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Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia

Nature Medicine volume 13, pages 736–741 (2007)Cite this article

Abstract

Calcineurin is a calcium-activated serine/threonine phosphatase critical to a number of developmental processes in the cardiovascular, nervous and immune systems. In the T-cell lineage, calcineurin activation is important for pre–T-cell receptor (TCR) signaling, TCR-mediated positive selection of thymocytes into mature T cells, and many aspects of the immune response1,2. The critical role of calcineurin in the immune response is underscored by the fact that calcineurin inhibitors, such as cyclosporin A (CsA) and FK506, are powerful immunosuppressants in wide clinical use. We observed sustained calcineurin activation in human B- and T-cell lymphomas and in all mouse models of lymphoid malignancies analyzed. In intracellular NOTCH1 (ICN1)- and TEL-JAK2–induced T-cell lymphoblastic leukemia3,4,5, two mouse models relevant to human malignancies6,7,8, in vivo inhibition of calcineurin activity by CsA or FK506 induced apoptosis of leukemic cells and rapid tumor clearance, and substantially prolonged mouse survival. In contrast, ectopic expression of a constitutively activated mutant of calcineurin favored leukemia progression. Moreover, CsA treatment induced apoptosis in human lymphoma and leukemia cell lines. Thus, calcineurin activation is critical for the maintenance of the leukemic phenotype in vivo, identifying this pathway as a relevant therapeutic target in lymphoid malignancies.

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Figure 1: Sustained calcineurin activation in leukemic cells from ICN1- and TEL-JAK2–induced T-ALL.
Figure 2: CsA and FK506 treatment induces T-ALL regression and prolongs mouse survival.
Figure 3: Calcineurin inhibition leads to reduced proliferation and induces apoptosis of leukemic cells in mouse models of human leukemia and in human leukemia cell lines in vitro.
Figure 4: Ectopic expression of a constitutively active mutant of CnAα (CnA*) in leukemic cells favors leukemia progression and invasion.

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Acknowledgements

We thank H. Soilihi, O. Fehri, S. Belhadj and C. Leboeuf for technical assistance; S. Candon for determining blood levels of FK 506 in FK506-treated mice; A. Vincent-Salomon (Institut Curie) for providing the human lymphoma samples; N. Clipstone (Northwestern University) for the cDNA for calcineurinAα; W. Pear (University of Pennsylvania) for the pMig retroviral vector encoding the cDNA for ICN1; G. Crabtree, A. Rao and J. Aramburu for discussions; and C. Tran Quang and M. Von Lindern for critical reading of the manuscript. H.M. was supported by predoctoral fellowships from the Ministère de l'Education Nationale et de la Recherche and the Association pour la Recherche contre le Cancer (ARC). N.R.d.S. was supported by a Marie Curie Fellowship from the European Community program. This work was supported by funds from the Centre National de la Recherche Scientifique (CNRS), Institut Curie, Institut National du Cancer (INCA), Cancéropôle Ile-de-France, Agence Nationale de la Recherche (ANR) and Ligue Nationale contre le Cancer (J.G. and H.d.T. are supported by the Ligue Nationale Contre le Cancer as 'Équipe Labelisée Ligue'). In vivo treatment of mouse tumors was performed and supported by the preclinical mouse platform established by the Alliance de Recherche sur le Cancer (ARECA) program.

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Authors and Affiliations

  1. Institut Curie, Batiment 110, Centre Universitaire, 91405, Orsay, France

    Hind Medyouf, Hélène Alcalde, Nuno R dos Santos & Jacques Ghysdael

  2. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 146, Centre Universitaire, Batiment 110, 91405, Orsay, France

    Hind Medyouf, Hélène Alcalde, Nuno R dos Santos & Jacques Ghysdael

  3. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7151, Université Paris VII, Hôpital Saint-Louis, 2 Avenue C. Vellefaux, Paris, 75475, France

    Caroline Berthier, Marie Claude Guillemin & Hugues de Thé

  4. Institut National de la Santé et de la Recherche Médicale, Unité 728, Université Paris VII, Hôpital Saint-Louis, 2 Avenue C. Vellefaux, Paris, 75475, France

    Anne Janin

  5. Department of Clinical Hematology, Institut Curie, 26 Rue d'Ulm, Paris, 75248, France

    Didier Decaudin

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  1. Hind Medyouf
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Contributions

H.M. designed and conducted the in vivo and in vitro experiments and contributed to manuscript writing. H.A., C.B. and M.C.G. assisted in conducting the experiments. N.R.d.S. generated the EμSRα-TEL-JAK2/Cd3e−/− and EμSRα-TEL-JAK2/Rag2−/− compound mice. A.J supervised histological analyses. D.D. provided human tumor samples. H.D.T. designed experiments and contributed to manuscript writing. J.G. designed the project, assisted in conducting experiments and contributed to manuscript writing.

Corresponding author

Correspondence to Jacques Ghysdael.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Sustained calcineurin activation in leukemic cells from intracellular NOTCH1-induced T-ALL. (PDF 133 kb)

Supplementary Fig. 2

Sustained calcineurin activation in tumor cells from mouse models of human lymphoma and leukemia. (PDF 232 kb)

Supplementary Fig. 3

Therapeutic treatment of TEL-JAK2-diseased mice with CsA or FK506 induces leukemia regression in bone marrow. (PDF 682 kb)

Supplementary Fig. 4

In vivo antiproliferative effect of FK506 and CsA on TJ2 leukemic cells. (PDF 444 kb)

Supplementary Fig. 5

Sustained calcineurin activation in cell lines derived from human B and T lymphoid malignancies. (PDF 175 kb)

Supplementary Fig. 6

Ectopic expression of a constitutively active mutant of CnA (CnA*) in leukemic cells favors leukemia progression and invasion. (PDF 108 kb)

Supplementary Fig. 7

Increased tumor load in the kidney of mice transplanted with CnA*-transduced TJ2 cells as compared to mice engrafted with mock-transduced TJ2 cells. (PDF 265 kb)

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Medyouf, H., Alcalde, H., Berthier, C. et al. Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. Nat Med 13, 736–741 (2007). https://doi.org/10.1038/nm1588

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