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The Hox genes and their roles in oncogenesis

Abstract

Hox genes, a highly conserved subgroup of the homeobox superfamily, have crucial roles in development, regulating numerous processes including apoptosis, receptor signalling, differentiation, motility and angiogenesis. Aberrations in Hox gene expression have been reported in abnormal development and malignancy, indicating that altered expression of Hox genes could be important for both oncogenesis and tumour suppression, depending on context. Therefore, Hox gene expression could be important in diagnosis and therapy.

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Figure 1: Hox clusters, Hox genes and Hox function.

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References

  1. Bridges, C. B. Current maps of the location of the mutant genes of Drosophila Melanogaster. Proc. Natl Acad. Sci. USA 7, 127–132 (1921).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Shen, W. F., Krishnan, K., Lawrence, H. J. & Largman, C. The HOX homeodomain proteins block CBP histone acetyltransferase activity. Mol. Cell. Biol. 21, 7509–7522 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Dolle, P., Izpisua-Belmonte, J. C., Brown, J., Tickle, C. & Duboule, D. Hox genes and the morphogenesis of the vertebrate limb. Prog. Clin. Biol. Res. 383A, 11–20 (1993).

    CAS  PubMed  Google Scholar 

  4. Mortlock, D. P. & Innis, J. W. Mutation of HOXA13 in hand-foot-genital syndrome. Nature Genet. 15, 179–180 (1997).

    CAS  PubMed  Google Scholar 

  5. Perez-Cabrera, A., Kofman-Alfaro, S. & Zenteno, J. C. Mutational analysis of HOXD13 and HOXA13 genes in the triphalangeal thumb-brachyectrodactyly syndrome. J. Orthop. Res. 20, 899–901 (2002).

    CAS  PubMed  Google Scholar 

  6. Zacchetti, G., Duboule, D. & Zakany, J. Hox gene function in vertebrate gut morphogenesis: the case of the caecum. Development 134, 3967–3973 (2007).

    CAS  PubMed  Google Scholar 

  7. Cardoso, W. V. Transcription factors and pattern formation in the developing lung. Am. J. Physiol. 269, L429–L442 (1995).

    CAS  PubMed  Google Scholar 

  8. Simpson, J. L. Genetics of the female reproductive ducts. Am. J. Med. Genet. 89, 224–239 (1999).

    CAS  PubMed  Google Scholar 

  9. Wellik, D. M. Hox genes and vertebrate axial pattern. Curr. Top. Dev. Biol. 88, 257–278 (2009).

    CAS  PubMed  Google Scholar 

  10. Jung, C., Kim, R. S., Lee, S. J., Wang, C. & Jeng, M. H. HOXB13 homeodomain protein suppresses the growth of prostate cancer cells by the negative regulation of T-cell factor 4. Cancer Res. 64, 3046–3051 (2004).

    CAS  PubMed  Google Scholar 

  11. Economides, K. D. & Capecchi, M. R. Hoxb13 is required for normal differentiation and secretory function of the ventral prostate. Development 130, 2061–2069 (2003).

    CAS  PubMed  Google Scholar 

  12. Wang, Z. et al. The prognostic biomarkers HOXB13, IL17BR, and CHDH are regulated by estrogen in breast cancer. Clin. Cancer Res. 13, 6327–6334 (2007).

    CAS  PubMed  Google Scholar 

  13. Calvo, K. R., Sykes, D. B., Pasillas, M. P. & Kamps, M. P. 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 (2002).

    CAS  PubMed  Google Scholar 

  14. Zhang, X. et al. HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells. J. Cell. Mol. Med. 11, 299–306 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Chen, H. et al. HOXA5 acts directly downstream of retinoic acid receptor beta and contributes to retinoic acid-induced apoptosis and growth inhibition. Cancer Res. 67, 8007–8013 (2007).

    CAS  PubMed  Google Scholar 

  16. Miao, J. et al. HOXB13 promotes ovarian cancer progression. Proc. Natl Acad. Sci. USA 104, 17093–17098 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu, X. et al. HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition. Cancer Res. 66, 9527–9534 (2006).

    CAS  PubMed  Google Scholar 

  18. Zhai, Y. et al. Gene expression analysis of preinvasive and invasive cervical squamous cell carcinomas identifies HOXC10 as a key mediator of invasion. Cancer Res. 67, 10163–10172 (2007).

    CAS  PubMed  Google Scholar 

  19. Abate-Shen, C. Deregulated homeobox gene expression in cancer: cause or consequence? Nature Rev. Cancer 2, 777–785 (2002).

    CAS  Google Scholar 

  20. Hershko, A. Y., Kafri, T., Fainsod, A. & Razin, A. Methylation of HoxA5 and HoxB5 and its relevance to expression during mouse development. Gene 302, 65–72 (2003).

    CAS  PubMed  Google Scholar 

  21. Rauch, T. et al. Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay. Proc. Natl Acad. Sci. USA 104, 5527–5532 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Fanti, L. et al. The trithorax group and Pc group proteins are differentially involved in heterochromatin formation in Drosophila. Chromosoma 117, 25–39 (2008).

    CAS  PubMed  Google Scholar 

  23. Hanson, R. D. et al. Mammalian Trithorax and polycomb-group homologues are antagonistic regulators of homeotic development. Proc. Natl Acad. Sci. USA 96, 14372–14377 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Krivtsov, A. V. & Armstrong, S. A. MLL translocations, histone modifications and leukaemia stem-cell development. Nature Rev. Cancer 7, 823–833 (2007).

    CAS  Google Scholar 

  25. Ferrando, A. A. et al. Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation. Blood 102, 262–268 (2003).

    CAS  PubMed  Google Scholar 

  26. Armstrong, S. A., Golub, T. R. & Korsmeyer, S. J. MLL-rearranged leukemias: insights from gene expression profiling. Semin. Hematol. 40, 268–273 (2003).

    CAS  PubMed  Google Scholar 

  27. Golub, T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999).

    CAS  PubMed  Google Scholar 

  28. Faber, J. et al. HOXA9 is required for survival in human MLL-rearranged acute leukemias. Blood 113, 2375–2385 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Yekta, S., Tabin, C. J. & Bartel, D. P. MicroRNAs in the Hox network: an apparent link to posterior prevalence. Nature Rev. Genet. 9, 789–796 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Chopra, V. S. & Mishra, R. K. “Mir”acles in hox gene regulation. Bioessays 28, 445–448 (2006).

    CAS  PubMed  Google Scholar 

  31. Stark, A. et al. A single Hox locus in Drosophila produces functional microRNAs from opposite DNA strands. Genes Dev. 22, 8–13 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Weiss, F. U. et al. Retinoic acid receptor (RAR) antagonists inhibit miR-10a expression and block metastatic behaviour of pancreatic cancer. Gastroenterology 137, 2136–2145 (2009).

    CAS  PubMed  Google Scholar 

  33. Popovic, R. et al. Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood 113, 3314–3322 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Han, L., Witmer, P. D., Casey, E., Valle, D. & Sukumar, S. DNA methylation regulates MicroRNA expression. Cancer Biol. Ther. 6, 1284–1288 (2007).

    CAS  PubMed  Google Scholar 

  35. Sessa, L. et al. Noncoding RNA synthesis and loss of Polycomb group repression accompanies the colinear activation of the human HOXA cluster. RNA 13, 223–239 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Sasaki, Y. T., Sano, M., Kin, T., Asai, K. & Hirose, T. Coordinated expression of ncRNAs and HOX mRNAs in the human HOXA locus. Biochem. Biophys. Res. Commun. 357, 724–730 (2007).

    CAS  PubMed  Google Scholar 

  37. Petruk, S., Sedkov, Y., Brock, H. W. & Mazo, A. A model for initiation of mosaic HOX gene expression patterns by non-coding RNAs in early embryos. RNA Biol. 4, 1–6 (2007).

    CAS  PubMed  Google Scholar 

  38. Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Gupta, R.A., et al. Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature (in the press). 2010.

  40. Khalil, A. M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl Acad. Sci. USA 106, 11667–11672 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Takahashi, O. et al. Dysregulated expression of HOX and ParaHOX genes in human esophageal squamous cell carcinoma. Oncol. Rep. 17, 753–760 (2007).

    CAS  PubMed  Google Scholar 

  42. Jung, C. et al. HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation. Br. J. Cancer 92, 2233–2239 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Ghannam, G. et al. The oncogene Nup98-HOXA9 induces gene transcription in myeloid cells. J. Biol. Chem. 279, 866–875 (2004).

    CAS  PubMed  Google Scholar 

  44. Lawrence, H. J. et al. Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis. Blood 89, 1922–1930 (1997).

    CAS  PubMed  Google Scholar 

  45. Lu, Q. & Kamps, M. P. Heterodimerization of Hox proteins with Pbx1 and oncoprotein E2a-Pbx1 generates unique DNA-binding specifities at nucleotides predicted to contact the N-terminal arm of the Hox homeodomain—demonstration of Hox-dependent targeting of E2a-Pbx1 in vivo. Oncogene 14, 75–83 (1997).

    CAS  PubMed  Google Scholar 

  46. Crijns, A. P. et al. MEIS and PBX homeobox proteins in ovarian cancer. Eur. J. Cancer 43, 2495–2505 (2007).

    CAS  PubMed  Google Scholar 

  47. Kawagoe, H., Humphries, R. K., Blair, A., Sutherland, H. J. & Hogge, D. E. 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 (1999).

    CAS  PubMed  Google Scholar 

  48. Shimamoto, T., Ohyashiki, K., Toyama, K. & Takeshita, K. Homeobox genes in hematopoiesis and leukemogenesis. Int. J. Hematol. 67, 339–350 (1998).

    CAS  PubMed  Google Scholar 

  49. Laurent, A., Bihan, R., Omilli, F., Deschamps, S. & Pellerin, I. PBX proteins: much more than Hox cofactors. Int. J. Dev. Biol. 52, 9–20 (2008).

    CAS  PubMed  Google Scholar 

  50. Myers, C., Charboneau, A., Cheung, I., Hanks, D. & Boudreau, N. Sustained expression of homeobox D10 inhibits angiogenesis. Am. J. Pathol. 161, 2099–2109 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Hansen, S. L., Dosanjh, A., Young, D. M., Boudreau, N. & Hoffman, W. Y. Hemangiomas and homeobox gene expression. J. Craniofac Surg. 17, 767–771 (2006).

    PubMed  Google Scholar 

  52. Myers, C., Charboneau, A. & Boudreau, N. Homeobox B3 promotes capillary morphogenesis and angiogenesis. J. Cell Biol. 148, 343–351 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Huang, L., Pu, Y., Hepps, D., Danielpour, D. & Prins, G. S. Posterior Hox gene expression and differential androgen regulation in the developing and adult rat prostate lobes. Endocrinology 148, 1235–1245 (2007).

    CAS  PubMed  Google Scholar 

  54. Trivedi, C. M., Patel, R. C. & Patel, C. V. Homeobox gene HOXA9 inhibits nuclear factor-κB dependent activation of endothelium. Atherosclerosis 195, e50–e60 (2007).

    Google Scholar 

  55. McMullin, R. P., Mutton, L. N. & Bieberich, C. J. Hoxb13 regulatory elements mediate transgene expression during prostate organogenesis and carcinogenesis. Dev. Dyn. 238, 664–672 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Patel, C. V., Sharangpani, R., Bandyopadhyay, S. & DiCorleto, P. E. Endothelial cells express a novel, tumor necrosis factor-alpha-regulated variant of HOXA9. J. Biol. Chem. 274, 1415–1422 (1999).

    CAS  PubMed  Google Scholar 

  57. Trivedi, C. M., Patel, R. C. & Patel, C. V. Differential regulation of HOXA9 expression by nuclear factor kappa B (NF-κB) and HOXA9. Gene 408, 187–195 (2008).

    CAS  PubMed  Google Scholar 

  58. Park, J. R., Eggert, A. & Caron, H. Neuroblastoma: biology, prognosis, and treatment. Pediatr. Clin. North Am. 55, 97–120 (2008).

    PubMed  Google Scholar 

  59. Abbracchio, M. P., Cattabeni, F., Clementi, F. & Sher, E. Adenosine receptors linked to adenylate cyclase activity in human neuroblastoma cells: modulation during cell differentiation. Neuroscience 30, 819–825 (1989).

    CAS  PubMed  Google Scholar 

  60. Horii, Y. et al. Differential expression of N-myc and c-src proto-oncogenes during neuronal and schwannian differentiation of human neuroblastoma cells. Int. J. Cancer 43, 305–309 (1989).

    CAS  PubMed  Google Scholar 

  61. Manohar, C. F., Salwen, H. R., Furtado, M. R. & Cohn, S. L. Up-regulation of HOXC6, HOXD1, and HOXD8 homeobox gene expression in human neuroblastoma cells following chemical induction of differentiation. Tumour Biol. 17, 34–47 (1996).

    CAS  PubMed  Google Scholar 

  62. Jung, C., Kim, R. S., Zhang, H. J., Lee, S. J. & Jeng, M. H. HOXB13 induces growth suppression of prostate cancer cells as a repressor of hormone-activated androgen receptor signaling. Cancer Res. 64, 9185–9192 (2004).

    CAS  PubMed  Google Scholar 

  63. Miller, G. J. et al. Aberrant HOXC expression accompanies the malignant phenotype in human prostate. Cancer Res. 63, 5879–5888 (2003).

    CAS  PubMed  Google Scholar 

  64. Waltregny, D., Alami, Y., Clausse, N., de Leval, J. & Castronovo, V. Overexpression of the homeobox gene HOXC8 in human prostate cancer correlates with loss of tumor differentiation. Prostate 50, 162–169 (2002).

    CAS  PubMed  Google Scholar 

  65. Kikugawa, T. et al. PLZF regulates Pbx1 transcription and Pbx1-HoxC8 complex leads to androgen-independent prostate cancer proliferation. Prostate 66, 1092–1099 (2006).

    CAS  PubMed  Google Scholar 

  66. Cheng, W., Liu, J., Yoshida, H., Rosen, D. & Naora, H. Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract. Nature Med. 11, 531–537 (2005).

    CAS  PubMed  Google Scholar 

  67. Dubeau, L. The cell of origin of ovarian epithelial tumors and the ovarian surface epithelium dogma: does the emperor have no clothes? Gynecol. Oncol. 72, 437–442 (1999).

    CAS  PubMed  Google Scholar 

  68. Lawrence, H. J., Sauvageau, G., Humphries, R. K. & Largman, C. The role of HOX homeobox genes in normal and leukemic hematopoiesis. Stem Cells 14, 281–291 (1996).

    CAS  PubMed  Google Scholar 

  69. Bijl, J. et al. Expression of HOXC4, HOXC5, and HOXC6 in human lymphoid cell lines, leukemias, and benign and malignant lymphoid tissue. Blood 87, 1737–1745 (1996).

    CAS  PubMed  Google Scholar 

  70. Armstrong, S. A. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nature Genet. 30, 41–47 (2002).

    CAS  PubMed  Google Scholar 

  71. Ayton, P. M. & Cleary, M. L. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev. 17, 2298–2307 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Rubin, E. et al. A role for the HOXB7 homeodomain protein in DNA repair. Cancer Res. 67, 1527–1535 (2007).

    CAS  PubMed  Google Scholar 

  73. Chen, H. et al. Hoxb7 inhibits transgenic HER-2/neu-induced mouse mammary tumor onset but promotes progression and lung metastasis. Cancer Res. 68, 3637–3644 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Chirnomas, D. et al. Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Mol. Cancer Ther. 5, 952–961 (2006).

    CAS  PubMed  Google Scholar 

  75. Ma, X. J. et al. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 5, 607–616 (2004).

    CAS  PubMed  Google Scholar 

  76. Jerevall, P. L. et al. Exploring the two-gene ratio in breast cancer—independent roles for HOXB13 and IL17BR in prediction of clinical outcome. Breast Cancer Res. Treat 107, 225–234 (2008).

    CAS  PubMed  Google Scholar 

  77. Ma, X. J. et al. Gene expression profiles of human breast cancer progression. Proc. Natl Acad. Sci. USA 100, 5974–5979 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Raman, V. et al. Compromised HOXA5 function can limit p53 expression in human breast tumours. Nature 405, 974–978 (2000).

    CAS  PubMed  Google Scholar 

  79. Chen, H., Chung, S. & Sukumar, S. HOXA5-induced apoptosis in breast cancer cells is mediated by caspases 2 and 8. Mol. Cell. Biol. 24, 924–935 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Gendronneau, G. et al. Influence of Hoxa5 on p53 tumorigenic outcome in mice. Am. J. Pathol. 176(2), 995–1005 (2010)

    Google Scholar 

  81. Chu, M. C., Selam, F. B. & Taylor, H. S. HOXA10 regulates p53 expression and matrigel invasion in human breast cancer cells. Cancer Biol. Ther. 3, 568–572 (2004).

    CAS  PubMed  Google Scholar 

  82. Plowright, L., Harrington, K. J., Pandha, H. S. & Morgan, R. HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer). Br. J. Cancer 100, 470–475 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Morgan, R. et al. Antagonism of HOX/PBX dimer formation blocks the in vivo proliferation of melanoma. Cancer Res. 67, 5806–5813 (2007).

    CAS  PubMed  Google Scholar 

  84. Kasibhatla, S. et al. DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-κB and AP-1. Mol. Cell 1, 543–551 (1998).

    CAS  PubMed  Google Scholar 

  85. Argiropoulos, B. & Humphries, R. K. Hox genes in hematopoiesis and leukemogenesis. Oncogene 26, 6766–6776 (2007).

    CAS  PubMed  Google Scholar 

  86. Lawrence, H. J. & Largman, C. Homeobox genes in normal hematopoiesis and leukemia. Blood 80, 2445–2453 (1992).

    CAS  PubMed  Google Scholar 

  87. Hu, Y. L., Fong, S., Ferrell, C., Largman, C. & Shen, W. F. HOXA9 modulates its oncogenic partner Meis1 to influence normal hematopoiesis. Mol. Cell. Biol. 29, 5181–5192 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Whelan, J. T., Ludwig, D. L. & Bertrand, F. E. HoxA9 induces insulin-like growth factor-1 receptor expression in B-lineage acute lymphoblastic leukemia. Leukemia 22, 1161–1169 (2008).

    CAS  PubMed  Google Scholar 

  89. Carrio, M., Arderiu, G., Myers, C. & Boudreau, N. J. Homeobox D10 induces phenotypic reversion of breast tumor cells in a three-dimensional culture model. Cancer Res. 65, 7177–7185 (2005).

    CAS  PubMed  Google Scholar 

  90. Daftary, G. S. & Taylor, H. S. Endocrine regulation of HOX genes. Endocr. Rev. 27, 331–355 (2006).

    CAS  PubMed  Google Scholar 

  91. Loi, S. et al. Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer. BMC Med. Genomics 2, 37 (2009).

    PubMed Central  PubMed  Google Scholar 

  92. Qiu, Y. et al. Pre-B-cell leukemia transcription factor 1 regulates expression of valosin-containing protein, a gene involved in cancer growth. Am. J. Pathol. 170, 152–159 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Crickmore, M. A., Ranade, V. & Mann, R. S. Regulation of Ubx expression by epigenetic enhancer silencing in response to Ubx levels and genetic variation. PLoS Genet. 5, e1000633 (2009).

    PubMed Central  PubMed  Google Scholar 

  94. Kannan, R., Berger, C., Myneni, S., Technau, G. M. & Shashidhara, L. S. Abdominal-A mediated repression of Cyclin E expression during cell-fate specification in the Drosophila central nervous system. Mech. Dev. 127, 137–145 (2009).

    PubMed  Google Scholar 

  95. Leucht, P. et al. Embryonic origin and Hox status determine progenitor cell fate during adult bone regeneration. Development 135, 2845–2854 (2008).

    CAS  PubMed  Google Scholar 

  96. Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).

    CAS  PubMed  Google Scholar 

  97. Korkaya, H. & Wicha, M. S. HER-2, notch, and breast cancer stem cells: targeting an axis of evil. Clin. Cancer Res. 15, 1845–1847 (2009).

    CAS  PubMed  Google Scholar 

  98. Wang, G. G., Cai, L., Pasillas, M. P. & Kamps, M. P. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nature Cell Biol. 9, 804–812 (2007).

    CAS  PubMed  Google Scholar 

  99. Yang, Y. C. et al. A tumorigenic homeobox (HOX) gene expressing human gastric cell line derived from putative gastric stem cell. Eur. J. Gastroenterol. Hepatol 21, 1016–1023 (2009).

    CAS  PubMed  Google Scholar 

  100. Palmqvist, L., Pineault, N., Wasslavik, C. & Humphries, R. K. Candidate genes for expansion and transformation of hematopoietic stem cells by NUP98-HOX fusion genes. PLoS ONE 2, e768 (2007).

    PubMed Central  PubMed  Google Scholar 

  101. Wong, P., Iwasaki, M., Somervaille, T. C., So, C. W. & Cleary, M. L. Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. Genes Dev. 21, 2762–2774 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Chou, W. C. et al. Acute myeloid leukemia bearing t(7;11)(p15;p15) is a distinct cytogenetic entity with poor outcome and a distinct mutation profile: comparative analysis of 493 adult patients. Leukemia 23, 1303–1310 (2009).

    CAS  PubMed  Google Scholar 

  103. Goetz, M. P. et al. A two-gene expression ratio of homeoBOX 13 and interleukin-17B receptor for prediction of recurrence and survival in women receiving adjuvant tamoxifen. Clin. Cancer Res. 12, 2080–2087 (2006).

    CAS  PubMed  Google Scholar 

  104. Jansen, M. P. et al. HOXB13-to-IL17BR expression ratio is related with tumor aggressiveness and response to tamoxifen of recurrent breast cancer: a retrospective study. J. Clin. Oncol. 25, 662–668 (2007).

    CAS  PubMed  Google Scholar 

  105. Zaremba, T. & Curtin, N. J. PARP inhibitor development for systemic cancer targeting. Anticancer Agents Med. Chem. 7, 515–523 (2007).

    CAS  PubMed  Google Scholar 

  106. Kmita, M. et al. Early developmental arrest of mammalian limbs lacking HoxA/HoxD gene function. Nature 435, 1113–1116 (2005).

    CAS  PubMed  Google Scholar 

  107. Dhanasekaran, S. M. et al. Molecular profiling of human prostate tissues: insights into gene expression patterns of prostate development during puberty. FASEB J. 19, 243–245 (2005).

    CAS  PubMed  Google Scholar 

  108. Yahagi, N. et al. Position-specific expression of Hox genes along the gastrointestinal tract. Congenit Anom (Kyoto) 44, 18–26 (2004).

    CAS  Google Scholar 

  109. Volpe, M. V. et al. Aberrant cell adhesion molecule expression in human bronchopulmonary sequestration and congenital cystic adenomatoid malformation. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L143–L152 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Goodman, F. R. Limb malformations and the human HOX genes. Am. J. Med. Genet. 112, 256–265 (2002).

    PubMed  Google Scholar 

  111. Maeda, Y., Dave, V. & Whitsett, J. A. Transcriptional control of lung morphogenesis. Physiol. Rev. 87, 219–244 (2007).

    CAS  PubMed  Google Scholar 

  112. Abramovich, C., Pineault, N., Ohta, H. & Humphries, R. K. Hox genes: from leukemia to hematopoietic stem cell expansion. Ann. NY Acad. Sci. 1044, 109–116 (2005).

    CAS  PubMed  Google Scholar 

  113. Lawrence, H. J. et al. Loss of expression of the Hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells. Blood 106, 3988–3994 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Thorsteinsdottir, U., Sauvageau, G. & Humphries, R. K. Hox homeobox genes as regulators of normal and leukemic hematopoiesis. Hematol. Oncol. Clin. North Am. 11, 1221–1237 (1997).

    CAS  PubMed  Google Scholar 

  115. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    CAS  PubMed  Google Scholar 

  116. Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnol. 26, 101–106 (2008).

    CAS  Google Scholar 

  117. Atkinson, S. P. et al. Epigenetic marking prepares the human HOXA cluster for activation during differentiation of pluripotent cells. Stem Cells 26, 1174–1185 (2008).

    CAS  PubMed  Google Scholar 

  118. Gouti, M. & Gavalas, A. Hoxb1 controls cell fate specification and proliferative capacity of neural stem and progenitor cells. Stem Cells 26, 1985–1997 (2008).

    CAS  PubMed  Google Scholar 

  119. Abramovich, C. & Humphries, R. K. Hox regulation of normal and leukemic hematopoietic stem cells. Curr. Opin. Hematol. 12, 210–216 (2005).

    CAS  PubMed  Google Scholar 

  120. Naguibneva, I. et al. The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation. Nature Cell Biol. 8, 278–284 (2006).

    CAS  PubMed  Google Scholar 

  121. Charboneau, A., East, L., Mulholland, N., Rohde, M. & Boudreau, N. Pbx1 is required for Hox D3-mediated angiogenesis. Angiogenesis 8, 289–296 (2005).

    CAS  PubMed  Google Scholar 

  122. Shen, W., Chrobak, D., Krishnan, K., Lawrence, H. J. & Largman, C. HOXB6 protein is bound to CREB-binding protein and represses globin expression in a DNA binding-dependent, PBX interaction-independent process. J. Biol. Chem. 279, 39895–39904 (2004).

    CAS  PubMed  Google Scholar 

  123. Li, X., Nie, S., Chang, C., Qiu, T. & Cao, X. Smads oppose Hox transcriptional activities. Exp. Cell Res. 312, 854–864 (2006).

    CAS  PubMed  Google Scholar 

  124. Abe, M. et al. Disordered expression of HOX genes in human non-small cell lung cancer. Oncol. Rep. 15, 797–802 (2006).

    CAS  PubMed  Google Scholar 

  125. Alami, Y., Castronovo, V., Belotti, D., Flagiello, D. & Clausse, N. HOXC5 and HOXC8 expression are selectively turned on in human cervical cancer cells compared to normal keratinocytes. Biochem. Biophys. Res. Commun. 257, 738–745 (1999).

    CAS  PubMed  Google Scholar 

  126. Lewis, E. B. Pseudoallelism and gene evolution. Cold Spring Harb. Symp. Quant. Biol. 16, 159–174 (1951).

    CAS  PubMed  Google Scholar 

  127. Lewis, E. B. A gene complex controlling segmentation in Drosophila. Nature 276, 565–570 (1978).

    CAS  PubMed  Google Scholar 

  128. Kaufman, T. C., Lewis, R. & Wakimoto, B. Cytogenetic Analysis of Chromosome 3 in DROSOPHILA MELANOGASTER: The Homoeotic Gene Complex in Polytene Chromosome Interval 84a-B. Genetics 94, 115–133 (1980).

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Scott, M. P. et al. The molecular organization of the Antennapedia locus of Drosophila. Cell 35, 763–776 (1983).

    CAS  PubMed  Google Scholar 

  130. Garber, R. L., Kuroiwa, A. & Gehring, W. J. Genomic and cDNA clones of the homeotic locus Antennapedia in Drosophila. EMBO J. 2, 2027–2036 (1983).

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Duboule, D., Baron, A., Mahl, P. & Galliot, B. A new homeo-box is present in overlapping cosmid clones which define the mouse Hox-1 locus. EMBO J. 5, 1973–1980 (1986).

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Hart, C. P., Awgulewitsch, A., Fainsod, A., McGinnis, W. & Ruddle, F. H. Homeo box gene complex on mouse chromosome 11: molecular cloning, expression in embryogenesis, and homology to a human homeo box locus. Cell 43, 9–18 (1985).

    CAS  PubMed  Google Scholar 

  133. Lonai, P., Arman, E., Czosnek, H., Ruddle, F. H. & Blatt, C. New murine homeoboxes: structure, chromosomal assignment, and differential expression in adult erythropoiesis. DNA 6, 409–418 (1987).

    CAS  PubMed  Google Scholar 

  134. Kongsuwan, K., Webb, E., Housiaux, P. & Adams, J. M. Expression of multiple homeobox genes within diverse mammalian haemopoietic lineages. EMBO J. 7, 2131–2138 (1988).

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Kamps, M. P., 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 60, 547–555 (1990).

    CAS  PubMed  Google Scholar 

  136. Nourse, J. et al. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 60, 535–545 (1990).

    CAS  PubMed  Google Scholar 

  137. Zeltser, L., Desplan, C. & Heintz, N. Hoxb-13: a new Hox gene in a distant region of the HOXB cluster maintains colinearity. Development 122, 2475–2484 (1996).

    CAS  PubMed  Google Scholar 

  138. Biondi, A., Cimino, G., Pieters, R. & Pui, C. H. Biological and therapeutic aspects of infant leukemia. Blood 96, 24–33 (2000).

    CAS  PubMed  Google Scholar 

  139. Yekta, S., Shih, I. H. & Bartel, D. P. MicroRNA-directed cleavage of HOXB8 mRNA. Science 304, 594–596 (2004).

    CAS  PubMed  Google Scholar 

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Shah, N., Sukumar, S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer 10, 361–371 (2010). https://doi.org/10.1038/nrc2826

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