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Molecular Targets for Therapy

Heterogeneous sensitivity of human acute myeloid leukemia to β-catenin down-modulation

Leukemia volume 25, pages 770–780 (2011)Cite this article

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Abstract

Dysregulation of the Wnt/β-catenin pathway has been observed in various malignancies, including acute myeloid leukemia (AML), where the overexpression of β-catenin is an independent adverse prognostic factor. β-catenin was found upregulated in the vast majority of AML samples and more frequently localized in the nucleus of leukemic stem cells compared with normal bone marrow CD34+ cells. The knockdown of β-catenin, using a short hairpin RNA (shRNA) lentiviral approach, accelerates all-trans retinoic acid-induced differentiation and impairs the proliferation of HL60 leukemic cell line. Using in vivo quantitative tracking of these cells, we observed a reduced engraftment potential after xenotransplantation when β-catenin was silenced. However, when studying primary AML cells, despite effective downregulation of β-catenin we did not observe any impairment of their in vitro long-term maintenance on MS-5 stroma nor of their engraftment potential in vivo. Altogether, these results show that despite a frequent β-catenin upregulation in AML, leukemia-initiating cells might not be ‘addicted’ to this pathway and thus targeted therapy against β-catenin might not be successful in all patients.

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Acknowledgements

We thank all members of the London Research Institute Flow Cytometry and Equipment Park facilities and Christopher Ridler for technical assistance; Stuart Horswell for statistical analysis; Katie Foster and Yasmin Reyal for proof reading of the final paper and David Taussig for helpful discussions. We are grateful to R De Maria for kindly providing us with the TWR Luc−Fluc+RFP plasmid construct and to Fernando Anjos-Afonso for providing us with some of the qPCR primers used here. This work was funded by Cancer Research UK (DB) and by European grant (contract No. 037632) to DB. AG, SP, EG and JV are supported by London Research Institute Cancer Research UK fellowships.

Author Contributions

AG and SP: designed experiments, performed research, analyzed data and wrote the paper; FL and EG: performed some of the experiments; JV: provided clinical data and performed screening for engraftment and phenotype of the LSC used; AF: performed research and analyzed data; TAL: provided AML samples; DB: designed experiments, performed research, analyzed data and wrote the paper.

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Author notes

  1. A Gandillet and S Park: These authors contributed equally to this work.

  2. F Lassailly and E Griessinger: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Research UK Haematopoietic Stem Cell Group, London Research Institute, Cancer Research UK, London, UK

    A Gandillet, S Park, F Lassailly, E Griessinger, J Vargaftig & D Bonnet

  2. Flow Cytometry Core Facility, London Research Institute, Cancer Research UK, London, UK

    A Filby

  3. Department of Medical Oncology, St Bartholomew's Hospital, Queen Mary University of London, London, UK

    T A Lister

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  1. A Gandillet
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Correspondence to D Bonnet.

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Gandillet, A., Park, S., Lassailly, F. et al. Heterogeneous sensitivity of human acute myeloid leukemia to β-catenin down-modulation. Leukemia 25, 770–780 (2011). https://doi.org/10.1038/leu.2011.17

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