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Molecular Targets for Therapy

NFATc1 as a therapeutic target in FLT3-ITD-positive AML

Leukemia volume 29, pages 1470–1477 (2015)Cite this article

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Abstract

Internal tandem duplications (ITD) in the Fms-related tyrosine kinase 3 receptor (FLT3) are associated with a dismal prognosis in acute myeloid leukemia (AML). FLT3 inhibitors such as sorafenib may improve outcome, but only few patients display long-term responses, prompting the search for underlying resistance mechanisms and therapeutic strategies to overcome them. Here we identified that the nuclear factor of activated T cells, NFATc1, is frequently overexpressed in FLT3-ITD-positive (FLT3-ITD+) AML. NFATc1 knockdown using inducible short hairpin RNA or pharmacological NFAT inhibition with cyclosporine A (CsA) or VIVIT significantly augmented sorafenib-induced apoptosis of FLT3-ITD+ cells. CsA also potently overcame sorafenib resistance in FLT3-ITD+ cell lines and primary AML. Vice versa, de novo expression of a constitutively nuclear NFATc1-mutant mediated instant and robust sorafenib resistance in vitro. Intriguingly, FLT3-ITD+ AML patients (n=26) who received CsA as part of their rescue chemotherapy displayed a superior outcome when compared with wild-type FLT3 (FLT3-WT) AML patients. Our data unveil NFATc1 as a novel mediator of sorafenib resistance in FLT3-ITD+ AML. CsA counteracts sorafenib resistance and may improve treatment outcome in AML by means of inhibiting NFAT.

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Acknowledgements

This work was supported by the ‘Deutsche Forschungsgemeinschaft, DFG, Klinische Forschergruppe 210 ‘Genetics of Drug resistance in Cancer’, TP7; the Deutsche José Carreras Leukämiestiftung (AR12/12 and AH06/01) to AB and AN, respectively, and by the Deutsche Krebshilfe (110092) to CM. We are indebted to Tamara Alpermann from the Münchner Leukemia Laboratory, MLL, for performing the microarrays and analysis. We would also like to thank Sonja Tajstra for their technical assistance. We thank Gavin Giel for performing cell sorting.

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  1. S K Metzelder and C Michel: These authors contributed equally to this work.

Authors and Affiliations

  1. Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps Universität Marburg, Baldingerstraße, Marburg, Germany,

    S K Metzelder, C Michel, M Rehberger, S Inselmann, M Solovey, Y Wang, K Sohlbach, C Brendel, A Neubauer & A Burchert

  2. Universitätsklinikum Carl-Gustav-Carus, Technische Universität Dresden, Fetscherstraße Dresden, Germany,

    M von Bonin & M Bornhäuser

  3. Universitätsmedizin Göttingen, Klinik für Gastroenterologie II, Göttingen, Germany

    E Hessmann & V Ellenrieder

  4. Division of Molecular Oncology, Philipps Universität, Marburg, Germany

    T Stiewe & J Charles

  5. Institut für Pathologie, Universitätsklinikum Gießen und Marburg, Standort Gießen, Gießen, Germany

    A Ten Haaf & S Gattenlöhner

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  1. S K Metzelder
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Correspondence to A Burchert.

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Competing interests

AB received funding from Bayer Healthcare in support of the SORMAIN trial, which is testing sorafenib maintenance therapy after allogeneic stem cell transplantation in FLT3-ITD+ AML (EudraCT 2010-018539-16). The remaining authors declare no conflict of interest.

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Metzelder, S., Michel, C., von Bonin, M. et al. NFATc1 as a therapeutic target in FLT3-ITD-positive AML. Leukemia 29, 1470–1477 (2015). https://doi.org/10.1038/leu.2015.95

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