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.

  • Original Manuscript
  • Published:

Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia

Abstract

We used a degenerate RT-PCR screen and subsequent real-time quantitative RT-PCR assays to examine the expression of HOX and TALE-family genes in 34 cases of chromosomally defined AML for which outcome data were available. AMLs with favorable cytogenetic features were associated with low overall HOX gene expression whereas poor prognostic cases had high levels. Characteristically, multiple HOXA family members including HOXA3–HOXA10 were jointly overexpressed in conjunction with HOXB3, HOXB6, MEIS1 and PBX3. Higher levels of expression were also observed in the FAB subtype, AML-M1. Spearmann correlation coefficients indicated that the expression levels for many of these genes were highly inter-related. While we did not detect any significant correlations between HOX expression and complete response rates or age in this limited set of patients, there was a significant correlation between event-free survival and HOXA7 with a trend toward significance for HoxA9, HoxA4 and HoxA5. While patients with elevated HOX expression did worse, there were notable exceptions. Thus, although HOX overexpression and clinical resistance to chemotherapy often coincide, they are not inextricably linked. Our results indicate that quantitative HOX analysis has the potential to add new information to the management of patients with AML, especially where characteristic chromosomal alterations are lacking.

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

Access options

Buy this article

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

Similar content being viewed by others

References

  1. Scott MP, Tamkun JW, Hartzell GW III . The structure and function of the homeodomain Biochim Biophys Acta 1989 989: 25–48

    CAS  PubMed  Google Scholar 

  2. Graham A, Papalopulu N, Krumlauf R . The murine and Drosophila homeobox gene complexes have common features of organization and expression Cell 1989 57: 367–378

    Article  CAS  Google Scholar 

  3. Flagiello D, Gibaud A, Dutrillaux B, Poupon MF, Malfoy B . Distinct patterns of all-trans retinoic acid dependent expression of HOXB and HOXC homeogenes in human embryonal and small-cell lung carcinoma cell lines FEBS Lett 1997 415: 263–267

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Aplan PD . NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia Cancer Res 1998 58: 4269–4273

    CAS  PubMed  Google Scholar 

  6. Nakamura T, Yamazaki Y, Hatano Y, Miura I . NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15) Blood 1999 94: 741–747

    CAS  PubMed  Google Scholar 

  7. Borrow J, Shearman AM, Stanton VP Jr, Becher R, Collins T, Williams AJ, Dube I, Katz F, Kwong YL, Morris C, Ohyashiki K, Toyama K, Rowley J, Housman DE . The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9 Nat Genet 1996 12: 159–167

    Article  CAS  Google Scholar 

  8. Hatano M, Roberts CW, Minden M, Crist WM, Korsmeyer SJ . Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia Science 1991 253: 79–82

    Article  CAS  Google Scholar 

  9. Nourse J, Mellentin JD, Galili N, Wilkinson J, Stanbridge E, Smith SD, Cleary ML . Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor Cell 1990 60: 535–545

    Article  CAS  Google Scholar 

  10. Kamps MP, Murre C, Sun XH, Baltimore D . A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL Cell 1990 60: 547–555

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Thorsteinsdottir U, Sauvageau G, Hough MR, Dragowska W, Lansdorp PM, Lawrence HJ, Largman C, Humphries RK . 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

    Article  CAS  Google Scholar 

  13. 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

    Article  CAS  Google Scholar 

  14. Perkins A, Kongsuwan K, Visvader J, Adams JM, Cory S . Homeobox gene expression plus autocrine growth factor productionelicits myeloid leukemia Proc Natl Acad Sci USA 1990 87: 8398–8402

    Article  CAS  Google Scholar 

  15. Joh T, Hosokawa Y, Suzuki R, Takahashi T, Seto M . Establishment of an inducible expression system of chimeric MLL-LTG9 protein and inhibition of Hox a7, Hox b7 and Hox c9 expression by MLL-LTG9 in 32Dcl3 cells Oncogene 1999 18: 1125–1130

    Article  CAS  Google Scholar 

  16. Rozovskaia T, Feinstein O, Foa R, Blechman J, Nakamura T, Croce CM, Cimino G, Canaani E . Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4:11) abnormality Oncogene 2001 20: 874–878

    Article  CAS  Google Scholar 

  17. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, Coller H, Loh ML, Downing JR, Caligiuri MA, Bloomfield CD, Lander ES . Molecular classification of cancer: class discovery and class prediction by gene expression monitoring Science 1999 286: 531–537

    Article  CAS  Google Scholar 

  18. Calvo R, West J, Franklin W, Erickson P, Bemis L, Li E, Helfrich B, Bunn P, Roche J, Brambilla E, Rosell R, Gemmill RM, Drabkin HA . Altered HOX and WNT7A expression in human lung cancer Proc Natl Acad Sci USA 2000 97: 12776–12781

    Article  CAS  Google Scholar 

  19. Wheatley K, Burnett AK, Goldstone AH, Gray RG, Hann IM, Harrison CJ, Rees JK, Stevens RF, Walker H . A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council's Adult and Childhood Leukaemia Working Parties Br J Haematol 1999 107: 69–79

    Article  CAS  Google Scholar 

  20. Thirman MJ, Gill HJ, Burnett RC, Mbangkollo D, McCabe NR, Kobayashi H, Ziemin-van der Poel S, Kaneko Y, Morgan R, Sandberg AA, Rowley JD . Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations N Engl J Med 1993 329: 909–914

    Article  CAS  Google Scholar 

  21. Baer MR, Stewart CC, Lawrence D, Arthur DC, Mrozek K, Strout MP, Davey FR, Schiffer CA, Bloomfield CD . Acute myeloid leukemia with 11q23 translocations: myelomonocytic immunophenotype by multiparameter flow cytometry Leukemia 1998 12: 317–325

    Article  CAS  Google Scholar 

  22. Bedford FK, Ashworth A, Enver T, Wiedemann LM . HEX: a novel homeobox gene expressed during haematopoiesis and conserved between mouse and human Nucleic Acids Res 1993 21: 1245–1249

    Article  CAS  Google Scholar 

  23. Jayaraman PS, Frampton J, Goodwin G . The homeodomain protein PRH influences the differentiation of haematopoietic cells Leuk Res 2000 24: 1023–1031

    Article  CAS  Google Scholar 

  24. Manfioletti G, Gattei V, Buratti E, Rustighi A, De Iuliis A, Aldinucci D, Goodwin GH, Pinto A . Differential expression of a novel proline-rich homeobox gene (Prh) in human hematolymphopoietic cells Blood 1995 85: 1237–1245

    CAS  PubMed  Google Scholar 

  25. Murphy JM, Berwick DM, Weinstein MC, Borus JF, Budman SH, Klerman GL . Performance of screening and diagnostic tests. Application of receiver operating characteristic analysis Arch Gen Psychiatry 1987 44: 550–555

    Article  CAS  Google Scholar 

  26. Hanley JA, McNeil BJ . A method of comparing the areas under receiver operating characteristic curves derived from the same cases Radiology 1983 148: 839–843

    Article  CAS  Google Scholar 

  27. 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 USA 1991 88: 6348–6352

    Article  CAS  Google Scholar 

  28. Sauvageau G, Lansdorp PM, Eaves CJ, Hogge DE, Dragowska WH, Reid DS, Largman C, Lawrence HJ, Humphries RK . Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells Proc Natl Acad Sci USA 1994 91: 12223–12227

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Lawrence HJ, Sauvageau G, Ahmadi N, Lopez AR, LeBeau MM, Link M, Humphries K, Largman C . Stage- and lineage-specific expression of the HOXA10 homeobox gene in normal and leukemic hematopoietic cells Exp Hematol 1995 23: 1160–1166

    CAS  PubMed  Google Scholar 

  31. Lawrence HJ, Rozenfeld S, Cruz C, Matsukuma K, Kwong A, Komuves L, Buchberg AM, Largman C . Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias Leukemia 1999 13: 1993–1999

    Article  CAS  Google Scholar 

  32. Caligiuri MA, Strout MP, Lawrence D, Arthur DC, Baer MR, Yu F, Knuutila S, Mrozek K, Oberkircher AR, Marcucci G, de la Chapelle A, Elonen E, Block AW, Rao PN, Herzig GP, Powell BL, Ruutu T, Schiffer CA, Bloomfield CD . Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics Cancer Res 1998 58: 55–59

    CAS  PubMed  Google Scholar 

  33. 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

    Article  CAS  Google Scholar 

  34. Schnabel CA, Jacobs Y, Cleary ML . HoxA9-mediated immortalization of myeloid progenitors requires functional interactions with TALE cofactors Pbx and Meis Oncogene 2000 19: 608–616

    Article  CAS  Google Scholar 

  35. Buske C, Feuring-Buske M, Antonchuk J, Rosten P, Hogge DE, Eaves CJ, Humphries RK . Overexpression of HOXA10 perturbs human lymphomyelopoiesis in vitro and in vivo Blood 2001 97: 2286–2292

    Article  CAS  Google Scholar 

  36. Sauvageau G, Thorsteinsdottir U, Eaves CJ, Lawrence HJ, Largman C, Lansdorp PM, Humphries RK . 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

    Article  CAS  Google Scholar 

  37. Crooks GM, Fuller J, Petersen D, Izadi P, Malik P, Pattengale PK, Kohn DB, Gasson JC . Constitutive HOXA5 expression inhibits erythropoiesis and increases myelopoiesis from human hematopoietic progenitors Blood 1999 94: 519–528

    CAS  PubMed  Google Scholar 

  38. Nakamura T, Largaespada DA, Shaughnessy JD Jr, Jenkins NA, Copeland NG . Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias Nat Genet 1996 12: 149–153

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  40. Saleh M, Rambaldi I, Yang XJ, Featherstone MS . Cell signaling switches HOX-PBX complexes from repressors to activators of transcription mediated by histone deacetylases and histone acetyltransferases Mol Cell Biol 2000 20: 8623–8633

    Article  CAS  Google Scholar 

  41. Ferrara FF, Fazi F, Bianchini A, Padula F, Gelmetti V, Minucci S, Mancini M, Pelicci PG, Lo Coco F, Nervi C . Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia Cancer Res 2001 61: 2–7

    PubMed  Google Scholar 

  42. Shen WF, Rozenfeld S, Kwong A, Kom ves LG, Lawrence HJ, Largman C . HOXA9 forms triple complexes with PBX2 and MEIS1 in myeloid cells Mol Cell Biol 1999 19: 3051–3061

    Article  CAS  Google Scholar 

  43. Shanmugam K, Green NC, Rambaldi I, Saragovi HU, Featherstone MS . PBX and MEIS as non-DNA-binding partners in trimeric complexes with HOX proteins Mol Cell Biol 1999 19: 7577–7588

    Article  CAS  Google Scholar 

  44. Mitelman F (ed). ISCN (1995): An International System for Human Cytogenetic Nomenclature S Karger: Basel 1995 Reference added in proof

    Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the generous support from the Lulu Frankel Foundation. DNA sequencing support was provided by the University of Colorado Cancer Center DNA Sequencing Core. We also wish to acknowledge the generous support from L'Association pour la Recherche sur le Cancer (JR, AB, FB) and La Ligue Nationale Contre le Cancer, Comité de la Vienne et de Charente-Maritime (JR, AB, FB).

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Drabkin, H., Parsy, C., Ferguson, K. et al. Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia. Leukemia 16, 186–195 (2002). https://doi.org/10.1038/sj.leu.2402354

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402354

Keywords

This article is cited by

Search

Quick links