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Gene transfer of SHIP-1 inhibits proliferation of juvenile myelomonocytic leukemia cells carrying KRAS2 or PTPN11 mutations

Gene Therapy volume 14, pages 699–703 (2007)Cite this article

Abstract

Juvenile myelomonocytic leukemia (JMML) is a malignant disease of early childhood characterized by a hypersensitivity to granulocyte/macrophage colony-stimulating factor (GM-CSF). Mutations in RAS or PTPN11 are frequently detected in JMML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP-1) is a negative regulator of GM-CSF signaling, and inactivation of SHIP-1 in mice results in a myeloproliferative disease. Here, we report the effects of SHIP-1 expression on GM-CSF-dependent proliferation and colony formation of human hematopoietic cells. After retroviral-mediated transduction of SHIP-1 into CD34+ cells from cord blood of healthy newborns or peripheral blood of JMML patients carrying mutations in KRAS2 or PTPN11, we observed a reduction in GM-CSF-dependent proliferation and colony formation. An enzymatically inactive form of SHIP-1 (D672A) had no effect. These data indicate that SHIP-1 can effectively block GM-CSF hypersensitivity in JMML progenitor cells with mutations in KRAS2 or PTPN11 and may be a useful approach for the treatment of JMML patients.

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Acknowledgements

The excellent technical assistance of W Wegner, M Engel and A Düsedau is gratefully acknowledged. We also thank G Nolan for the Phoenix-GP packaging cell line, C Baum for the retroviral vector pSF91-I-eGFP-PRE, D von Laer for a plasmid encoding the retroviral gag and pol proteins (pSVgp), F-L Cosset for a plasmid encoding a glykoprotein of the feline endogenous virus (RD114), W Fiedler for recombinant human GM-CSF and R Fischer for statistical analysis of the data. This work was supported by grants from the Deutsche-Forschungsgemeinschaft to M J and G W M (JU255/2-4 and JU255/2-5).

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Authors and Affiliations

  1. University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I, Cellular Signal Transduction, Hamburg, Germany

    A Metzner, G W Mayr & M Jücker

  2. Department of Pediatric Hematology and Oncology, Hamburg, Germany

    M A Horstmann

  3. Bone Marrow Transplantation Center, Hamburg, Germany

    B Fehse

  4. Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    G Ortmeyer

  5. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany

    C M Niemeyer

  6. Heinrich-Pette-Institute for Experimental Virology and Immunology, University of Hamburg, Hamburg, Germany

    C Stocking

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  1. A Metzner
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  2. M A Horstmann
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  3. B Fehse
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  4. G Ortmeyer
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  5. C M Niemeyer
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  6. C Stocking
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  7. G W Mayr
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  8. M Jücker
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Correspondence to M Jücker.

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Metzner, A., Horstmann, M., Fehse, B. et al. Gene transfer of SHIP-1 inhibits proliferation of juvenile myelomonocytic leukemia cells carrying KRAS2 or PTPN11 mutations. Gene Ther 14, 699–703 (2007). https://doi.org/10.1038/sj.gt.3302912

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  • DOI: https://doi.org/10.1038/sj.gt.3302912

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