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Molecules and Cells

, Volume 34, Issue 2, pp 201–208 | Cite as

MYC and PIM2 co-expression in mouse bone marrow cells readily establishes permanent myeloid cell lines that can induce lethal myeloid sarcoma in vivo

  • Su Hwa Jang
  • Hee Yong Chung
Research Article

Abstract

The hematopoietic cell malignancy is one of the most prevalent type of cancer and the disease has multiple pathologic molecular signatures. Research on the origin of hematopoietic cancer stem cells and the mode of subsequent maintenance and differentiation needs robust animal models that can reproduce the transformation and differentiation event in vivo. Here, we show that co-transduction of MYC and PIM2 proto-oncogenes into mouse bone marrow cells readily establishes permanent cell lines that can induce lethal myeloid sarcoma in vivo. Unlike the previous doubly transgenic mouse model in which coexpression of MYC and PIM2 transgenes exclusively induced B cell lymphoma, we were able to show that the same combination of genes can also transform primary bone marrow myeloid cells in vitro resulting in permanent cell lines which induce myeloid sarcoma upon in vivo transplantation. By inducing cancerous transformation of fresh bone marrow cells in a controlled environment, the model we established will be useful for detailed study of the molecular events involved in initial transformation process of primary myeloid bone marrow cells and provides a model that can give insight to the molecular pathologic characteristics of human myeloid sarcoma, a rare presentation of solid tumors of undifferentiated myeloid blast cells associated with various types of myeloid leukemia.

Keywords

animal model MYC myeloid sarcoma PIM2 

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References

  1. Allen, J.D., Verhoeven, E., Domen, J., van der Valk, M., and Berns, A. (1997). Pim-2 transgene induces lymphoid tumors, exhibiting potent synergy with c-myc. Oncogene 15, 1133–1141.PubMedCrossRefGoogle Scholar
  2. Brown, D., Kogan, S., Lagasse, E., Weissman, I., Alcalay, M., Pelicci, P.G., Atwater, S., and Bishop, J.M. (1997). A PMLRARalpha transgene initiates murine acute promyelocytic leukemia. Proc. Natl. Acad. Sci. USA 94, 2551–2556.PubMedCrossRefGoogle Scholar
  3. Cashman, J.D., Lapidot, T., Wang, J.C., Doedens, M., Shultz, L.D., Lansdorp, P., Dick, J.E., and Eaves, C.J. (1997). Kinetic evidence of the regeneration of multilineage hematopoiesis from primitive cells in normal human bone marrow transplanted into immunodeficient mice. Blood 89, 4307–4316.PubMedGoogle Scholar
  4. Chen, W.W., Chan, D.C., Donald, C., Lilly, M.B., and Kraft, A.S. (2005). Pim family kinases enhance tumor growth of prostate cancer cells. Mol. Cancer Res. 3, 443–451.PubMedCrossRefGoogle Scholar
  5. Cheng, G.X., Zhu, X.H., Men, X.Q., Wang, L., Huang, Q.H., Jin, X.L., Xiong, S.M., Zhu, J., Guo, W.M., Chen, J.Q., et al. (1999). Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARalpha and NPM-RARalpha. Proc. Natl. Acad. Sci. USA 96, 6318–6323.PubMedCrossRefGoogle Scholar
  6. Cuenco, G.M., Nucifora, G., and Ren, R. (2000). Human AML1/MDS1/EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: a model for human AML. Proc. Natl. Acad. Sci. USA 97, 1760–1765.PubMedCrossRefGoogle Scholar
  7. Deme, S., Deodhare, S.S., Tucker, W.S., and Bilbao, J.M. (1997). Granulocytic sarcoma of the spine in nonleukemic patients: report of three cases. Neurosurgery 40, 1283–1287.PubMedCrossRefGoogle Scholar
  8. Dick, J.E., Bhatia, M., Gan, O., Kapp, U., and Wang, J.C. (1997). Assay of human stem cells by repopulation of NOD/SCID mice. Stem Cells 15Suppl 1, 199–203; discussion 204-197.PubMedCrossRefGoogle Scholar
  9. Grisolano, J.L., Sclar, G.M., and Ley, T.J. (1994). Early myeloid cellspecific expression of the human cathepsin G gene in transgenic mice. Proc. Natl. Acad. Sci. USA 91, 8989–8993.PubMedCrossRefGoogle Scholar
  10. Grisolano, J.L., Wesselschmidt, R.L., Pelicci, P.G., and Ley, T.J. (1997). Altered myeloid development and acute leukemia in transgenic mice expressing PML-RAR alpha under control of cathepsin G regulatory sequences. Blood 89, 376–387.PubMedGoogle Scholar
  11. Grisolano, J.L., O’Neal, J., Cain, J., and Tomasson, M.H. (2003). An activated receptor tyrosine kinase, TEL/PDGFbetaR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. Proc. Natl. Acad. Sci. USA 100, 9506–9511.PubMedCrossRefGoogle Scholar
  12. Guzman, M.L., Swiderski, C.F., Howard, D.S., Grimes, B.A., Rossi, R.M., Szilvassy, S.J., and Jordan, C.T. (2002). Preferential induction of apoptosis for primary human leukemic stem cells. Proc. Natl. Acad. Sci. USA 99, 16220–16225.PubMedCrossRefGoogle Scholar
  13. Iversen, P.O., Sorensen, D.R., and Benestad, H.B. (2002). Inhibitors of angiogenesis selectively reduce the malignant cell load in rodent models of human myeloid leukemias. Leukemia 16, 376–381.PubMedCrossRefGoogle Scholar
  14. Kroon, E., Krosl, J., Thorsteinsdottir, U., Baban, S., Buchberg, A.M., and Sauvageau, G. (1998). Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 17, 3714–3725.PubMedCrossRefGoogle Scholar
  15. Lapidot, T., Fajerman, Y., and Kollet, O. (1997). Immune-deficient SCID and NOD/SCID mice models as functional assays for studying normal and malignant human hematopoiesis. J. Mol. Med. 75, 664–673.PubMedCrossRefGoogle Scholar
  16. Lavau, C., Luo, R.T., Du, C., and Thirman, M.J. (2000). Retrovirusmediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice. Proc. Natl. Acad. Sci. USA 97, 10984–10989.PubMedCrossRefGoogle Scholar
  17. Lawrence, H.J., Rozenfeld, S., Cruz, C., Matsukuma, K., Kwong, A., Komuves, L., Buchberg, A.M., and Largman, C. (1999). Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias. Leukemia 13, 1993–1999.PubMedCrossRefGoogle Scholar
  18. Luo, H., Li, Q., O’Neal, J., Kreisel, F., Le Beau, M.M., and Tomasson, M.H. (2005). c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations. Blood 106, 2452–2461.PubMedCrossRefGoogle Scholar
  19. Mizuki, M., Schwable, J., Steur, C., Choudhary, C., Agrawal, S., Sargin, B., Steffen, B., Matsumura, I., Kanakura, Y., Bohmer, F.D., et al. (2003). Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood 101, 3164–3173.PubMedCrossRefGoogle Scholar
  20. Ory, D.S., Neugeboren, B.A., and Mulligan, R.C. (1996). A stable human-derived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes. Proc. Natl. Acad. Sci. USA 93, 11400–11406.PubMedCrossRefGoogle Scholar
  21. Philpott, N.J., Turner, A.J., Scopes, J., Westby, M., Marsh, J.C., Gordon-Smith, E.C., Dalgleish, A.G., and Gibson, F.M. (1996). The use of 7-amino actinomycin D in identifying apoptosis: simplicity of use and broad spectrum of application compared with other techniques. Blood 87, 2244–2251.PubMedGoogle Scholar
  22. Robbins, P.B., Yu, X.J., Skelton, D.M., Pepper, K.A., Wasserman, R.M., Zhu, L., and Kohn, D.B. (1997). Increased probability of expression from modified retroviral vectors in embryonal stem cells and embryonal carcinoma cells. J. Virol. 71, 9466–9474.PubMedGoogle Scholar
  23. Schmid, I., Uittenbogaart, C.H., Keld, B., and Giorgi, J.V. (1994). A rapid method for measuring apoptosis and dual-color immunofluorescence by single laser flow cytometry. J. Immunol. Methods 170, 145–157.PubMedCrossRefGoogle Scholar
  24. Thorsteinsdottir, U., Krosl, J., Kroon, E., Haman, A., Hoang, T., and Sauvageau, G. (1999). The oncoprotein E2A-Pbx1a collaborates with Hoxa9 to acutely transform primary bone marrow cells. Mol. Cell. Biol. 19, 6355–6366.PubMedGoogle Scholar
  25. Wang, J., Kimura, T., Asada, R., Harada, S., Yokota, S., Kawamoto, Y., Fujimura, Y., Tsuji, T., Ikehara, S., and Sonoda, Y. (2003). SCID-repopulating cell activity of human cord blood-derived CD34-cells assured by intra-bone marrow injection. Blood 101, 2924–2931.PubMedCrossRefGoogle Scholar
  26. Wang, Z., Zhang, Y., Gu, J.J., Davitt, C., Reeves, R., and Magnuson, N.S. (2010). Pim-2 phosphorylation of p21(Cip1/WAF1) enhances its stability and inhibits cell proliferation in HCT116 cells. Int. J. Biochem. Cell Biol. 42, 1030–1038.PubMedCrossRefGoogle Scholar
  27. Wierenga, P.K., Setroikromo, R., Kamps, G., Kampinga, H.H., and Vellenga, E. (2003). Differences in heat sensitivity between normal and acute myeloid leukemic stem cells: feasibility of hyperthermic purging of leukemic cells from autologous stem cell grafts. Exp. Hematol. 31, 421–427.PubMedCrossRefGoogle Scholar
  28. Yang, H., Wang, Y., Qian, H., Zhang, P., and Huang, C. (2011). Pim protein kinase-3 is regulated by TNF-alpha and promotes endothelial cell sprouting. Mol. Cells 32, 235–241.PubMedCrossRefGoogle Scholar
  29. Yilmaz, O.H., Valdez, R., Theisen, B.K., Guo, W., Ferguson, D.O., Wu, H., and Morrison, S.J. (2006). Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482.PubMedCrossRefGoogle Scholar
  30. Yuan, Y., Zhou, L., Miyamoto, T., Iwasaki, H., Harakawa, N., Hetherington, C.J., Burel, S.A., Lagasse, E., Weissman, I.L., Akashi, K., et al. (2001). AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc. Natl. Acad. Sci. USA 98, 10398–10403.PubMedCrossRefGoogle Scholar
  31. Zhang, J., Grindley, J.C., Yin, T., Jayasinghe, S., He, X.C., Ross, J.T., Haug, J.S., Rupp, D., Porter-Westpfahl, K.S., Wiedemann, L.M., et al. (2006). PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441, 518–522.PubMedCrossRefGoogle Scholar
  32. Zhang, Y., Wang, Z., Li, X., and Magnuson, N.S. (2008). Pim kinase-dependent inhibition of c-Myc degradation. Oncogene 27, 4809–4819.PubMedCrossRefGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2012

Authors and Affiliations

  1. 1.Department of Biomedical Science, Graduate School of Biomedical Science and EngineeringHanyang UniversitySeoulKorea

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