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Bcr-Abl induces autocrine IGF-1 signaling

Oncogene volume 27, pages 3831–3844 (2008)Cite this article

Abstract

Bcr-Abl oncogene is responsible for the initial phase of chronic myelogenous leukemia (CML), which is effectively treated by the Bcr-Abl inhibitor imatinib. Over time patients become resistant to treatment and progress to blast crisis, an event that is driven by additional genetic and epigenetic aberrations. Recently, we showed that Riz1 expression decreases in blast crisis and that re-expression of Riz1 inhibits IGF-1 expression. IGF-1 signaling is required in many stages of hematopoiesis and inappropriate activation of autocrine IGF-1 signaling may facilitate transformation to blast crisis. We observed that in 8 out of 11 matched CML patient biopsies the IGF-1 expression is elevated in blast crisis. We examined mechanisms used by CML blast crisis cell lines to activate IGF-1 expression. We found that Bcr-Abl activates autocrine IGF-1 signaling using Hck and Stat5b. Inhibition of these signaling components using small molecule drugs or shRNA decreases proliferation and enhances apoptosis. Together, our study suggests that aberrant IGF-1 signaling is an important event in blast crisis transformation and it provides a mechanism to explain the activity of IGF-1R and Hck inhibitors in blocking CML blast crisis phenotypes.

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Acknowledgements

This work was supported by grants from the Canadian Institute for Health Research. CRG is a CIHR-RPP New Investigator, AL is a Lymphoma Foundation of Canada Postdoctoral Fellow and EP is a CIHR Postdoctoral Fellow.

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Author notes

  1. A Lakshmikuttyamma and E Pastural: These authors contributed equally to this work.

Authors and Affiliations

  1. Genomic Medicine and Pathobiology Research Group, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    A Lakshmikuttyamma, E Pastural, D P Sheridan, J F DeCoteau & C R Geyer

  2. Department of Pathology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    A Lakshmikuttyamma & J F DeCoteau

  3. Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    E Pastural & C R Geyer

  4. Akita University School of Medicine, Akita, Japan

    N Takahashi & K Sawada

  5. Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    D P Sheridan

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  1. A Lakshmikuttyamma
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Correspondence to C R Geyer.

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Lakshmikuttyamma, A., Pastural, E., Takahashi, N. et al. Bcr-Abl induces autocrine IGF-1 signaling. Oncogene 27, 3831–3844 (2008). https://doi.org/10.1038/onc.2008.8

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