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Reduced proliferation of CD34+ cells from patients with acute myeloid leukemia after gene transfer of INPP5D

Gene Therapy volume 16, pages 570–573 (2009)Cite this article

Abstract

Acute myeloid leukemia (AML) is a malignant disease characterized by deregulated proliferation of immature myeloid cells. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently detected in approximately 50–70% of AML patients. The gene INPP5D encodes the SH2-containing inositol 5-phosphatase 1 (SHIP1), which is a negative regulator of PI3K/AKT signaling. After lentiviral-mediated gene transfer of INPP5D into CD34+ cells derived from AML patients (n=12) the granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent proliferation was reduced in all samples analyzed (average 86%; range 72–93%). An enzymatically inactive form of SHIP1 (D672A) had no effect. In addition, SHIP1 reduced the autonomous proliferation of CD34+ cells from a patient with a secondary AML who had a very high peripheral blast count (300 × 109 l−1). These data show that SHIP1 can effectively block GM-CSF-dependent and autonomous proliferation of AML cells.

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Acknowledgements

The excellent technical assistance of W Wegner, M Engel and A Düsedau is thankfully acknowledged. We thank L Naldini for the lentiviral vector system including the plasmids pRRL.PPT.CMV.GFPpre, pRSV-Rev, pMDLg/p and W Beyer for the plasmid pHCMV-VSV-G. This work was supported by grants from the Deutsche-Forschungsgemeinschaft to MJ and GWM (JU255/2-4 and JU255/2-5).

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Authors and Affiliations

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

    A Metzner, C Precht, G W Mayr & M Jücker

  2. Clinic for Stem Cell Transplantation, Hamburg, Germany

    B Fehse

  3. Department of Medicine II, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    W Fiedler

  4. Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg, Germany

    C Stocking

  5. Division of Stem Cell Transplantation and Immunotherapy, Second Department of Medicine, University Hospital Schleswig-Holstein, Kiel, Germany

    A Günther

Authors
  1. A Metzner
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  2. C Precht
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  3. B Fehse
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  4. W Fiedler
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  5. C Stocking
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  6. A Günther
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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., Precht, C., Fehse, B. et al. Reduced proliferation of CD34+ cells from patients with acute myeloid leukemia after gene transfer of INPP5D. Gene Ther 16, 570–573 (2009). https://doi.org/10.1038/gt.2008.184

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  • DOI: https://doi.org/10.1038/gt.2008.184

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