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The calcineurin protein phosphatase is dispensable for BCR-ABL-induced B-ALL maintenance, propagation and response to dasatinib

Leukemia volume 31, pages 248–251 (2017)Cite this article

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Development of BCR-ABL-targeted tyrosine kinase inhibitors (TKIs) has revolutionized chronic myeloid leukemia (CML) treatment, achieving an overall survival of >80% of patients.1 TKI inclusion in the chemotherapeutic regimen of Ph+ B-ALL also improved hematological and cytogenetic responses and patient survival, but not to the level achieved in Ph− B-ALL.2 Thus, ongoing investigations seek to identify molecular pathways and drugs that enhance responsiveness to TKI therapy. Along these lines, cyclosporin A (CsA), a drug commonly used as immunosuppressant and an inhibitor of the protein phosphatase calcineurin (PPP3; referred to as Cn), was shown to sensitize the Ph+ B-ALL cell line Sup-B15 to imatinib's cytotoxic effects in vitro and potently prolong survival in combination with dasatinib in a mouse model of BCR-ABL-induced B-ALL.3 The authors concluded that Cn targeting can synergize with BCR-ABL inhibition and that this regimen could be beneficial to Ph+ B-ALL treatment. We previously reported a critical function of Cn and Cn effectors in T-ALL maintenance in vivo.4, 5, 6 We report here that, in contrast to T-ALL, Cn is dispensable to leukemia maintenance in BCR-ABL-induced B-ALL mouse models and that the reported anti-leukemic effects of CsA are independent of its Cn inhibitory activity.

To rule out the possibility that the absence of effects linked to Cn inactivation was a peculiarity of the model used, we addressed the same question in a transgenic BCR-ABL-induced B-ALL model. We generated mice carrying a BCR-ABL transgene,11 RCT2 and one copy of a floxed (fl) and null (Δ) alleles of CnB1 (Supplementary Figure 2a) that, as expected, developed B-ALL with high penetrance (data not shown). Following the experimental scheme described above, B-ALL cells retrieved from these animals were injected into syngeneic, wild-type recipients that, when leukemic, were either treated with tamoxifen (Tam), resulting in the generation of CnB1-null cells (data not shown), or the solvent carrier. Recipients carrying the Cn-deficient and Cn+ versions of the same leukemia were followed over time and showed no difference in leukemic load (Supplementary Figure 2b) nor survival (data not shown). We also investigated the importance of Cn to the ability of BCR-ABL-induced B-ALL cells to propagate leukemia to syngeneic recipients upon serial transplantation. Upon four consecutive serial transplantations, we failed to observe any difference in either time-to-death or tumor load at the terminal phase of the disease between mice injected with CnB1fl/Δ and CnB1Δ/Δ leukemic cells (Supplementary Figures 2c and d). As expected, similar results were obtained using a BCR-ABL; RCT2; CnB1+/+ leukemia (data not shown). We conclude that Cn is dispensable for B-ALL maintenance and leukemia-propagating activity in mouse models of BCR-ABL-induced B-ALL.

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Acknowledgements

This study was supported by funds from CNRS, Institut Curie, Institut National du Cancer (INCA, PLBIO-2015-114) and the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007-2013/ under REA grant agreement no. 289611 (HEM_ID Project). FR was supported by a pre-doctoral fellowship from the EU (Marie Curie HEM_ID Project) and the Fondation Recherche Médicale (FDT20140931211). ALM was supported by a pre-doctoral fellowship from the Institut Curie.

Author contributions

FR and JG designed and performed the experiments, analyzed the data and wrote the manuscript. CTQ and ALM generated BCR-ABL-induced leukemias with conditional CnB1 in the BM transplantation model; JN helped in generating BCR-ABL transgenic mice with conditional CnB1; CL flow cytometry-sorted the leukemic cells.

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Authors and Affiliations

  1. Institut Curie, PSL Research University, Orsay, France

    F Rocchetti, C Tran Quang, A L Maragno, J Nguyen & J Ghysdael

  2. Université Paris Sud, Université Paris-Saclay, Orsay, France

    F Rocchetti, C Tran Quang, A L Maragno, J Nguyen & J Ghysdael

  3. Institut Curie, Plateforme Cytométrie, Orsay, France

    C Lasgi

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  1. F Rocchetti
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Correspondence to J Ghysdael.

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Rocchetti, F., Tran Quang, C., Maragno, A. et al. The calcineurin protein phosphatase is dispensable for BCR-ABL-induced B-ALL maintenance, propagation and response to dasatinib. Leukemia 31, 248–251 (2017). https://doi.org/10.1038/leu.2016.269

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