Back
 OJBD  Vol.2 No.1 , March 2012
Leukemogenic Fusion Gene (p190 BCR-ABL) Transduction into Hematopoietic Stem/Progenitor Cells in the Common Marmoset
Abstract: Patients with Philadelphia chromosome (p190 BCR-ABL fusion gene)-positive acute lymphoblastic leukemia have a poor prognosis despite intensive therapeutic intervention.In this study, we attempted to develop a leukemia nonhuman primate model that mimics various human systems. Hematopoietic stem/progenitor cells in the common marmoset were transduced with a lentiviral vector containing the p190 BCR-ABL fusion gene by ex vivo transduction or in vivo direct bone marrow injection. In the latter model, BCR-ABL gene expression was maintained for more than one and a half years. One marmoset unexpectedly developed myelofibrosis-like disease. However, none of the marmosets have developed leukemia to date. In conclusion, we successfully achieved sustained p190 BCR-ABL gene expression in vivo. However, a genetic mutation in addition to p190 BCR-ABL may be required for the malignant transformation of hematopoietic stem/progenitor cells in the common marmoset during the short observation period. This novel in vivo approach will help develop a marmoset leukemia model in the future.
Cite this paper: Y. Dong, S. Kobayashi, Y. Tian, M. Ozawa, T. Hiramoto, K. Izawa, Y. Bai, Y. Soda, E. Sasaki, T. Itoh, Y. Maru, S. Takahashi, K. Uchimaru, N. Oyaizu, A. Tojo, C. Kai and K. Tani, "Leukemogenic Fusion Gene (p190 BCR-ABL) Transduction into Hematopoietic Stem/Progenitor Cells in the Common Marmoset," Open Journal of Blood Diseases, Vol. 2 No. 1, 2012, pp. 1-10. doi: 10.4236/ojbd.2012.21001.
References

[1]   R. E. Donahue and C. E. Dunbar, “Update on the Use of Non-human Primate Models for Preclinical Testing of Gene Therapy Approaches Targeting Hematopoietic Cells,” Human Gene Therapy, Vol. 12, No. 6, 2001, pp. 607-617. doi:10.1089/104303401300057289

[2]   D. W. Emery, R. G. Andrews and T. Papayannopoulou, “Differences among Non-human Primates in Susceptibility to Bone Marrow Progenitor Transduction with Retrovirus Vectors,” Gene Therapy, Vol. 7, No. 5, 2000, pp. 359-367. doi:10.1038/sj.gt.3301107

[3]   H. P. Kiem, S. Sellers, B. Thomasson, J. C. Morris, J. F. Tisdale, P. A. Horn, P. Hematti, R. Adler, K. Kuramoto, B. Calmels, A. Bonifacino, J. Hu, C. von Kalle, M. Schmidt, B. Sorrentino, A. Nienhuis, C. A. Blau, R. G. Andrews, R. E. Donahue and C. E. Dunbar, “Long-Term Clinical and Molecular Follow-Up of Large Animals Receiving Retrovirally Transduced Stem and Progenitor Cells: No Progression to Clonal Hematopoiesis or Leukemia,” Molecular Therapy, Vol. 9, No. 3, 2004, pp. 389-395. doi:10.1016/j.ymthe.200

[4]   H. Hibino, K. Tani, K. Ikebuchi, M. S. Wu, H. Sugiyama, Y. Nakazaki, T. Tanabe, S. Takahashi, A. Tojo, S. Suzuki, Y. Tanioka, Y. Sugimoto, T. Nakahata and S. Asano, “The Common Marmoset as a Target Preclinical Primate Model for Cytokine and Gene Therapy Studies,” Blood, Vol. 93, No. 9, 1999, pp. 2839-2848.

[5]   E. Sasaki, H. Suemizu, A. Shimada, K. Hanazawa, R. Oiwa, M. Kamioka, I. Tomioka, Y. Sotomaru, R. Hirakawa, T. Eto, S. Shiozawa, T. Maeda, M. Ito, R. Ito, C. Kito, C. Yagihashi, K. Kawai, H. Miyoshi, Y. Tanioka, N. Tamaoki, S. Habu, H. Okano and T. Nomura, “Generation of Transgenic Non-Human Primates with Germline Transmission,” Nature, Vol. 459, No. 7246, 2009, pp. 523-527. doi:10.1038/nature08090

[6]   M. Arico, M.G. Valsecchi, B. Camitta, M. Schrappe, J. Chessells, A. Baruchel, P. Gaynon, L. Silverman, G. Janka-Schaub, W. Kamps, C. H. Pui and G. Masera, “Outcome of Treatment in Children with Philadelphia Chromosome-Positive Acute Lym-phoblastic Leukemia,” New England Journal of Medicine, Vol. 342, No. 14, 2000, pp. 998-1006. doi:10.1056/NEJM200004063421402

[7]   E. A. Copelan and E. A. McGuire, “The Biology and Treatment of Acute Lym-phoblastic Leukemia in Adults,” Blood, Vol. 85, No. 5, 1995, pp. 1151-1168.

[8]   O. G. Ottmann, B. J. Druker, C. L. Sawyers, J. M. Goldman, J. Reiffers, R. T. Silver, S. Tura, T. Fischer, M. W. Deininger, C. A. Schiffer, M. Baccarani, A. Gratwohl, A. Hochhaus, D. Hoelzer, S. Fernandes-Reese, I. Gathmann, R. Capdeville and S. G. O’Brien, “A Phase 2 Study of Imatinib in Patients with Relapsed or Refractory Philadelphia Chromo-some-Positive Acute Lymphoid Leukemias,” Blood, Vol. 100, No. 6, 2002, pp. 1965-1971. doi:10.1182/blood-2001-12-0181

[9]   N. Heisterkamp, G. Jenster, J. Ten Hoeve, D. Zovich, P. K. Pattengale and J. Grof-fen, “Acute Leukaemia in bcr/ abl Transgenic Mice,” Nature, Vol. 344, No. 6263, 1990, pp. 251-253. doi:10.1038/344251a0

[10]   S. Li, R. L. Ilaria Jr., R. P. Million, G. Q. Daley and R. A. Van Etten, “The P190, P210, and P230 forms of the BCR/ABL Oncogene Induce a Similar Chronic Myeloid Leukemia-Like Syndrome in Mice But Have Different Lymphoid Leukemogenic Activity,” Journal of Experimental Medicine, Vol. 189, No. 9, 1999, pp. 1399-1412. doi:10.1084/jem.189.9.1399

[11]   J. W. Voncken, S. Griffiths, M. F. Greaves, P. K. Pattengale, N. Heisterkamp and J. Groffen, “Restricted Oncogenicity of BCR/ABL p190 in Transgenic Mice,” Cancer Research, Vol. 52, No. 16, 1992, pp. 4534-4539.

[12]   Y. Bai, Y. Soda, K. Izawa, T. Tanabe, X. Kang, A. Tojo, H. Hoshino, H. Miyoshi, S. Asano and K. Tani, “Effective Transduction and Stable Transgene Expression in Human Blood Cells by a Third-Generation Lentiviral Vector,” Gene Therapy, Vol. 10, No. 17, 2003, pp. 1446-1457. doi:10.1038/sj.gt.3302026

[13]   Y. Inoue, A. Tojo, R. Sekine, Y. Soda, S. Kobayashi, A. Nomura, K. Izawa, T. Kitamura, T. Okubo and K. Ohtomo, “In Vitro Validation of Bioluminescent Monitoring of Disease Progression and Therapeutic Response in Leukaemia Model Animals,” European Journal of Nuclear Medicine and Molecular Imaging, Vol. 33, No. 5, 2006, pp. 557-565. doi:10.1007/s00259-005-0048-4

[14]   L. Sastry, T. Johnson, M. J. Hobson, B. Smucker and K. Cornetta, “Titering Lentiviral Vectors: Comparison of DNA, RNA and Marker Expression Methods,” Gene Therapy, Vol. 9, No. 17, 2002, pp. 1155-1162. doi:10.1038/sj.gt.3301731

[15]   A. Tojo, M. Futami, T. Hatano, Y. Soda, S. Kobayashi and M. Miyagishi, “RNAi-Mediated Silencing of p190 (Bcr-Abl) Inactivates Stat5 and Cooperates with Imatinib Mesylate and 17-Allylamino-17-demetoxygeldanamycin in Selective Killing of p190(Bcr-Abl)-Expressing Leukemia Cells,” Leukemia, Vol. 22, No. 6, 2008, pp. 1131- 1138. doi:10.1038/leu.2008.60

[16]   M. Towatari, M. Yanada, N. Usui, J. Takauchi, S. I, M. Takeuchi, F. Yagasaki, Y. Kawai, S. Miyawaki, S. Ohtake, J. I. K. Matsuo, T. Naoe, R. Ohno and J. A. L. S. Grp, “Combination of Intensive Chemotherapy and Imatinib Can Rapidly Induce High-Quality Complete Remission for a Majority of Patients with Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia,” Blood, Vol. 104, No. 12, 2004, pp. 3507-3512. doi:10.1182/blood-2004-04-1389

[17]   K. Izawa, K. Tani, Y. Nakazaki, H. Hibino, H. Sugiyama, A. Kawasaki, E. Sasaki, C. Nishioka, H. Ishii, Y. Soda, H. Yagita, Y. Tanioka, A. Tojo and S. Asano, “Hematopoietic Activity of Common Marmoset CD34 Cells Isolated by a Novel Monoclonal Antibody MA24,” Experimental Hematology, Vol. 32, No. 9, 2004, pp. 843-851. doi:10.1016/j.exphem.2004.06.007

[18]   A. Aiuti, S. Slavin, M. Aker, F. Ficara, S. Deola, A. Mortellaro, S. Morecki, G. Andolfi, A. Tabucchi, F. Carlucci, E. Marinello, F. Cattaneo, S. Vai, P. Servida, R. Miniero, M. G. Roncarolo and C. Bordignon, “Correction of ADA-SCID by Stem Cell Gene Therapy Com-bined with Nonmyeloablative Conditioning,” Science, Vol. 296, No. 5577, 2002, pp. 2410-2413. doi:10.1126/science.1070104

[19]   M. B. Bradley, P. Satwani, L. Baldinger, E. Morris, C. van de Ven, G. Del Toro, J. Garvin, D. George, M. Bhatia, E. Roman, L. A. Baxter-Lowe, J. Schwartz, E. Qualter, R. Hawks, K. Wolownik, S. Foley, O. Militano, J. Leclere, Y. K. Cheung and M. S. Cairo, “Reduced Intensity Allogeneic Umbilical Cord Blood Transplantation in Children and Adolescent Recipients with Malignant and Non-Malignant Diseases,” Bone Marrow Transplant, Vol. 40, No. 7, 2007, pp. 621-631. doi:10.1038/sj.bmt.1705785

[20]   L. Naldini, U. Blomer, P. Gallay, D. Ory, R. Mulligan, F. H. Gage, I. M. Verma and D. Trono, “In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector,” Science, Vol. 272, No. 5259, 1996, pp. 263-267. doi:10.1126/science.272.5259.263

[21]   H. Hibino, K. Tani, H. Sugiyama, S. Suzuki, M. S. Wu, K. Izawa, H. Hase, Y. Nakazaki, T. Tanabe, J. Ooi, T. Izeki, A. Tojo, I. Saitoh, Y. Tanioka and S. Asano, “Haematopoietic Progenitor Cells from the Common Marmoset as Targets of Gene Transduction by Retro-viral and Adenoviral Vectors,” European Journal of Haematology, Vol. 66, No. 4, 2001, pp. 272-280. doi:10.1034/j.1600-0609.2001.066004272.x

[22]   M. S. Wu, K. Tani, H. Sugiyama, H. Hibino, K. Izawa, T. Tanabe, Y. Nakazaki, H. Ishii, J. Ohashi, H. Hohjoh, T. Iseki, A. Tojo, Y. Nakamura, Y. Tanioka, K. Tokunaga and S. Asano, “MHC (Major Histocompatibility Complex)-DRB Genes and Polymorphisms in Common Marmoset,” Journal of Molecular Evolution, Vol. 51, No. 3, 2000, pp. 214-222.

[23]   E. Montini, D. Cesana, M. Schmidt, F. Sanvito, M. Ponzoni, C. Bartholomae, L. Sergi Sergi, F. Benedicenti, A. Ambrosi, C. Di Serio, C. Doglioni, C. von Kalle and L. Naldini, “Hematopoietic Stem Cell Gene Transfer in a tumor-Prone Mouse Model Uncovers Low Genotoxicity of Lentiviral Vector Integration,” Nature Biotechnology, Vol. 24, No. 6, 2006, pp. 687-696. doi:10.1038/nbt1216

[24]   L. Naldini, U. Blomer, F. H. Gage, D. Trono and I. M. Verma, “Efficient Transfer, Integration, and Sustained Long-Term Expression of the Transgene in Adult Rat Brains Injected with a Lentiviral Vector,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 21, 1996, pp. 11382-11388. doi:10.1073/pnas.93.21.11382

[25]   B. S. Carver and P. P. Pandolfi, “Mouse Modeling in Oncologic Preclinical and Translational Research,” Clini- cal Cancer Research, Vol. 12, No. 18, 2006, pp. 5305-5311. doi:10.1158/1078-0432.CCR-06-0482

[26]   A. W. Nienhuis, C. E. Dunbar and B. P. Sorrentino, “Genotoxicity of Retroviral Integration in Hematopoietic cells,” Molecular Therapy, Vol. 13, No. 6, 2006, pp. 1031- 1049. doi:10.1016/j.ymthe.2006.03.001

[27]   N. B. Woods, V. Bottero, M. Schmidt, C. von Kalle and I. M. Verma, “Gene Therapy: Therapeutic Gene Causing Lymphoma,” Nature, Vol. 440, No. 7088, 2006, p. 1123. doi:10.1038/4401123a

[28]   B. Calmels, C. Ferguson, M. O. Laukkanen, R. Adler, M. Faulhaber, H. J. Kim, S. Sellers, P. Hematti, M. Schmidt, C. von Kalle, K. Akagi, R. E. Donahue and C. E. Dunbar, “Recurrent Retroviral Vector Integration at the Mds1/ Evi1 Locus in Nonhuman Primate Hematopoietic Cells,” Blood, Vol. 106, No. 7, 2005, pp. 2530-2533. doi:10.1182/blood-2005-03-1115

[29]   A. S. Kim, D. A. East-mond and R. J. Preston, “Childhood Acute Lymphocytic Leukemia and Perspectives on Risk Assessment of Early-Life Stage Exposures,” Mutation Research, Vol. 613, No. 2-3, 2006, pp. 138-160. doi:10.1016/j.mrrev.2006.09.001

[30]   Y. Chalandon, X. Jiang, O. Christ, S. Loutet, E. Thano- poulou, A. Eaves and C. Eaves, “BCR-ABL-Transduced Human Cord Blood Cells Produce Abnormal Populations in Immunodeficient Mice,” Leukemia, Vol. 19, No. 3, 2005, pp. 442-448. doi:10.1038/sj.leu.2403650

[31]   W. C. Hahn and R. A. Wein-berg, “Rules for Making Human Tumor Cells,” New England Journal of Medicine, Vol. 347, No. 20, 2002, pp. 1593-1603. doi:10.1056/NEJMra021902

[32]   R. Ono, H. Nakajima, K. Ozaki, H. Kumagai, T. Kawashima, T. Taki, T. Kitamura, Y. Hayashi and T. Nosaka, “Dimerization of MLL Fusion Proteins and FLT3 Activation Synergize to Induce Multiple-Lineage Leukemogenesis,” Journal of Clinical Investigation, Vol. 115, No. 4, 2005, pp. 919-929.

[33]   R. L. Levine, M. Wadleigh, J. Cools, B. L. Ebert, G. Wernig, B. J. Huntly, T. J. Boggon, I. Wlodarska, J. J. Clark, S. Moore, J. Adelsperger, S. Koo, J. C. Lee, S. Gabriel, T. Mercher, A. D’Andrea, S. Frohling, K. Dohner, P. Marynen, P. Vandenberghe, R. A. Mesa, A. Tefferi, J. D. Griffin, M. J. Eck, W. R. Sellers, M. Meyerson, T. R. Golub, S. J. Lee and D. G. Gilliland, “Activating Mutation in the Tyrosine Kinase JAK2 in Polycythemia Vera, Essential Thrombocythemia, and Myeloid Metaplasia with Myelofibrosis

[34]   M. Schmidt, K. Schwarz-waelder, C. Bartholomae, K. Zaoui, C. Ball, I. Pilz, S. Braun, H. Glimm and C. von Kalle, “High-Resolution Insertion-Site Analysis by Linear Amplification-Mediated PCR (LAM-PCR),” Nature Methods, Vol. 4, No. 12, 2007, pp. 1051-1057. doi:10.1038/nmeth1103

 
 
Top