Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Jan;17(1):495–505. doi: 10.1128/mcb.17.1.495

Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia.

U Thorsteinsdottir 1, G Sauvageau 1, M R Hough 1, W Dragowska 1, P M Lansdorp 1, H J Lawrence 1, C Largman 1, R K Humphries 1
PMCID: PMC231774  PMID: 8972230

Abstract

Multiple members of the A, B, and C clusters of Hox genes are expressed in hematopoietic cells. Several of these Hox genes have been found to display distinctive expression patterns, with genes located at the 3' side of the clusters being expressed at their highest levels in the most primitive subpopulation of human CD34+ bone marrow cells and genes located at the 5' end having a broader range of expression, with downregulation at later stages of hematopoietic differentiation. To explore if these patterns reflect different functional activities, we have retrovirally engineered the overexpression of a 5'-located gene, HOXA10, in murine bone marrow cells and demonstrate effects strikingly different from those induced by overexpression of a 3'-located gene, HOXB4. In contrast to HOXB4, which causes selective expansion of primitive hematopoietic cells without altering their differentiation, overexpression of HOXA10 profoundly perturbed myeloid and B-lymphoid differentiation. The bone marrow of mice reconstituted with HOXA10-transduced bone marrow cells contained in high frequency a unique progenitor cell with megakaryocytic colony-forming ability and was virtually devoid of unilineage macrophage and pre-B-lymphoid progenitor cells derived from the transduced cells. Moreover, and again in contrast to HOXB4, a significant proportion of HOXA10 mice developed a transplantable acute myeloid leukemia with a latency of 19 to 50 weeks. These results thus add to recognition of Hox genes as important regulators of hematopoiesis and provide important new evidence of Hox gene-specific functions that may correlate with their normal expression pattern.

Full Text

The Full Text of this article is available as a PDF (596.2 KB).

Selected References

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

  1. Boncinelli E., Acampora D., Pannese M., D'Esposito M., Somma R., Gaudino G., Stornaiuolo A., Cafiero M., Faiella A., Simeone A. Organization of human class I homeobox genes. Genome. 1989;31(2):745–756. doi: 10.1139/g89-133. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Celetti A., Barba P., Cillo C., Rotoli B., Boncinelli E., Magli M. C. Characteristic patterns of HOX gene expression in different types of human leukemia. Int J Cancer. 1993 Jan 21;53(2):237–244. doi: 10.1002/ijc.2910530211. [DOI] [PubMed] [Google Scholar]
  4. Damen J. E., Liu L., Rosten P., Humphries R. K., Jefferson A. B., Majerus P. W., Krystal G. The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1689–1693. doi: 10.1073/pnas.93.4.1689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Giampaolo A., Sterpetti P., Bulgarini D., Samoggia P., Pelosi E., Valtieri M., Peschle C. Key functional role and lineage-specific expression of selected HOXB genes in purified hematopoietic progenitor differentiation. Blood. 1994 Dec 1;84(11):3637–3647. [PubMed] [Google Scholar]
  6. Hawley R. G., Fong A. Z., Burns B. F., Hawley T. S. Transplantable myeloproliferative disease induced in mice by an interleukin 6 retrovirus. J Exp Med. 1992 Oct 1;176(4):1149–1163. doi: 10.1084/jem.176.4.1149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hawley R. G., Fong A. Z., Lu M., Hawley T. S. The HOX11 homeobox-containing gene of human leukemia immortalizes murine hematopoietic precursors. Oncogene. 1994 Jan;9(1):1–12. [PubMed] [Google Scholar]
  8. 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]
  9. 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]
  10. Kulessa H., Frampton J., Graf T. GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. Genes Dev. 1995 May 15;9(10):1250–1262. doi: 10.1101/gad.9.10.1250. [DOI] [PubMed] [Google Scholar]
  11. Lansdorp P. M., Dragowska W. Long-term erythropoiesis from constant numbers of CD34+ cells in serum-free cultures initiated with highly purified progenitor cells from human bone marrow. J Exp Med. 1992 Jun 1;175(6):1501–1509. doi: 10.1084/jem.175.6.1501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lawrence H. J., Sauvageau G., Humphries R. K., Largman C. The role of HOX homeobox genes in normal and leukemic hematopoiesis. Stem Cells. 1996 May;14(3):281–291. doi: 10.1002/stem.140281. [DOI] [PubMed] [Google Scholar]
  13. Levine M., Hoey T. Homeobox proteins as sequence-specific transcription factors. Cell. 1988 Nov 18;55(4):537–540. doi: 10.1016/0092-8674(88)90209-7. [DOI] [PubMed] [Google Scholar]
  14. Lowney P., Corral J., Detmer K., LeBeau M. M., Deaven L., Lawrence H. J., Largman C. A human Hox 1 homeobox gene exhibits myeloid-specific expression of alternative transcripts in human hematopoietic cells. Nucleic Acids Res. 1991 Jun 25;19(12):3443–3449. doi: 10.1093/nar/19.12.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Magli M. C., Barba P., Celetti A., De Vita G., Cillo C., Boncinelli E. Coordinate regulation of HOX genes in human hematopoietic cells. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6348–6352. doi: 10.1073/pnas.88.14.6348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Moretti P., Simmons P., Thomas P., Haylock D., Rathjen P., Vadas M., D'Andrea R. Identification of homeobox genes expressed in human haemopoietic progenitor cells. Gene. 1994 Jul 8;144(2):213–219. doi: 10.1016/0378-1119(94)90380-8. [DOI] [PubMed] [Google Scholar]
  17. Nakamura T., Largaespada D. A., Lee M. P., Johnson L. A., Ohyashiki K., Toyama K., Chen S. J., Willman C. L., Chen I. M., Feinberg A. P. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet. 1996 Feb;12(2):154–158. doi: 10.1038/ng0296-154. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Orkin S. H. Transcription factors and hematopoietic development. J Biol Chem. 1995 Mar 10;270(10):4955–4958. doi: 10.1074/jbc.270.10.4955. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Pevny L., Simon M. C., Robertson E., Klein W. H., Tsai S. F., D'Agati V., Orkin S. H., Costantini F. Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature. 1991 Jan 17;349(6306):257–260. doi: 10.1038/349257a0. [DOI] [PubMed] [Google Scholar]
  22. Rebel V. I., Dragowska W., Eaves C. J., Humphries R. K., Lansdorp P. M. Amplification of Sca-1+ Lin- WGA+ cells in serum-free cultures containing steel factor, interleukin-6, and erythropoietin with maintenance of cells with long-term in vivo reconstituting potential. Blood. 1994 Jan 1;83(1):128–136. [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. Shivdasani R. A., Mayer E. L., Orkin S. H. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 1995 Feb 2;373(6513):432–434. doi: 10.1038/373432a0. [DOI] [PubMed] [Google Scholar]
  26. Shivdasani R. A., Rosenblatt M. F., Zucker-Franklin D., Jackson C. W., Hunt P., Saris C. J., Orkin S. H. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell. 1995 Jun 2;81(5):695–704. doi: 10.1016/0092-8674(95)90531-6. [DOI] [PubMed] [Google Scholar]
  27. Takeshita K., Bollekens J. A., Hijiya N., Ratajczak M., Ruddle F. H., Gewirtz A. M. A homeobox gene of the Antennapedia class is required for human adult erythropoiesis. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3535–3538. doi: 10.1073/pnas.90.8.3535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Thompson M. A., Ramsay R. G. Myb: an old oncoprotein with new roles. Bioessays. 1995 Apr;17(4):341–350. doi: 10.1002/bies.950170410. [DOI] [PubMed] [Google Scholar]
  30. Tsai F. Y., Keller G., Kuo F. C., Weiss M., Chen J., Rosenblatt M., Alt F. W., Orkin S. H. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature. 1994 Sep 15;371(6494):221–226. doi: 10.1038/371221a0. [DOI] [PubMed] [Google Scholar]
  31. Vieille-Grosjean I., Roullot V., Courtois G. Lineage and stage specific expression of HOX 1 genes in the human hematopoietic system. Biochem Biophys Res Commun. 1992 Mar 31;183(3):1124–1130. doi: 10.1016/s0006-291x(05)80307-9. [DOI] [PubMed] [Google Scholar]
  32. Visvader J. E., Crossley M., Hill J., Orkin S. H., Adams J. M. The C-terminal zinc finger of GATA-1 or GATA-2 is sufficient to induce megakaryocytic differentiation of an early myeloid cell line. Mol Cell Biol. 1995 Feb;15(2):634–641. doi: 10.1128/mcb.15.2.634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wu J., Zhu J. Q., Zhu D. X., Scharfman A., Lamblin G., Han K. K. Selective inhibition of normal murine myelopoiesis "in vitro" by a Hox 2.3 antisense oligodeoxynucleotide. Cell Mol Biol. 1992 Jul;38(4):367–376. [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES