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Acute Leukemias

Leukemia-initiating cell activity requires calcineurin in T-cell acute lymphoblastic leukemia

Leukemia volume 27, pages 2289–2300 (2013)Cite this article

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Abstract

Despite their initial efficient response to induction chemotherapy, relapse remains frequent in patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive malignancy of immature T-cell progenitors. We previously reported sustained calcineurin (Cn) activation in human lymphoid malignancies, and showed that Cn inhibitors have antileukemic effects in mouse models of T-ALL. It was unclear, however, from these studies whether these effects resulted from Cn inhibition in leukemic cells themselves or were an indirect consequence of impaired Cn function in the supportive tumor microenvironment. We thus generated a Notch (intracellular Notch 1, ICN1)-induced T-ALL mouse model, in which conditional Cn genetic deletion is restricted to leukemic cells. Ex vivo, Cn deletion altered the adhesive interactions between leukemic cells and their supportive stroma, leukemic cell survival, proliferation, migration and clonogenic potential. In vivo, Cn activation was found to be critical for leukemia initiating/propagating cell activity as demonstrated by the failure of Cn-deficient leukemic cells to transplant the disease to syngeneic recipient mice. Importantly, combination of vincristine treatment with Cre-mediated Cn ablation cooperated to induce long-term remission of ICN1-induced T-ALL. These findings indicate that Cn is a promising target in T-ALL relapse prevention, and call for clinical trials incorporating Cn inhibitors during consolidation therapy.

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Acknowledgements

We thank G Crabtree for the generous gift of CnB1fl/Δ mice, W Pear for ICN1 retroviral, C da Costa for assistance in vincristine experiments, Z Maciorowski for assistance in cell sorting, F Cordelières for assistance in cell migration analyses, C Thibault and P de la Grange for assistance in transcriptomic analyses, Y Bourgeois, N Mebirouk, J Ropers for assistance with mouse husbandry, J Soulier for discussions and C Tran Quang for critical reading of the manuscript. SG was supported by predoctoral fellowships from the Ministère de l’Education Nationale et de la Recherche and Ligue Nationale Contre le Cancer; EG was supported by funds from the Agence Nationale de la Recherche (ANR) and Institut National du Cancer (INCa); DP was supported by a predoctoral fellowship from the Région Ile-de-France and Fondation ARC pour la recherche sur le cancer; MI was supported by postdoctoral fellowships from Institut Curie and Fondation pour la Recherche Médicale; CC was supported by postdoctoral fellowships from the Association for International Cancer Research (AICR) and Fondation de France; SP was supported by INCa. This work was supported by funds from the Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, CEA, Ligue Nationale Contre le Cancer (JG an FP are Equipes Labelisées la Ligue), INCa, Fondation de France, ANR and AICR.

Author information

Author notes

  1. S Gachet, E Genescà and D Passaro: These authors contributed equally to this study.

Authors and Affiliations

  1. Institut Curie, Centre Universitaire, Orsay, France

    S Gachet, E Genescà, D Passaro, M Irigoyen, H Alcalde, C Clémenson, C Lasgi, S Dodier & J Ghysdael

  2. Centre National de la Recherche Scientifique UMR 3306, Orsay, France

    S Gachet, E Genescà, D Passaro, M Irigoyen, H Alcalde, C Clémenson, C Lasgi, S Dodier & J Ghysdael

  3. Institut National de la Santé et de la Recherche Médicale U1005, Orsay, France

    S Gachet, E Genescà, D Passaro, M Irigoyen, H Alcalde, C Clémenson, C Lasgi, S Dodier & J Ghysdael

  4. CEA, Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Fontenay-aux-Roses, France

    S Poglio & F Pflumio

  5. Institut National de la Santé et de la Recherche Médicale UMR 967, Fontenay-aux-Roses, France

    S Poglio & F Pflumio

  6. Université Paris Diderot, UMR 967, Sorbonne Paris Cité, Fontenay-aux-Roses, France

    S Poglio & F Pflumio

  7. Université Paris-Sud, UMR 967, Fontenay-aux-Roses, France

    S Poglio & F Pflumio

  8. Institut National de la Santé et de la Recherche Médicale UMR S728, Paris, France

    A Janin

  9. Université Paris Diderot, UMRS 728, Paris, France

    A Janin

  10. Laboratoire de Pathologie, AP-HP-Hôpital Saint-Louis, Paris, France

    A Janin

  11. Université Paris Descartes, Faculté de Médecine, Paris, France

    M Soyer & G Duménil

  12. Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France

    M Soyer & G Duménil

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  1. S Gachet
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  2. E Genescà
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Correspondence to J Ghysdael.

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Gachet, S., Genescà, E., Passaro, D. et al. Leukemia-initiating cell activity requires calcineurin in T-cell acute lymphoblastic leukemia. Leukemia 27, 2289–2300 (2013). https://doi.org/10.1038/leu.2013.156

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  • DOI: https://doi.org/10.1038/leu.2013.156

Keywords

  • T-ALL
  • calcineurin
  • NFAT

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