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Infectious medicine, virology

Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph+ leukemia patients treated with dasatinib

Leukemia volume 31, pages 203–212 (2017)Cite this article

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A Corrigendum to this article was published on 04 January 2017

Abstract

Dasatinib treatment markedly increases the number of large granular lymphocytes (LGLs) in a proportion of Ph+ leukemia patients, which associates with a better prognosis. The lymphocytosis is predominantly observed in cytomegalovirus (CMV)-seropositive patients, yet detectable CMV reactivation exists only in a small fraction of patients. Thus, etiology of the lymphocytosis still remains unclear. Here, we identified NK cells as the dominant LGLs expanding in dasatinib-treated patients, and applied principal component analysis (PCA) to an extensive panel of NK cell markers to explore underlying factors in NK cell activation. PCA displayed phenotypic divergence of NK cells that reflects CMV-associated differentiation and genetic differences, and the divergence was markedly augmented in CMV-seropositive dasatinib-treated patients. Notably, the CMV-associated highly differentiated status of NK cells was already observed at leukemia diagnosis, and was further enhanced after starting dasatinib in virtually all CMV-seropositive patients. Thus, the extensive characterization of NK cells by PCA strongly suggests that CMV is an essential factor in the NK cell activation, which progresses stepwise during leukemia and subsequent dasatinib treatment most likely by subclinical CMV reactivation. This study provides a rationale for the exploitation of CMV-associated NK cell activation for treatment of leukemias.

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Acknowledgements

We thank K Ohmori, K Fukunaga, M Tozaki, M Takahara and M Ohnishi for the excellent technical support. This work was supported by research funding from Bristol-Myers Squibb.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    K-i Ishiyama, T Kitawaki, N Sugimoto & A Takaori-Kondo

  2. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

    N Sugimoto

  3. Department of Management Science, Faculty of Engineering, Tokyo University of Science, Tokyo, Japan

    T Sozu

  4. Department of Hematology and Oncology, Takatsuki Red Cross Hospital, Takatsuki, Japan

    N Anzai & M Okada

  5. Department of Hematology, Wakayama Red Cross Hospital, Wakayama, Japan

    M Nohgawa & K Hatanaka

  6. Department of Hematology, Kitano Hospital, Osaka, Japan

    N Arima

  7. Department of Hematology, Kobe City Medical Center, Kobe, Japan

    T Ishikawa & S Tabata

  8. Department of Hematology, Kokura Memorial Hospital, Kitakyusyu, Japan

    T Onaka

  9. Department of Hematology and Oncology, Shiga Medical Center for Adults, Moriyama, Japan

    S Oka

  10. The Center for Hematological Diseases, Takeda General Hospital, Kyoto, Japan

    Y Nakabo

  11. Department of Hematology, The Japan Baptist Hospital, Kyoto, Japan

    R Amakawa

  12. Department of Hematology, Kyoto City Hospital, Kyoto, Japan

    M Matsui

  13. Department of Hematology, Kyoto-Katsura Hospital, Kyoto, Japan

    T Moriguchi

  14. Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan

    N Kadowaki

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Correspondence to N Kadowaki.

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Ishiyama, Ki., Kitawaki, T., Sugimoto, N. et al. Principal component analysis uncovers cytomegalovirus-associated NK cell activation in Ph+ leukemia patients treated with dasatinib. Leukemia 31, 203–212 (2017). https://doi.org/10.1038/leu.2016.174

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