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Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells

Oncogene volume 29, pages 4885–4895 (2010)Cite this article

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Abstract

The Hedgehog (Hh) pathway regulates cell proliferation and survival and contributes to tumorigenesis. We investigated the expression and function of this pathway in B-cell chronic lymphocytic leukemia (CLL) cells and in healthy B lymphocytes. Profiling of cognate Hh pathway members revealed reduced expression of two key Hh signaling effectors, Smoothened (SMOH) and GLI, in CLL cells, whereas transcription levels of other investigated members resembled normal B-lymphocyte levels. Examining the functional role of SMOH and GLI in cell survival, we found that CLL cells were hardly sensitive toward specific SMOH inhibition, but showed an unspecific decline in cell viability in response to high concentrations of the SMOH antagonist cyclopamine. In contrast, treatment with the novel GLI antagonist GANT61 reduced expression of the target gene Patched and preferentially decreased the viability of malignant cells. Specific RNA interference knockdown experiments in a CLL-derived cell line confirmed the autonomous role of GLI in malignant cell survival. GANT61-induced apoptosis in primary leukemic cells was partly attenuated by protective stromal cells, but not soluble sonic hedgehog ligand. In summary, our data show a downregulation of the classical Hh pathway in CLL and suggest an intrinsic SMOH-independent role of GLI in the ex vivo survival of CLL cells.

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Acknowledgements

This work was supported by the Klinische Malignom und Zytokinforschung Salzburg-Innsbruck GmbH, SFB program P021 to RG, ÖNB research Grant 13420 to TNH., an unrestricted grant from PFIZER corporation Austria Ges.m.b.H, Vienna, and grants from the province of Salzburg. We thank Dr Reinhard Vlasak for help with the production of recombinant Shh protein. FA was supported by Austrian Science Fund (FWF) Grants W1213, P20652 and by the Austrian Genome programme Gen-AU.

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  1. T N Hartmann and R Greil: These authors contributed equally to this work.

Authors and Affiliations

  1. IIIrd Medical Department with Hematology, Laboratory for Immunological and Molecular Cancer Research, Medical Oncology, Hemostaseology, Rheumatology and Infectiology, Paracelsus Medical University, Salzburg, Austria

    P Desch, D Asslaber, M Stoecher, S W Hofbauer, I Tinhofer, T N Hartmann & R Greil

  2. Department of Molecular Biology, University of Salzburg, Salzburg, Austria

    D Kern, H Schnidar, D Mangelberger & F Aberger

  3. Institute of Pathology, Paracelsus Medical University, Salzburg, Austria

    B Alinger & D Neureiter

  4. Clinical Department for Radiotherapy (CCM/CVK), Translational Radiobiology and Radiooncology Research Laboratory, Charité University Hospital Berlin, Berlin, Germany

    I Tinhofer

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Desch, P., Asslaber, D., Kern, D. et al. Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells. Oncogene 29, 4885–4895 (2010). https://doi.org/10.1038/onc.2010.243

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