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 response^{1, 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 leukemia^{3, 4, 5}, two mouse models relevant to human malignancies^{6, 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.

1. Institut Curie, Batiment 110, Centre Universitaire, 91405 Orsay, France.
2. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 146, Centre Universitaire, Batiment 110, 91405 Orsay, France.
3. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7151, Université Paris VII, Hôpital Saint-Louis, 2 Avenue C. Vellefaux, 75475 Paris, France.
4. Institut National de la Santé et de la Recherche Médicale, Unité 728, Université Paris VII, Hôpital Saint-Louis, 2 Avenue C. Vellefaux, 75475 Paris, France.
5. Institut Curie, Department of Clinical Hematology, 26 Rue d'Ulm, 75248 Paris, France.

Correspondence to: Jacques Ghysdael^1,2 e-mail: Jacques.Ghysdael@curie.u-psud.fr

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