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  • Molecular Targets For Therapy (MTT)
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Molecular Targets For Therapy (MTT)

Identification of a gene element essential for leukemia-specific expression of transgenes

Leukemia volume 18, pages 415–419 (2004)Cite this article

Abstract

Leukemia-specific promoters and enhancers for gene therapy had never been reported. Since the Wilms' tumor gene WT1 is overexpressed in almost all types of leukemia, WT1 is an ideal target of leukemia-specific therapy. To explore the possibility of gene therapy for leukemia using WT1 promoter and enhancer, their activities in several kinds of cells were analyzed by using the enhanced green fluorescent protein (EGFP) gene as a reporter. First, we identified the best combination (654P/EGFP/int3- enh/3′-enh vector) of the 654-bp WT1 promoter and the two WT1 enhancers located in intron 3 and at the 3′ end of the WT1 gene for inducing EGFP expression in K562 cells, which endogenously expressed WT1. When this was transfected into WT1-expressing leukemia cells (K562, HEL), WT1-nonexpressing hematopoietic cells (Daudi, U937), and WT1-expressing nonhematopoietic cells (TYK-nu-CPr, SW480, 293 T), 19.8, 22.9, 1.47, 1.43, 4.50, 4.16, and 1.09 times EGFP expression was induced, respectively, compared to that by the promoter-less EGFP vector. These results showed that the 654P/EGFP/int3-enh/3′-enh vector specifically induced high levels of EGFP expression in WT1-expressing leukemia cells. 654P/int3- enh/3′-enh vector containing transgenes such as suicide genes might become useful tools for leukemia-specific gene therapy.

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References

  1. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome Wilms tumor locus. Cell 1990; 60: 509–520.

    Article  CAS  Google Scholar 

  2. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA . Homozygous deletion in Wilms tumors of a zinc-finger gene identified by chromosome jumping. Nature 1990; 343: 774–778.

    Article  CAS  Google Scholar 

  3. Menke AL, Van der Eb AJ, Jochemsen AG . The Wilms'tumor gene: Oncogene or tumor suppressor gene? Int Rev Cytol 1998; 181: 151–212.

    Article  CAS  Google Scholar 

  4. Buckler AJ, Pelletier J, Haber DA, Glaser T, Housman DE . Isolation characterization expression of the murine Wilm's tumor gene (WT1) during kidney development. Mol Cell Biol 1991; 11: 1707–1712.

    Article  CAS  Google Scholar 

  5. Park S, Schalling M, Bernard A, Maheswaran S, Shipley GC, Roberts D et al. The Wilms tumor gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma. Nature Genet 1993; 4: 415–420.

    Article  CAS  Google Scholar 

  6. Pritchard-Jones K, Renshaw J, King-Underwood L . The Wilms' tumor (WT1) gene is mutated in a secondary leukemia in WAGR patient. Hum Mol Genet 1994; 3: 1633–1637.

    Article  CAS  Google Scholar 

  7. Fraizer GC, Patmasiriwat P, Zhang X, Saunders GF . Expression of the tumor suppressor gene WT1 in both human and mouse bone marrow. Blood 1995; 86: 4704–4706.

    CAS  PubMed  Google Scholar 

  8. Baird PN, Simmons PJ . Expression of the Wilms'tumor gene (WT1) in normal hematopoiesis. Exp Hematol 1997; 25: 312–320.

    CAS  PubMed  Google Scholar 

  9. Inoue K, Ogawa H, Sonoda Y, Kimura T, Sakabe H, Oka Y et al. Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood 1997; 89: 1405–1412.

    CAS  PubMed  Google Scholar 

  10. Maurer U, Weidmann E, Karakas T, Hoelzer D, Bergmann L . Wilms tumor gene (wt1) mRNA is equally expressed in blast cells from acute myeloid leukemia and normal CD34+ progenitors. Blood 1997; 90: 4230–4232.

    CAS  PubMed  Google Scholar 

  11. Menssen HD, Renkl HJ, Entezami M, Thiel E . Wilms' tumor gene expression in human CD34+ hematopoietic progenitors during fetal development and early clonogenic growth. Blood 1997; 89: 3486–3487.

    CAS  PubMed  Google Scholar 

  12. Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R . WT-1 is required for early kidney development. Cell 1993; 74: 679–691.

    Article  CAS  Google Scholar 

  13. Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 1994; 84: 3071–3079.

    CAS  PubMed  Google Scholar 

  14. Menssen HD, Renkl HJ, Rodeck U, Mauer J, Notter M, Schwartz S et al. Presence of Wilms' tumor gene (wt1) transcripts and WT1 nuclear protein in the majority of human acute leukemia. Leukemia 1995; 9: 1060–1067.

    CAS  PubMed  Google Scholar 

  15. Miwa H, Beran M, Saunders GF . Expression of the Wilms' tumor gene (WT1) in human leukemias. Leukemia 1992; 6: 405–409.

    CAS  PubMed  Google Scholar 

  16. Miyagi T, Ahuja H, Kubota T, Kubonishi I, Koeffler HP, Miyoshi I . Expression of the candidate Wilm's tumor gene WT-1, in human leukemia cells. Leukemia 1993; 7: 970–977.

    CAS  PubMed  Google Scholar 

  17. Hosen N, Sonoda Y, Oji Y, Kimura T, Minamiguchi H, Tamaki H et al. Very low frequencies of human normal CD34+ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells. Br J Haematol 2002; 116: 409–420.

    Article  CAS  Google Scholar 

  18. Oka Y, Udaka K, Tsuboi A, Elisseeva OA, Ogawa H, Aozasa K, Kishimoto T, Sugiyama H . Cancer immunotherapy targeting Wilms' tumor gene WT1 product. J Immunol 2000; 164: 1873–1880.

    Article  CAS  Google Scholar 

  19. Ohminami H, Yasukawa M, Fujita S . HLA class I-restricted lysis of leukemia cells by a CD8(+) cytotoxic T-lymphocyte clone specific for WT1 peptide. Blood 2000; 95: 286–293.

    CAS  PubMed  Google Scholar 

  20. Gao L, Bellantuono I, Elsasser A, Marley SB, Gordon MY, Goldman JM et al. Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood 2000; 95: 2198–2203.

    CAS  PubMed  Google Scholar 

  21. Gaiger A, Reese V, Disis ML, Cheever MA . Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. Blood 2000; 96: 1480–1489.

    CAS  PubMed  Google Scholar 

  22. Miller N, Whelan J . Progress in transcriptionally targeted and regulatable vectors for genetic therapy. Hum Gene Ther 1997; 8: 803–815.

    Article  CAS  Google Scholar 

  23. Fraizer GC, Wu Y, Hewitt SM, Maity T, Ton CT, Huff V et al. Transcriptional regulation of the human Wilms' tumor gene (WT1). J Biol Chem 1994; 269: 8892–8900.

    CAS  PubMed  Google Scholar 

  24. Zhang X, Xing G, Fraizer GC, Saunders GF . Transactivation of an intronic hematopoietic-specific enhancer of the human Wilms' tumor 1 gene by GATA-1 and c-Myb. J Biol Chem 1997; 272: 29272–29280.

    Article  CAS  Google Scholar 

  25. Yoshiya N . Establishment of a cell line from human ovarian cancer (undifferentiated carcinoma of FIGO classification) and analysis of its cell-biological characteristics and sensitivity to anticancer drugs. Acta Obstet Gynaecol Jpn 1986; 38: 1747–1753.

    CAS  Google Scholar 

  26. Leibovitz A, Stinson JC, McCombs III WB, McCoy CE, Mazur KC, Mabry ND . Classification of human colorectal adenocarcinoma cell lines. Cancer Res 1976; 36: 4562–4569.

    CAS  PubMed  Google Scholar 

  27. Alberrta JA, Springett GM, Raybum H, Natoli TA, Loring J, Kreidberg JA et al. Role of the WT1 tumor suppressor in murine hematopoiesis. Blood 2003; 101: 2570–2574.

    Article  Google Scholar 

  28. Mundlos S, Pelletier J, Darveau A, Bachmann M, Winterpacht A, Zabel B . Nuclear localization of the protein encoded by the Wilms' tumor gene WT1 in embryonic and adult tissues. Development 1993; 119: 1329–1341.

    CAS  PubMed  Google Scholar 

  29. Oji Y, Yamamoto H, Nomura M, Nakano Y, Ikeba A, Nakatsuka S, Abeno S et al. Overexpression of the Wilms' tumor gene WT1 in colorectal adenocarcinoma. Cancer Sci 2003; 94: 712–717.

    Article  CAS  Google Scholar 

  30. Wilcox DA, Olsen JC, Ishizawa L, Griffith M, White II GC . Integrin áIIb promoter-targeted expression of gene products in megakaryocytes derived from retrovirus-transduced human hematopoietic cells. Proc Natl Acad Sci USA 1999; 96: 9654–9659.

    Article  CAS  Google Scholar 

  31. Ido A, Nakata K, Kato Y, Nakao K, Murata K, Fujita M et al. Gene therapy for hepatoma cells using a retrovirus vector carrying herpes simplex virus thymidine kinase gene under the control of human á-fetoprotein gene promoter. Cancer Res 1995; 55: 3105–3109.

    CAS  PubMed  Google Scholar 

  32. Braiden V, Nagayama Y, Iitaka M, Namba H, Niwa M, Yamashita S . Retrovirus-mediated suicide gene/prodrug therapy targeting thyroid carcinoma using a thyroid-specific promoter. Endocrinology 1998; 139: 3996–3999.

    Article  CAS  Google Scholar 

  33. Moreau-Gaudry F, Xia P, Jiang G, Perelman NP, Bauer G, Ellis J et al. High-level erythroid-specific gene expression in primary human and murine hematopoietic cells with self-inactivating lentiviral vectors. Blood 2001; 98: 2664–2672.

    Article  CAS  Google Scholar 

  34. Marodon G, Mouly E, Blair EJ, Frisen C, Lemoine FM, Klatzmann D . Specific transgene expression in human and mouse CD4+ cells using lentiviral vectors with regulatory sequences from the CD4 gene. Blood 2003; 101: 3416–3423.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan

    N Hosen, S Nishida, T Shirakata, M Asada, T Masuda, Y Taniguchi, Y Oka, H Ogawa & I Kawase

  2. Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan

    M Yanagihara, T Nakazawa, K Kanato, Y Oji & H Sugiyama

  3. Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan

    M Kawakami, A Tsuboi & K Ikegame

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  1. N Hosen
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  2. M Yanagihara
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  3. T Nakazawa
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  4. K Kanato
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  6. T Shirakata
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  7. M Asada
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  13. Y Oka
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  14. H Ogawa
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  17. H Sugiyama
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Correspondence to H Sugiyama.

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Hosen, N., Yanagihara, M., Nakazawa, T. et al. Identification of a gene element essential for leukemia-specific expression of transgenes. Leukemia 18, 415–419 (2004). https://doi.org/10.1038/sj.leu.2403260

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  • DOI: https://doi.org/10.1038/sj.leu.2403260

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