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Acute lymphoblastic leukemia

Calcineurin and GSK-3 inhibition sensitizes T-cell acute lymphoblastic leukemia cells to apoptosis through X-linked inhibitor of apoptosis protein degradation

Leukemia volume 30, pages 812–822 (2016)Cite this article

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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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Author notes

  1. J Yu

    Present address: 6Current address: Department of Precision Medicine, Oncology Research Unit, Pfizer Inc., Pearl River, NY 10965, USA.,

Authors and Affiliations

  1. UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy

    V Tosello, V Agnusdei, S Indraccolo, A Amadori & E Piovan

  2. Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita’ di Padova, Padova, Italy

    F Bordin, A Amadori & E Piovan

  3. Department of Biomedical Informatics, Columbia University, New York, NY, USA

    J Yu

  4. Department of Systems Biology, Columbia University, New York, NY, USA

    J Yu

  5. Dipartimento di Salute della Donna e del Bambino, Università di Padova, Padova, Italy

    G Basso

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Correspondence to E Piovan.

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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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