Abstract
The calcineurin (Cn)–nuclear factor of activated T cells signaling pathway is critically involved in many aspects of normal T-cell physiology; however, its direct implication in leukemogenesis is still ill-defined. Glycogen synthase kinase-3β (GSK-3β) has recently been reported to interact with Cn in neuronal cells and is implicated in MLL leukemia. Our biochemical studies clearly demonstrated that Cn was able to interact with GSK-3β in T-cell acute lymphoblastic leukemia (T-ALL) cells, and that this interaction was direct, leading to an increased catalytic activity of GSK-3β, possibly through autophosphorylation of Y216. Sensitivity to GSK-3 inhibitor treatment correlated with altered GSK-3β phosphorylation and was more prominent in T-ALL with Pre/Pro immunophenotype. In addition, dual Cn and GSK-3 inhibitor treatment in T-ALL cells promoted sensitization to apoptosis through proteasomal degradation of X-linked inhibitor of apoptosis protein (XIAP). Consistently, resistance to drug treatments in primary samples was strongly associated with higher XIAP protein levels. Finally, we showed that dual Cn and GSK-3 inhibitor treatment in vitro and in vivo is effective against available models of T-ALL, indicating an insofar untapped therapeutic opportunity.
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Acknowledgements
This work was supported by the Italian Association for Cancer Research (AIRC) grants to AA (IG#14032) and VT (MFGA#13053); Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) Ex 60% to AA and EP; and Istituto Oncologico Veneto 5 × 1000 fund to AA. We are grateful to Adolfo A Ferrando for sharing cells and reagents, Jon Aster for the MigR1-NOTCH1 L1601PΔP vector, Sonia Minuzzo and Marica Pinazza for providing T-ALL xenografts and Giorgia Pilotto for cell sorting.
Author contributions
VT performed and analyzed experiments. FB performed experiments. VA and SI provided primary T-ALL xenografts. JY performed bioinformatical analysis. GB provided primary T-ALL samples and clinical-immunophenotypical data. AA shared reagents and analyzed data. EP designed and performed experiments, directed research, analyzed data and wrote the paper. All the authors read and edited the manuscript.
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Tosello, V., Bordin, F., Yu, J. et al. Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation. Leukemia 30, 812–822 (2016). https://doi.org/10.1038/leu.2015.335
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DOI: https://doi.org/10.1038/leu.2015.335
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