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HOX genes: not just myeloid oncogenes any more

Leukemia volume 19, pages 1328–1330 (2005)Cite this article

The study of HOX homeobox genes in leukemia is a growth industry, as exemplified by a paper by Speleman et al in a recent issue of Leukemia describing a novel inversion of chromosome 7 in cases of T-cell acute lymphocytic leukemia.1, 2 This cryptic inversion involves the HOXA cluster of homeobox genes on the short arm of chromosome 7 and is associated with upregulated expression of several HOXA genes, including HOXA10 and HOXA11. The authors reasonably speculate that this inversion results in the juxtaposition of HOXA genes with enhancer elements of the TCRβ gene, which is active in T lymphocytes. What makes this study interesting and novel is that it adds to growing evidence that HOXA genes, which many workers in the field have regarded as myeloid oncogenes, are also involved in lymphoid malignancies.

There is abundant data showing that HOX genes are involved in human myeloid leukemias. Early evidence came from the identification of translocations involving the nucleoporin gene NUP98 and HOXA9, in rare cases of AML,2, 3 and subsequently, a number of NUP98 fusions with other HOX genes have been described.4, 5, 6, 7, 8 Although translocations involving HOX genes appear to be uncommon,9 other studies demonstrated that HOXA and HOXB genes are frequently overexpressed in human AML,10, 11, 12, 13, 14, 15, 16 presumably as secondary events to primary oncogenic ‘hits’. While in normal blood cell differentiation, HOXA and HOXB gene expression is downregulated as cells mature and leave the CD34+ progenitor pool, the observation that HOXA9 expression persists in CD34− myeloblasts from patients with AML provides further indirect evidence for a pathogenic role of HOXA genes in human myeloid leukemia.17 The association of HOXA9 with AML was particularly striking in the microarray study by Golub's group, where it emerged as one of a small group of genes whose expression could discriminate AML from ALL.18 That study further suggested that high-level expression of HOXA9 in AML was associated with a poor outcome, a suggestion that still needs further validation by more quantitative measurements of HOX gene expression levels in primary patient samples.

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References

  1. Speleman F, Cauwelier B, Dastugue N, Cools J, Verhasselt B, Poppe B et al. 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 2005; 19: 358–366.

    Article  CAS  Google Scholar 

  2. Borrow J, Shearman AM, Stanton VPJ, Becher R, Collins T, Williams AJ et al. The t(7;11) (p15;p15) translocation in acute myeloid leukemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nat Genet 1996; 12: 159–167.

    Article  CAS  Google Scholar 

  3. Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet 1996; 12: 154–158.

    Article  CAS  Google Scholar 

  4. 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 

  5. La Starza R, Trubia M, Crescenzi B, Matteucci C, Negrini M, Martelli MF et al. Human homeobox gene HOXC13 is the partner of NUP98 in adult acute myeloid leukemia with t(11;12)(p15;q13). Genes Chromosomes Cancer 2003; 36: 420–423.

    Article  CAS  Google Scholar 

  6. Taketani T, Taki T, Ono R, Kobayashi Y, Ida K, Hayashi Y . The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9. Genes Chromosomes Cancer 2002; 34: 437–443.

    Article  CAS  Google Scholar 

  7. Taketani T, Taki T, Shibuya N, Kikuchi A, Hanada R, Hayashi Y . Novel NUP98-HOXC11 fusion gene resulted from a chromosomal break within exon 1 of HOXC11 in acute myeloid leukemia with t(11;12)(p15;q13). Cancer Res 2002; 62: 4571–4574.

    CAS  PubMed  Google Scholar 

  8. Arai Y, Kyo T, Miwa H, Arai K, Kamada N, Kita K et al. Heterogenous fusion transcripts involving the NUP98 gene and HOXD13 gene activation in a case of acute myeloid leukemia with the t(2;11)(q31;p15) translocation. Leukemia 2000; 14: 1621–1629.

    Article  CAS  Google Scholar 

  9. Kwong YL, Pang A . Low frequency of rearrangements of the homeobox gene HOXA9/t(7;11) in adult acute myeloid leukemia. Genes Chromosomes Cancer 1999; 25: 70–74.

    Article  CAS  Google Scholar 

  10. Giampaolo A, Acampora D, Zappavigna V, Pannese M, D'Esposito M, Care A et al. Differential expression of human HOX-2 genes along the anterior-posterior axis in embryonic central nervous system. Differentiation 1989; 40: 191–197.

    Article  CAS  Google Scholar 

  11. Roche J, Zeng C, Baron A, Gadgil S, Gemmill RM, Tigaud I et al. Hox expression in AML identifies a distinct subset of patients with intermediate cytogenetics. Leukemia 2004; 18: 1059–1063.

    Article  CAS  Google Scholar 

  12. Giampaolo A, Felli N, Diverio D, Morsilli O, Samoggia P, Breccia M et al. Expression pattern of HOXB6 homeobox gene in myelomonocytic differentiation and acute myeloid leukemia. Leukemia 2002; 16: 1293–1301.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Debernardi S, Lillington DM, Chaplin T, Tomlinson S, Amess J, Rohatiner A et al. Genome-wide analysis of acute myeloid leukemia with normal karyotype reveals a unique pattern of homeobox gene expression distinct from those with translocation-mediated fusion events. Genes Chromosomes Cancer 2003; 37: 149–158.

    Article  CAS  Google Scholar 

  15. Lawrence HJ, Rozenfeld S, Cruz C, Matsukuma K, Shen W-F, Buchberg A et al. Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias. Leukemia 1999; 13: 1993–1999.

    Article  CAS  Google Scholar 

  16. Lawrence HJ, Sauvageau G, Ahmadi N, Lopez AR, LeBeau MM, Link M et al. 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 

  17. 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 

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

    Article  CAS  Google Scholar 

  19. Nakamura T, Largaespada DA, Shaughnessy JDJ, Jenkins NA, Copeland NG . Cooperative activation of Hoxa and Pbx-1-related genes in murine myeloid leukemias. Nat Genet 1996; 12: 149–153.

    Article  CAS  Google Scholar 

  20. 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 

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

    Article  CAS  Google Scholar 

  22. Fischbach NA, Rozenfeld S, Shen W, Fong S, Chrobak D, Ginzinger D 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.

    Article  CAS  Google Scholar 

  23. Thorsteinsdottir U, Sauvageau G, Hough MR, Dragowska W, Lansdorp PM, Lawrence HJ 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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. 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 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Dorsam TS, Ferrell MC, Dorsam PG, Vijapurkar U, Khodabakhsh D, Pau B et al. The transcriptome of the leukemogenic homeoprotein HOXA9 in human hematopoietic cells. Blood 2004; 103: 1676–1684.

    Article  CAS  Google Scholar 

  29. Bijl J, van Oostveen JW, Kreike M, Rieger E, van der Raaij-Helmer LMH, Walboomers JMM 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.

    CAS  PubMed  Google Scholar 

  30. Lawrence HJ, Stage KM, Mathews CHE, Detmer K, Scibenski R, MacKenzie M et al. Expression of HOXC homeobox genes in lymphoid cells. Cell Growth Differ 1993; 4: 665–669.

    CAS  PubMed  Google Scholar 

  31. Taghon T, Thys K, De Smedt M, Weerkamp F, Staal FJ, Plum J et al. Homeobox gene expression profile in human hematopoietic multipotent stem cells and T-cell progenitors: implications for human T-cell development. Leukemia 2003; 17: 1157–1163.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  33. Kamps MP, Murre C, Sun X-H, 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 

  34. Chang C-P, Shen W-F, Rozenfeld S, Lawrence HJ, Largman C, Cleary ML . Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins. Genes Dev 1995; 9: 663–674.

    Article  CAS  Google Scholar 

  35. Kamps MP, Baltimore D . E2A-Pbx1, the t(1;19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice. Mol Cell Biol 1993; 13: 351–357.

    Article  CAS  Google Scholar 

  36. Dedera DA, Waller EK, LeBrun DP, Sen-Majumdar A, Stevens ME, Barsh GS et al. Chimeric homeobox gene E2A-PBX1 induces proliferation, apaptosis and malignant lymphomas in transgenic mice. Cell 1993; 74: 833–843.

    Article  CAS  Google Scholar 

  37. Bijl J, Sauvageau M, Thompson A, Sauvageau G . High incidence of proviral integrations in the Hoxa locus in a new model of E2a-PBX1-induced B-cell leukemia. Genes Dev 2005; 19: 224–233.

    Article  CAS  Google Scholar 

  38. Abate-Shen C . Deregulated homeobox gene expression in cancer: cause or consequence? Nat Rev Cancer 2002; 2: 777–785.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  40. Ma XJ, Wang Z, Ryan PD, Isakoff SJ, Barmettler A, Fuller A et al. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 2004; 5: 607–616.

    Article  CAS  Google Scholar 

  41. Singh D, Febbo PG, Ross K, Jackson DG, Manola J, Ladd C et al. Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 2002; 1: 203–209.

    Article  CAS  Google Scholar 

  42. Raman V, Martensen SA, Reisman D, Evron E, Odenwald WF, Jaffee E et al. Compromised HOXA5 function can limit p53 expression in human breast tumours. Nature 2000; 405: 974–978.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology and Medical Oncology, University of California School of Medicine, VA Medical Center, San Francisco, CA, USA

    H J Lawrence, N A Fischbach & C Largman

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  1. H J Lawrence
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  2. N A Fischbach
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Correspondence to H J Lawrence.

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HJL and NAF are both recipients of VA Career Development Awards. CL is a VA Career Scientist.

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Lawrence, H., Fischbach, N. & Largman, C. HOX genes: not just myeloid oncogenes any more. Leukemia 19, 1328–1330 (2005). https://doi.org/10.1038/sj.leu.2403816

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