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Chronic Myeloproliferative Neoplasias

NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR–ABL-positive mice

Leukemia volume 26, pages 465–474 (2012)Cite this article

Abstract

Although BCR–ABL+ stem cells in chronic myeloid leukemia (CML) resist elimination by targeted pharmacotherapy in most patients, immunological graft-versus-leukemia effects can cure the disease. Besides cytotoxic T cells, natural killer (NK) cells may have a role in immune control of CML. Here, we explored the functionality of NK cells in CML patients and in a transgenic inducible BCR–ABL mouse model. Compared with controls, NK-cell proportions among lymphocytes were decreased at diagnosis of CML and did not recover during imatinib-induced remission for 10–34 months. Functional experiments revealed limited in vitro expansion of NK cells from CML patients and a reduced degranulation response to K562 target cells both at diagnosis and during imatinib therapy. Consistent with the results in human CML, relative numbers of NK1.1+ NK cells were reduced following induction of BCR–ABL expression in mice, and the defects persisted after BCR–ABL reversion. Moreover, target-induced degranulation by expanded BCR–ABL+ NK cells was compromised. We conclude that CML is associated with quantitative and functional defects within the NK-cell compartment, which is reproduced by induced BCR–ABL expression in mice. Further work will aim at identifying the mechanisms of NK-cell deficiency in CML and at developing strategies to exploit NK cells for immunotherapy.

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Acknowledgements

This study was supported by a grant from the program Innovative Medical Research (IMF Grant CH 220913) and from the German Research Foundation (DFG KO 2155/2-2) at the University Hospital Muenster. We would like to thank Rhoda Falkow for technical support.

Author contributionsCIUC, PPL, SK, BA, HJ, WEB and CR designed the experiments and analyzed the results. CIUC, MS, SP and LK performed the experiments. HTM contributed to cytokine flow cytometry. JG provided statistics support. CIUC, SK and CR wrote the paper. All authors discussed the results and commented on the paper.

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Author notes

  1. S Koschmieder

    Present address: 7Current address: Department of Medicine IV, University Hospital of Aachen, Aachen, Germany.,

  2. C I-U Chen and S Koschmieder: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany

    C I-U Chen, B Altvater, S Pscherer, H Juergens & C Rossig

  2. Department of Medicine A, Hematology and Oncology, University Hospital Muenster, Muenster, Germany

    S Koschmieder, L Kerstiens, M Schemionek & W E Berdel

  3. Institute of Biostatistics and Clinical Research, University Hospital Muenster, Muenster, Germany

    J Gerss

  4. Human Immune Monitoring Center, Stanford University School of Medicine, Stanford, CA, USA

    H T Maecker

  5. Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA

    P P Lee

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  1. C I-U Chen
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SK is a member of Novartis, BMS, GSK and Pfizer Advisory Boards. The remaining authors declare no conflict of interest.

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Chen, CU., Koschmieder, S., Kerstiens, L. et al. NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR–ABL-positive mice. Leukemia 26, 465–474 (2012). https://doi.org/10.1038/leu.2011.239

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  • DOI: https://doi.org/10.1038/leu.2011.239

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