Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b (original) (raw)

Abstract

Hoxa9, Meis1 and Pbx1 encode homeodomaincontaining proteins implicated in leukemic transformation in both mice and humans. Hoxa9, Meis1 and Pbx1 proteins have been shown to physically interact with each other, as Hoxa9 cooperatively binds consensus DNA sequences with Meis1 and with Pbx1, while Meis1 and Pbx1 form heterodimers in both the presence and absence of DNA. In this study, we sought to determine if Hoxa9 could transform hemopoietic cells in collaboration with either Pbx1 or Meis1. Primary bone marrow cells, retrovirally engineered to overexpress Hoxa9 and Meis1a simultaneously, induced growth factor-dependent oligoclonal acute myeloid leukemia in <3 months when transplanted into syngenic mice. In contrast, overexpression of Hoxa9, Meis1a or Pbx1b alone, or the combination of Hoxa9 and Pbx1b failed to transform these cells acutely within 6 months post-transplantation. Similar results were obtained when FDC-P1 cells, engineered to overexpress these genes, were transplanted to syngenic recipients. Thus, these studies demonstrate a selective collaboration between a member of the Hox family and one of its DNA-binding partners in transformation of hemopoietic cells.

Full Text

The Full Text of this article is available as a PDF (472.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berthelsen J., Zappavigna V., Mavilio F., Blasi F. Prep1, a novel functional partner of Pbx proteins. EMBO J. 1998 Mar 2;17(5):1423–1433. doi: 10.1093/emboj/17.5.1423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blatt C., Aberdam D., Schwartz R., Sachs L. DNA rearrangement of a homeobox gene in myeloid leukaemic cells. EMBO J. 1988 Dec 20;7(13):4283–4290. doi: 10.1002/j.1460-2075.1988.tb03326.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Borrow J., Shearman A. M., Stanton V. P., Jr, Becher R., Collins T., Williams A. J., Dubé I., Katz F., Kwong Y. L., Morris C. 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 Feb;12(2):159–167. doi: 10.1038/ng0296-159. [DOI] [PubMed] [Google Scholar]
  4. Bürglin T. R., Ruvkun G. New motif in PBX genes. Nat Genet. 1992 Aug;1(5):319–320. doi: 10.1038/ng0892-319. [DOI] [PubMed] [Google Scholar]
  5. Carè A., Testa U., Bassani A., Tritarelli E., Montesoro E., Samoggia P., Cianetti L., Peschle C. Coordinate expression and proliferative role of HOXB genes in activated adult T lymphocytes. Mol Cell Biol. 1994 Jul;14(7):4872–4877. doi: 10.1128/mcb.14.7.4872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chan S. K., Jaffe L., Capovilla M., Botas J., Mann R. S. The DNA binding specificity of Ultrabithorax is modulated by cooperative interactions with extradenticle, another homeoprotein. Cell. 1994 Aug 26;78(4):603–615. doi: 10.1016/0092-8674(94)90525-8. [DOI] [PubMed] [Google Scholar]
  7. Chang C. P., Brocchieri L., Shen W. F., Largman C., Cleary M. L. Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA-binding specificities across the Hox locus. Mol Cell Biol. 1996 Apr;16(4):1734–1745. doi: 10.1128/mcb.16.4.1734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chang C. P., Jacobs Y., Nakamura T., Jenkins N. A., Copeland N. G., Cleary M. L. Meis proteins are major in vivo DNA binding partners for wild-type but not chimeric Pbx proteins. Mol Cell Biol. 1997 Oct;17(10):5679–5687. doi: 10.1128/mcb.17.10.5679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cone R. D., Mulligan R. C. High-efficiency gene transfer into mammalian cells: generation of helper-free recombinant retrovirus with broad mammalian host range. Proc Natl Acad Sci U S A. 1984 Oct;81(20):6349–6353. doi: 10.1073/pnas.81.20.6349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. De Vita G., Barba P., Odartchenko N., Givel J. C., Freschi G., Bucciarelli G., Magli M. C., Boncinelli E., Cillo C. Expression of homeobox-containing genes in primary and metastatic colorectal cancer. Eur J Cancer. 1993;29A(6):887–893. doi: 10.1016/s0959-8049(05)80432-0. [DOI] [PubMed] [Google Scholar]
  11. Dexter T. M., Garland J., Scott D., Scolnick E., Metcalf D. Growth of factor-dependent hemopoietic precursor cell lines. J Exp Med. 1980 Oct 1;152(4):1036–1047. doi: 10.1084/jem.152.4.1036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Di Rocco G., Mavilio F., Zappavigna V. Functional dissection of a transcriptionally active, target-specific Hox-Pbx complex. EMBO J. 1997 Jun 16;16(12):3644–3654. doi: 10.1093/emboj/16.12.3644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Friedmann Y., Daniel C. A., Strickland P., Daniel C. W. Hox genes in normal and neoplastic mouse mammary gland. Cancer Res. 1994 Nov 15;54(22):5981–5985. [PubMed] [Google Scholar]
  14. González-Crespo S., Morata G. Control of Drosophila adult pattern by extradenticle. Development. 1995 Jul;121(7):2117–2125. doi: 10.1242/dev.121.7.2117. [DOI] [PubMed] [Google Scholar]
  15. Hassan H. T., Drexler H. G. Interleukins and colony stimulating factors in human myeloid leukemia cell lines. Leuk Lymphoma. 1995 Dec;20(1-2):1–15. doi: 10.3109/10428199509054748. [DOI] [PubMed] [Google Scholar]
  16. Hawley R. G., Fong A. Z., Reis M. D., Zhang N., Lu M., Hawley T. S. Transforming function of the HOX11/TCL3 homeobox gene. Cancer Res. 1997 Jan 15;57(2):337–345. [PubMed] [Google Scholar]
  17. Humphries R. K., Eaves A. C., Eaves C. J. Self-renewal of hemopoietic stem cells during mixed colony formation in vitro. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3629–3633. doi: 10.1073/pnas.78.6.3629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kamps M. P., 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 Jan;13(1):351–357. doi: 10.1128/mcb.13.1.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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. 1990 Feb 23;60(4):547–555. doi: 10.1016/0092-8674(90)90658-2. [DOI] [PubMed] [Google Scholar]
  20. Knoepfler P. S., Calvo K. R., Chen H., Antonarakis S. E., Kamps M. P. Meis1 and pKnox1 bind DNA cooperatively with Pbx1 utilizing an interaction surface disrupted in oncoprotein E2a-Pbx1. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14553–14558. doi: 10.1073/pnas.94.26.14553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Krumlauf R. Hox genes in vertebrate development. Cell. 1994 Jul 29;78(2):191–201. doi: 10.1016/0092-8674(94)90290-9. [DOI] [PubMed] [Google Scholar]
  22. Lapidot T., Sirard C., Vormoor J., Murdoch B., Hoang T., Caceres-Cortes J., Minden M., Paterson B., Caligiuri M. A., Dick J. E. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994 Feb 17;367(6464):645–648. doi: 10.1038/367645a0. [DOI] [PubMed] [Google Scholar]
  23. Lawrence H. J., Helgason C. D., Sauvageau G., Fong S., Izon D. J., Humphries R. K., Largman C. Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis. Blood. 1997 Mar 15;89(6):1922–1930. [PubMed] [Google Scholar]
  24. Lawrence H. J., Sauvageau G., Ahmadi N., Lopez A. R., LeBeau M. M., 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 Oct;23(11):1160–1166. [PubMed] [Google Scholar]
  25. Lindblad P., Zack M., Adami H. O., Ericson A. Maternal and perinatal risk factors for Wilms' tumor: a nationwide nested case-control study in Sweden. Int J Cancer. 1992 Apr 22;51(1):38–41. doi: 10.1002/ijc.2910510108. [DOI] [PubMed] [Google Scholar]
  26. Maconochie M. K., Nonchev S., Studer M., Chan S. K., Pöpperl H., Sham M. H., Mann R. S., Krumlauf R. Cross-regulation in the mouse HoxB complex: the expression of Hoxb2 in rhombomere 4 is regulated by Hoxb1. Genes Dev. 1997 Jul 15;11(14):1885–1895. doi: 10.1101/gad.11.14.1885. [DOI] [PubMed] [Google Scholar]
  27. Mann R. S., Chan S. K. Extra specificity from extradenticle: the partnership between HOX and PBX/EXD homeodomain proteins. Trends Genet. 1996 Jul;12(7):258–262. doi: 10.1016/0168-9525(96)10026-3. [DOI] [PubMed] [Google Scholar]
  28. Markowitz D., Goff S., Bank A. A safe packaging line for gene transfer: separating viral genes on two different plasmids. J Virol. 1988 Apr;62(4):1120–1124. doi: 10.1128/jvi.62.4.1120-1124.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Markowitz D., Goff S., Bank A. Construction and use of a safe and efficient amphotropic packaging cell line. Virology. 1988 Dec;167(2):400–406. [PubMed] [Google Scholar]
  30. Monica K., Galili N., Nourse J., Saltman D., Cleary M. L. PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1. Mol Cell Biol. 1991 Dec;11(12):6149–6157. doi: 10.1128/mcb.11.12.6149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Moskow J. J., Bullrich F., Huebner K., Daar I. O., Buchberg A. M. Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice. Mol Cell Biol. 1995 Oct;15(10):5434–5443. doi: 10.1128/mcb.15.10.5434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nakamura T., Largaespada D. A., Shaughnessy J. D., Jr, Jenkins N. A., Copeland N. G. Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias. Nat Genet. 1996 Feb;12(2):149–153. doi: 10.1038/ng0296-149. [DOI] [PubMed] [Google Scholar]
  33. Pai C. Y., Kuo T. S., Jaw T. J., Kurant E., Chen C. T., Bessarab D. A., Salzberg A., Sun Y. H. The Homothorax homeoprotein activates the nuclear localization of another homeoprotein, extradenticle, and suppresses eye development in Drosophila. Genes Dev. 1998 Feb 1;12(3):435–446. doi: 10.1101/gad.12.3.435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pawliuk R., Kay R., Lansdorp P., Humphries R. K. Selection of retrovirally transduced hematopoietic cells using CD24 as a marker of gene transfer. Blood. 1994 Nov 1;84(9):2868–2877. [PubMed] [Google Scholar]
  35. Peers B., Sharma S., Johnson T., Kamps M., Montminy M. The pancreatic islet factor STF-1 binds cooperatively with Pbx to a regulatory element in the somatostatin promoter: importance of the FPWMK motif and of the homeodomain. Mol Cell Biol. 1995 Dec;15(12):7091–7097. doi: 10.1128/mcb.15.12.7091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Peifer M., Wieschaus E. Mutations in the Drosophila gene extradenticle affect the way specific homeo domain proteins regulate segmental identity. Genes Dev. 1990 Jul;4(7):1209–1223. doi: 10.1101/gad.4.7.1209. [DOI] [PubMed] [Google Scholar]
  37. Perkins A. C., Cory S. Conditional immortalization of mouse myelomonocytic, megakaryocytic and mast cell progenitors by the Hox-2.4 homeobox gene. EMBO J. 1993 Oct;12(10):3835–3846. doi: 10.1002/j.1460-2075.1993.tb06062.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Perkins A., Kongsuwan K., Visvader J., Adams J. M., Cory S. Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8398–8402. doi: 10.1073/pnas.87.21.8398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Quaranta M. T., Petrini M., Tritarelli E., Samoggia P., Carè A., Bottero L., Testa U., Peschle C. HOXB cluster genes in activated natural killer lymphocytes: expression from 3'-->5' cluster side and proliferative function. J Immunol. 1996 Sep 15;157(6):2462–2469. [PubMed] [Google Scholar]
  40. Rauskolb C., Smith K. M., Peifer M., Wieschaus E. extradenticle determines segmental identities throughout Drosophila development. Development. 1995 Nov;121(11):3663–3673. doi: 10.1242/dev.121.11.3663. [DOI] [PubMed] [Google Scholar]
  41. Rieckhof G. E., Casares F., Ryoo H. D., Abu-Shaar M., Mann R. S. Nuclear translocation of extradenticle requires homothorax, which encodes an extradenticle-related homeodomain protein. Cell. 1997 Oct 17;91(2):171–183. doi: 10.1016/s0092-8674(00)80400-6. [DOI] [PubMed] [Google Scholar]
  42. Rodriguez-Cimadevilla J. C., Beauchemin V., Villeneuve L., Letendre F., Shaw A., Hoang T. Coordinate secretion of interleukin-1 beta and granulocyte-macrophage colony-stimulating factor by the blast cells of acute myeloblastic leukemia: role of interleukin-1 as an endogenous inducer. Blood. 1990 Oct 15;76(8):1481–1489. [PubMed] [Google Scholar]
  43. Sauvageau G., Lansdorp P. M., Eaves C. J., Hogge D. E., Dragowska W. H., Reid D. S., Largman C., Lawrence H. J., Humphries R. K. Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12223–12227. doi: 10.1073/pnas.91.25.12223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sauvageau G., Thorsteinsdottir U., Eaves C. J., Lawrence H. J., Largman C., Lansdorp P. M., Humphries R. K. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev. 1995 Jul 15;9(14):1753–1765. doi: 10.1101/gad.9.14.1753. [DOI] [PubMed] [Google Scholar]
  45. Sauvageau G., Thorsteinsdottir U., Hough M. R., Hugo P., Lawrence H. J., Largman C., Humphries R. K. Overexpression of HOXB3 in hematopoietic cells causes defective lymphoid development and progressive myeloproliferation. Immunity. 1997 Jan;6(1):13–22. doi: 10.1016/s1074-7613(00)80238-1. [DOI] [PubMed] [Google Scholar]
  46. Shen W. F., Montgomery J. C., Rozenfeld S., Moskow J. J., Lawrence H. J., Buchberg A. M., Largman C. AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol Cell Biol. 1997 Nov;17(11):6448–6458. doi: 10.1128/mcb.17.11.6448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Shen W. F., Rozenfeld S., Lawrence H. J., Largman C. The Abd-B-like Hox homeodomain proteins can be subdivided by the ability to form complexes with Pbx1a on a novel DNA target. J Biol Chem. 1997 Mar 28;272(13):8198–8206. doi: 10.1074/jbc.272.13.8198. [DOI] [PubMed] [Google Scholar]
  48. Steelman S., Moskow J. J., Muzynski K., North C., Druck T., Montgomery J. C., Huebner K., Daar I. O., Buchberg A. M. Identification of a conserved family of Meis1-related homeobox genes. Genome Res. 1997 Feb;7(2):142–156. doi: 10.1101/gr.7.2.142. [DOI] [PubMed] [Google Scholar]
  49. Sun B., Hursh D. A., Jackson D., Beachy P. A. Ultrabithorax protein is necessary but not sufficient for full activation of decapentaplegic expression in the visceral mesoderm. EMBO J. 1995 Feb 1;14(3):520–535. doi: 10.1002/j.1460-2075.1995.tb07028.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Thomas K. R., Capecchi M. R. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell. 1987 Nov 6;51(3):503–512. doi: 10.1016/0092-8674(87)90646-5. [DOI] [PubMed] [Google Scholar]
  51. Thorsteinsdottir U., Sauvageau G., Hough M. R., Dragowska W., Lansdorp P. M., Lawrence H. J., Largman C., Humphries R. K. Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia. Mol Cell Biol. 1997 Jan;17(1):495–505. doi: 10.1128/mcb.17.1.495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Watrin F., Wolgemuth D. J. Conservation and divergence of patterns of expression and lineage-specific transcripts in orthologues and paralogues of the mouse Hox-1.4 gene. Dev Biol. 1993 Mar;156(1):136–145. doi: 10.1006/dbio.1993.1064. [DOI] [PubMed] [Google Scholar]