Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia.
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. 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, two mouse models relevant to human malignancies, 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.
Medyouf
Hind
H
Institut Curie, Batiment 110, Centre Universitaire, 91405 Orsay, France.
Alcalde
Hélène
H
Berthier
Caroline
C
Guillemin
Marie Claude
MC
dos Santos
Nuno R
NR
Janin
Anne
A
Decaudin
Didier
D
de Thé
Hugues
H
Ghysdael
Jacques
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000172:deficiency / Q000235:genetics; D051881:Receptor, Notch1 / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein
D000970:Antineoplastic Agents; D019703:Calcineurin; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D015514:Oncogene Proteins, Fusion; D051881:Receptor, Notch1; D016559:Tacrolimus; C497761:NOTCH1 protein, human; C491568:TEL-JAK2 fusion protein, mouse; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein