Original Article | Published:

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 812822 (2016) | Download Citation

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.

Author information

Author notes

    • J Yu

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

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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The authors declare no conflict of interest.

Corresponding author

Correspondence to E Piovan.

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DOI

https://doi.org/10.1038/leu.2015.335

Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)

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