Google Scholar 

  • Camos M, Esteve J, Jares P, Colomer D, Rozman M, Villamor N et al. (2006). Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3-CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression. Cancer Res 66: 6947–6954.

    CAS  PubMed  Google Scholar 

  • Cauwelier B, Cave H, Gervais C, Lessard M, Barin C, Perot C et al. (2007). Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRbeta-HOXA rearrangement: a study of the Groupe Francophone de Cytogenetique Hematologique. Leukemia 21: 121–128.

    CAS  PubMed  Google Scholar 

  • Cellot S, Krosl J, Chagraoui J, Meloche S, Humphries RK, Sauvageau G . (2007). Sustained in vitro trigger of self-renewal divisions in Hoxb4hiPbxl(10) hematopoietic stem cells. Exp Hematol 35: 802–816.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen F, Capecchi MR . (1997). Targeted mutations in hoxa-9 and hoxb-9 reveal synergistic interactions. Dev Biol 181: 186–196.

    CAS  PubMed  Google Scholar 

  • Chung KY, Morrone G, Schuringa JJ, Plasilova M, Shieh JH, Zhang Y et al. (2006). Enforced expression of NUP98-HOXA9 in human CD34(+) cells enhances stem cell proliferation. Cancer Res 66: 11781–11791.

    CAS  PubMed  Google Scholar 

  • Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL . (2003). Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 17: 3029–3035.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Crump JG, Swartz ME, Eberhart JK, Kimmel CB . (2006). Moz-dependent Hox expression controls segment-specific fate maps of skeletal precursors in the face. Development 133: 2661–2669.

    CAS  PubMed  Google Scholar 

  • Daser A, Rabbitts TH . (2005). The versatile mixed lineage leukaemia gene MLL and its many associations in leukaemogenesis. Semin Cancer Biol 15: 175–188.

    CAS  PubMed  Google Scholar 

  • Davidson AJ, Ernst P, Wang Y, Dekens MP, Kingsley PD, Palis J et al. (2003). cdx4 mutants fail to specify blood progenitors and can be rescued by multiple hox genes. Nature 425: 300–306.

    CAS  PubMed  Google Scholar 

  • Davidson AJ, Zon LI . (2006). The caudal-related homeobox genes cdx1a and cdx4 act redundantly to regulate hox gene expression and the formation of putative hematopoietic stem cells during zebrafish embryogenesis. Dev Biol 292: 506–518.

    CAS  PubMed  Google Scholar 

  • De Braekeleer M, Morel F, Le Bris MJ, Herry A, Douet-Guilbert N . (2005). The MLL gene and translocations involving chromosomal band 11q23 in acute leukemia. Anticancer Res 25: 1931–1944.

    CAS  PubMed  Google Scholar 

  • Deshpande AJ, Cusan M, Rawat VP, Reuter H, Krause A, Pott C et al. (2006). Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia. Cancer Cell 10: 363–374.

    CAS  PubMed  Google Scholar 

  • Dik WA, Brahim W, Braun C, Asnafi V, Dastugue N, Bernard OA et al. (2005). CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes. Leukemia 19: 1948–1957.

    CAS  PubMed  Google Scholar 

  • DiMartino JF, Selleri L, Traver D, Firpo MT, Rhee J, Warnke R et al. (2001). The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver. Blood 98: 618–626.

    CAS  PubMed  Google Scholar 

  • Drabkin HA, Parsy C, Ferguson K, Guilhot F, Lacotte L, Roy L et al. (2002). Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia. Leukemia 16: 186–195.

    CAS  PubMed  Google Scholar 

  • Ekker SC, Jackson DG, von Kessler DP, Sun BI, Young KE, Beachy PA . (1994). The degree of variation in DNA sequence recognition among four Drosophila homeotic proteins. EMBO J 13: 3551–3560.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Ferrando AA, Armstrong SA, Neuberg DS, Sallan SE, Silverman LB, Korsmeyer SJ et al. (2003). Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation. Blood 102: 262–268.

    CAS  PubMed  Google Scholar 

  • Fine BM, Stanulla M, Schrappe M, Ho M, Viehmann S, Harbott J et al. (2004). Gene expression patterns associated with recurrent chromosomal translocations in acute lymphoblastic leukemia. Blood 103: 1043–1049.

    CAS  PubMed  Google Scholar 

  • Fischbach NA, Rozenfeld S, Shen W, Fong S, Chrobak D, Ginzinger D 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: 1456–1466.

    CAS  PubMed  Google Scholar 

  • Fuller JF, McAdara J, Yaron Y, Sakaguchi M, Fraser JK, Gasson JC . (1999). Characterization of HOX gene expression during myelopoiesis: role of HOX A5 in lineage commitment and maturation. Blood 93: 3391–3400.

    CAS  PubMed  Google Scholar 

  • Gehring WJ, Affolter M, Burglin T . (1994). Homeodomain proteins. Annu Rev Biochem 63: 487–526.

    CAS  PubMed  Google Scholar 

  • Ghannam G, Takeda A, Camarata T, Moore MA, Viale A, Yaseen NR . (2004). The oncogene Nup98-HOXA9 induces gene transcription in myeloid cells. J Biol Chem 279: 866–875.

    CAS  PubMed  Google Scholar 

  • Giampaolo A, Pelosi E, Valtieri M, Montesoro E, Sterpetti P, Samoggia P et al. (1995). HOXB gene expression and function in differentiating purified hematopoietic progenitors. Stem Cells 13 (Suppl 1): 90–105.

    CAS  PubMed  Google Scholar 

  • Giampaolo A, Sterpetti P, Bulgarini D, Samoggia P, Pelosi E, Valtieri M et al. (1994). Key functional role and lineage-specific expression of selected HOXB genes in purified hematopoietic progenitor differentiation. Blood 84: 3637–3647.

    CAS  PubMed  Google Scholar 

  • Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP et al. (1999). Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286: 531–537.

    CAS  PubMed  Google Scholar 

  • Greer JM, Puetz J, Thomas KR, Capecchi MR . (2000). Maintenance of functional equivalence during paralogous Hox gene evolution. Nature 403: 661–665.

    CAS  PubMed  Google Scholar 

  • Grier DG, Thompson A, Kwasniewska A, McGonigle GJ, Halliday HL, Lappin TR . (2005). The pathophysiology of HOX genes and their role in cancer. J Pathol 205: 154–171.

    CAS  PubMed  Google Scholar 

  • Hess JL, Bittner CB, Zeisig DT, Bach C, Fuchs U, Borkhardt A et al. (2006). c-Myb is an essential downstream target for homeobox-mediated transformation of hematopoietic cells. Blood 108: 297–304.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hoey T, Levine M . (1988). Divergent homeo box proteins recognize similar DNA sequences in Drosophila. Nature 332: 858–861.

    CAS  PubMed  Google Scholar 

  • Hope KJ, Jin L, Dick JE . (2004). Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 5: 738–743.

    CAS  PubMed  Google Scholar 

  • Horan GS, Kovacs EN, Behringer RR, Featherstone MS . (1995a). Mutations in paralogous Hox genes result in overlapping homeotic transformations of the axial skeleton: evidence for unique and redundant function. Dev Biol 169: 359–372.

    CAS  PubMed  Google Scholar 

  • Horan GS, Ramirez-Solis R, Featherstone MS, Wolgemuth DJ, Bradley A, Behringer RR . (1995b). 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 9: 1667–1677.

    CAS  PubMed  Google Scholar 

  • Horton SJ, Grier DG, McGonigle GJ, Thompson A, Morrow M, De Silva I et al. (2005). Continuous MLL-ENL expression is necessary to establish a ‘Hox Code’ and maintain immortalization of hematopoietic progenitor cells. Cancer Res 65: 9245–9252.

    CAS  PubMed  Google Scholar 

  • Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N et al. (2004). MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6: 587–596.

    CAS  PubMed  Google Scholar 

  • Imamura T, Morimoto A, Takanashi M, Hibi S, Sugimoto T, Ishii E et al. (2002). Frequent co-expression of HoxA9 and Meis1 genes in infant acute lymphoblastic leukaemia with MLL rearrangement. Br J Haematol 119: 119–121.

    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 M, Kuwata T, Yamazaki Y, Jenkins NA, Copeland NG, Osato M et al. (2005). Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model. Blood 105: 784–793.

    CAS  PubMed  Google Scholar 

  • Izon DJ, Rozenfeld S, Fong ST, Komuves L, Largman C, Lawrence HJ . (1998). Loss of function of the homeobox gene Hoxa-9 perturbs early T-cell development and induces apoptosis in primitive thymocytes. Blood 92: 383–393.

    CAS  PubMed  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 

  • Jin G, Yamazaki Y, Takuwa M, Takahara T, Kaneko K, Kuwata T et al. (2007). Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis. Blood 109: 3998–4005.

    CAS  PubMed  Google Scholar 

  • Kappen C . (2000). Disruption of the homeobox gene Hoxb-6 in mice results in increased numbers of early erythrocyte progenitors. Am J Hematol 65: 111–118.

    CAS  PubMed  Google Scholar 

  • Kasper LH, Brindle PK, Schnabel CA, Pritchard CE, Cleary ML, van Deursen JM . (1999). CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol Cell Biol 19: 764–776.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kato Y, Iwama A, Tadokoro Y, Shimoda K, Minoguchi M, Akira S et al. (2005). Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis. J Exp Med 202: 169–179.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kawagoe H, Humphries RK, Blair A, Sutherland HJ, Hogge DE . (1999). Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. Leukemia 13: 687–698.

    CAS  PubMed  Google Scholar 

  • Ko KH, Lam QL, Zhang M, Wong CK, Lo CK, Kahmeyer-Gabbe M et al. (2007). Hoxb3 deficiency impairs B lymphopoiesis in mouse bone marrow. Exp Hematol 35: 465–475.

    CAS  PubMed  Google Scholar 

  • Kohlmann A, Schoch C, Schnittger S, Dugas M, Hiddemann W, Kern W et al. (2003). Molecular characterization of acute leukemias by use of microarray technology. Genes Chromosomes Cancer 37: 396–405.

    CAS  PubMed  Google Scholar 

  • Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J et al. (2006). Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442: 818–822.

    CAS  PubMed  Google Scholar 

  • Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G . (1998). Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J 17: 3714–3725.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kroon E, Thorsteinsdottir U, Mayotte N, Nakamura T, Sauvageau G . (2001). NUP98-HOXA9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice. EMBO J 20: 350–361.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Krosl J, Beslu N, Mayotte N, Humphries RK, Sauvageau G . (2003). The competitive nature of HOXB4-transduced HSC is limited by PBX1: the generation of ultra-competitive stem cells retaining full differentiation potential. Immunity 18: 561–571.

    CAS  PubMed  Google Scholar 

  • Krumlauf R . (1994). Hox genes in vertebrate development. Cell 78: 191–201.

    CAS  PubMed  Google Scholar 

  • Kumar AR, Hudson WA, Chen W, Nishiuchi R, Yao Q, Kersey JH . (2004). Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia. Blood 103: 1823–1828.

    CAS  PubMed  Google Scholar 

  • Lam DH, Aplan PD . (2001). NUP98 gene fusions in hematologic malignancies. Leukemia 15: 1689–1695.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lawrence HJ, Helgason CD, Sauvageau G, Fong S, Izon DJ, Humphries RK et al. (1997). Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis. Blood 89: 1922–1930.

    CAS  PubMed  Google Scholar 

  • Lawrence HJ, Rozenfeld S, Cruz C, Matsukuma K, Kwong A, Komuves L et al. (1999). Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias. Leukemia 13: 1993–1999.

    CAS  PubMed  Google Scholar 

  • Lawrence HJ, Sauvageau G, Humphries RK, Largman C . (1996). The role of HOX homeobox genes in normal and leukemic hematopoiesis. Stem Cells 14: 281–291.

    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 

  • Lin YW, Slape C, Zhang Z, Aplan PD . (2005). NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. Blood 106: 287–295.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mamo A, Krosl J, Kroon E, Bijl J, Thompson A, Mayotte N et al. (2006). Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation. Blood 108: 622–629.

    CAS  PubMed  Google Scholar 

  • Mann RS . (1995). The specificity of homeotic gene function. BioEssays 17: 855–863.

    CAS  PubMed  Google Scholar 

  • Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y et al. (2004). Characterization of clonogenic multiple myeloma cells. Blood 103: 2332–2336.

    CAS  PubMed  Google Scholar 

  • Miller CT, Maves L, Kimmel CB . (2004). moz regulates Hox expression and pharyngeal segmental identity in zebrafish. Development 131: 2443–2461.

    CAS  PubMed  Google Scholar 

  • Miyamoto T, Weissman IL, Akashi K . (2000). AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc Natl Acad Sci USA 97: 7521–7526.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Moretti P, Simmons P, Thomas P, Haylock D, Rathjen P, Vadas M et al. (1994). Identification of homeobox genes expressed in human haemopoietic progenitor cells. Gene 144: 213–219.

    CAS  PubMed  Google Scholar 

  • Morgado E, Albouhair S, Lavau C . (2007). Flt3 is dispensable to the Hoxa9/Meis1 leukemogenic cooperation. Blood 109: 4020–4022.

    CAS  PubMed  Google Scholar 

  • Moskow JJ, Bullrich F, Huebner K, Daar IO, Buchberg AM . (1995). Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice. Mol Cell Biol 15: 5434–5443.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura T . (2005). NUP98 fusion in human leukemia: dysregulation of the nuclear pore and homeodomain proteins. Int J Hematol 82: 21–27.

    CAS  PubMed  Google Scholar 

  • O’Brien CA, Pollett A, Gallinger S, Dick JE . (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445: 106–110.

    PubMed  Google Scholar 

  • Ohta H, Sekulovic S, Bakovic S, Eaves CJ, Pineault N, Gasparetto M et al. (2007). Near maximal-expansions of hematopoietic stem cells in culture using NUP98-HOX fusions. Exp Hematol 35: 817–830.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Okada Y, Jiang Q, Lemieux M, Jeannotte L, Su L, Zhang Y . (2006). Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L. Nat Cell Biol 8: 1017–1024.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Owens BM, Hawley RG . (2002). HOX and non-HOX homeobox genes in leukemic hematopoiesis. Stem Cells 20: 364–379.

    CAS  PubMed  Google Scholar 

  • Ozeki K, Kiyoi H, Hirose Y, Iwai M, Ninomiya M, Kodera Y et al. (2004). Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 103: 1901–1908.

    CAS  PubMed  Google Scholar 

  • Palmqvist L, Argiropoulos B, Pineault N, Abramovich C, Sly LM, Krystal G et al. (2006). The Flt3 receptor tyrosine kinase collaborates with NUP98-HOX fusions in acute myeloid leukemia. Blood 108: 1030–1036.

    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 

  • Passegue E, Wagner EF, Weissman IL . (2004). JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119: 431–443.

    CAS  PubMed  Google Scholar 

  • Pineault N, Abramovich C, Humphries RK . (2005). Transplantable cell lines generated with NUP98-Hox fusion genes undergo leukemic progression by Meis1 independent of its binding to DNA. Leukemia 19: 636–643.

    CAS  PubMed  Google Scholar 

  • Pineault N, Abramovich C, Ohta H, Humphries RK . (2004). Differential and common leukemogenic potentials of multiple NUP98-Hox fusion proteins alone or with Meis1. Mol Cell Biol 24: 1907–1917.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pineault N, Buske C, Feuring-Buske M, Abramovich C, Rosten P, Hogge DE et al. (2003). Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1. Blood 101: 4529–4538.

    CAS  PubMed  Google Scholar 

  • Pineault N, Helgason CD, Lawrence HJ, Humphries RK . (2002). Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol 30: 49–57.

    CAS  PubMed  Google Scholar 

  • Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D et al. (2005). Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 65: 5506–5511.

    CAS  PubMed  Google Scholar 

  • Quentmeier H, Dirks WG, Macleod RA, Reinhardt J, Zaborski M, Drexler HG . (2004). Expression of HOX genes in acute leukemia cell lines with and without MLL translocations. Leuk Lymphoma 45: 567–574.

    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 

  • Rozovskaia T, Feinstein E, Mor O, Foa R, Blechman J, Nakamura T et al. (2001). Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4:11) abnormality. Oncogene 20: 874–878.

    CAS  PubMed  Google Scholar 

  • Satoh Y, Matsumura I, Tanaka H, Ezoe S, Sugahara H, Mizuki M et al. (2004). Roles for c-Myc in self-renewal of hematopoietic stem cells. J Biol Chem 279: 24986–24993.

    CAS  PubMed  Google Scholar 

  • Sauvageau G, Lansdorp PM, Eaves CJ, Hogge DE, Dragowska WH, Reid DS et al. (1994). Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells. Proc Natl Acad Sci USA 91: 12223–12227.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sauvageau G, Thorsteinsdottir U, Eaves CJ, Lawrence HJ, Largman C, Lansdorp PM et al. (1995). Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev 9: 1753–1765.

    CAS  PubMed  Google Scholar 

  • Sauvageau G, Thorsteinsdottir U, Hough MR, Hugo P, Lawrence HJ, Largman C et al. (1997). Overexpression of HOXB3 in hematopoietic cells causes defective lymphoid development and progressive myeloproliferation. Immunity 6: 13–22.

    CAS  PubMed  Google Scholar 

  • Schreiner S, Birke M, Garcia-Cuellar MP, Zilles O, Greil J, Slany RK . (2001). MLL-ENL causes a reversible and myc-dependent block of myelomonocytic cell differentiation. Cancer Res 61: 6480–6486.

    CAS  PubMed  Google Scholar 

  • Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G . (2007). Genome regulation by polycomb and trithorax proteins. Cell 128: 735–745.

    CAS  PubMed  Google Scholar 

  • Shen WF, Detmer K, Mathews CH, Hack FM, Morgan DA, Largman C et al. (1992). Modulation of homeobox gene expression alters the phenotype of human hematopoietic cell lines. EMBO J 11: 983–989.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shen WF, Montgomery JC, Rozenfeld S, Moskow JJ, Lawrence HJ, Buchberg AM et al. (1997). AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol Cell Biol 17: 6448–6458.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shimamoto T, Tang Y, Naot Y, Nardi M, Brulet P, Bieberich CJ et al. (1999). Hematopoietic progenitor cell abnormalities in Hoxc-8 null mutant mice. J Exp Zool 283: 186–193.

    CAS  PubMed  Google Scholar 

  • Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. (2004). Identification of human brain tumour initiating cells. Nature 432: 396–401.

    CAS  PubMed  Google Scholar 

  • Slape C, Aplan PD . (2004). The role of NUP98 gene fusions in hematologic malignancy. Leuk Lymphoma 45: 1341–1350.

    CAS  PubMed  Google Scholar 

  • So CW, Karsunky H, Wong P, Weissman IL, Cleary ML . (2004). Leukemic transformation of hematopoietic progenitors by MLL-GAS7 in the absence of Hoxa7 or Hoxa9. Blood 103: 3192–3199.

    CAS  PubMed  Google Scholar 

  • Somervaille TC, Cleary ML . (2006). Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10: 257–268.

    CAS  PubMed  Google Scholar 

  • Soulier J, Clappier E, Cayuela JM, Regnault A, Garcia-Peydro M, Dombret H et al. (2005). HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). Blood 106: 274–286.

    CAS  PubMed  Google Scholar 

  • Speleman F, Cauwelier B, Dastugue N, Cools J, Verhasselt B, Poppe B et al. (2005). A new recurrent inversion, inv(7)(p15q34), leads to transcriptional activation of HOXA10 and HOXA11 in a subset of T-cell acute lymphoblastic leukemias. Leukemia 19: 358–366.

    CAS  PubMed  Google Scholar 

  • Suemori H, Noguchi S . (2000). Hox C cluster genes are dispensable for overall body plan of mouse embryonic development. Dev Biol 220: 333–342.

    CAS  PubMed  Google Scholar 

  • Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G et al. (2005). Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 106: 4086–4092.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thorsteinsdottir U, Kroon E, Jerome L, Blasi F, Sauvageau G . (2001). Defining roles for HOX and MEIS1 genes in induction of acute myeloid leukemia. Mol Cell Biol 21: 224–234.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Thorsteinsdottir U, Sauvageau G, Hough MR, Dragowska W, Lansdorp PM, Lawrence HJ et al. (1997). Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia. Mol Cell Biol 17: 495–505.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thorsteinsdottir U, Sauvageau G, Humphries RK . (1999). Enhanced in vivo regenerative potential of HOXB4-transduced hematopoietic stem cells with regulation of their pool size. Blood 94: 2605–2612.

    CAS  PubMed  Google Scholar 

  • Tsutsumi S, Taketani T, Nishimura K, Ge X, Taki T, Sugita K et al. (2003). Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements. Cancer Res 63: 4882–4887.

    CAS  PubMed  Google Scholar 

  • Tupler R, Perini G, Green MR . (2001). Expressing the human genome. Nature 409: 832–833.

    CAS  PubMed  Google Scholar 

  • Uchida N, Dykstra B, Lyons KJ, Leung FY, Eaves CJ . (2003). Different in vivo repopulating activities of purified hematopoietic stem cells before and after being stimulated to divide in vitro with the same kinetics. Exp Hematol 31: 1338–1347.

    CAS  PubMed  Google Scholar 

  • van der Lugt NM, Alkema M, Berns A, Deschamps J . (1996). The polycomb-group homolog Bmi-1 is a regulator of murine Hox gene expression. Mech Dev 58: 153–164.

    CAS  PubMed  Google Scholar 

  • Varnum-Finney B, Xu L, Brashem-Stein C, Nourigat C, Flowers D, Bakkour S et al. (2000). Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med 6: 1278–1281.

    CAS  PubMed  Google Scholar 

  • Wang GG, Pasillas MP, Kamps MP . (2005). Meis1 programs transcription of FLT3 and cancer stem cell character, using a mechanism that requires interaction with Pbx and a novel function of the Meis1 C-terminus. Blood 106: 254–264.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang GG, Pasillas MP, Kamps MP . (2006). Persistent transactivation by meis1 replaces hox function in myeloid leukemogenesis models: evidence for co-occupancy of meis1-pbx and hox-pbx complexes on promoters of leukemia-associated genes. Mol Cell Biol 26: 3902–3916.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xin L, Lawson DA, Witte ON . (2005). The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci USA 102: 6942–6947.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R et al. (2002). Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1: 133–143.

    CAS  PubMed  Google Scholar 

  • Zakany J, Fromental-Ramain C, Warot X, Duboule D . (1997). Regulation of number and size of digits by posterior Hox genes: a dose-dependent mechanism with potential evolutionary implications. Proc Natl Acad Sci USA 94: 13695–13700.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zakany J, Gerard M, Favier B, Potter SS, Duboule D . (1996). Functional equivalence and rescue among group 11 Hox gene products in vertebral patterning. Dev Biol 176: 325–328.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang XB, Beard BC, Beebe K, Storer B, Humphries RK, Kiem HP . (2006). Differential effects of HOXB4 on nonhuman primate short- and long-term repopulating cells. PLoS Med 3: e173.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to authors whose work could not be cited due to space constraints. We acknowledge all members of our laboratory for stimulating discussions. We also thank Kim Gall for critical reading of the manuscript. Our work cited is supported by grants from the National Cancer Institute of Canada with funds from the Terry Fox Foundation, Genome Canada/BC, the Canadian NCE Stem Cell Network and the National Institutes of Health. BA is a recipient of a postdoctoral fellowship from the Leukemia Research Fund of Canada.

Author information

Authors and Affiliations

  1. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada

    B Argiropoulos & R K Humphries

  2. Department of Medicine, University of British Columbia, Vancouver, BC, Canada

    R K Humphries

Authors
  1. B Argiropoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R K Humphries
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R K Humphries.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Argiropoulos, B., Humphries, R. Hox genes in hematopoiesis and leukemogenesis. Oncogene 26, 6766–6776 (2007). https://doi.org/10.1038/sj.onc.1210760

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210760

Keywords

This article is cited by

Search

Advanced search

Quick links