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SHIP1, but not an AML-derived SHIP1 mutant, suppresses myeloid leukemia growth in a xenotransplantation mouse model

Gene Therapy volume 24, pages 749–753 (2017)Cite this article

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Abstract

Constitutive activation of the PI3K/AKT signaling pathway is found in ~50–70% of AML patients. The SH2-containing inositol 5-phosphatase 1 (SHIP1) is a negative regulator of PI3K/AKT signaling in hematopoietic cells. SHIP1 knockout mice develop a myeloproliferative syndrome and concomitant deletion of SHIP1 and the tumor suppressor PTEN leads to the development of lethal B-cell lymphomas. In the study presented here, we investigated the role of SHIP1 as a tumor suppressor in myeloid leukemia cells in an in vivo xenograft transplantation model. NSG Mice transplanted with UKE-1 cells derived from a secondary AML showed a significantly extended lifespan after lentiviral-mediated overexpression of SHIP1 in comparison to the vector control cohort. In contrast, the AML-derived SHIP1Y643H mutant, which has a strongly reduced enzymatic activity showed a significant reversion of the SHIP1-induced prolongation of the survival time. In addition, the analysis of 290 AML patients revealed a correlation between expression of SHIP1 and overall survival of the AML patients. These results indicate that SHIP1 can act as a tumor suppressor in acute myeloid leukemia cells and that higher SHIP1 expression is associated with prolonged overall survival in AML patients. SHIP1 may be an interesting candidate for gene therapy.

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Acknowledgements

We acknowledge with special thanks the excellent technical assistance of Bettina Bettin, Christine Blechner und Susanne Giehler. This study was supported by a post-doctoral fellowship from the Werner Otto Stiftung, Hamburg, Germany to MT, a grant from the Hamburger Krebsgesellschaft to SH and a grant from the Erich und Gertrud Roggenbuck-Stiftung to MJ.

Author contributions

MT designed and performed experiments, analyzed results and wrote the manuscript; SH and JW designed and performed experiments, analyzed results; EL assisted mouse experiments; JW performed bioinformatics analysis; PE and MS performed western blot and RT-PCR analysis; MN and BF provided the material and gave advice; WF and CS contributed to data collection and approved the final version of the manuscript; MJ designed the research, analyzed data and wrote the manuscript.

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Authors and Affiliations

  1. Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    M Täger, P Ehm, M Schaks, M Nalaskowski & M Jücker

  2. Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    S Horn & B Fehse

  3. Department of Oncology, Haematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    E Latuske, W Fiedler & J Wellbrock

  4. Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Molecular Pathology, Hamburg, Germany

    C Stocking

Authors
  1. M Täger
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  2. S Horn
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  3. E Latuske
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  4. P Ehm
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  5. M Schaks
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  6. M Nalaskowski
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  7. B Fehse
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  8. W Fiedler
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  9. C Stocking
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  11. M Jücker
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Corresponding author

Correspondence to M Jücker.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on Gene Therapy website

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Täger, M., Horn, S., Latuske, E. et al. SHIP1, but not an AML-derived SHIP1 mutant, suppresses myeloid leukemia growth in a xenotransplantation mouse model. Gene Ther 24, 749–753 (2017). https://doi.org/10.1038/gt.2017.88

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