Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

NK cell dynamics and association with molecular response in early chronic phase chronic myelogenous leukemia (CML-CP) patients treated with nilotinib

Leukemia volume 31, pages 2264–2267 (2017)Cite this article

Subjects

Access through your institution
Buy or subscribe

In summary, we clearly show that absolute NK cell numbers are increased at CML diagnosis in chronic phase and in parallel to the eradication of clonal CML cells by nilotinib return to normal values. NK cell progenitors have been shown to harbor the Philadelphia chromosome (Ph)12, 13 and there are reports of BCR-ABL positive NK cells in the periphery of patients with advanced CML.12 Most studies however failed to detect Ph+ NK cells in CML-CP.13, 14, 15 Still, we cannot exclude the possibility that malignant NK cells contributed to the increased NK cell counts at least in some patients thus potentially explaining in part the reduced NK cell numbers during nilotinib therapy. Moreover, NK cell frequencies during therapy are linked to molecular outcome. In addition, the cytotoxic competence of NK cell at diagnosis is linked to later deep molecular response, suggesting that NK cell activity may contribute to the clearance of clonal cells resulting in improved molecular outcome in CP-CML patients exposed to nilotinib. It remains however elusive whether specific disease conditions associated with higher BCR-ABL transcript levels in CML-CP leads to lower NK cell numbers or whether lower NK cell numbers are functionally involved in inferior treatment response. Finally, the data also suggest that potential NK cell activating therapies, such as KIR-targeting monoclonal antibodies (for example, lirilumab) may be of benefit to improve therapy outcome, particularly in patients with insufficient NK cell activity. This idea is also supported by findings that presence of the KIR2DL5B in CML patients is associated with an inferior molecular outcome.5

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  1. Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boque C et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014; 123: 494–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 2012; 26: 2197–2203.

    Article  CAS  PubMed  Google Scholar 

  3. Hughes A, Clarson J, Tang C, Vidovic L, White DL, Hughes TP et al. CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors. Blood 2017; 129: 1166–1176.

    Article  CAS  PubMed  Google Scholar 

  4. Sopper S, Mustjoki S, White D, Hughes T, Valent P, Burchert A et al. Reduced CD62L expression on T cells and increased soluble CD62L levels predict molecular response to tyrosine kinase inhibitor therapy in early chronic-phase chronic myelogenous leukemia. J Clin Oncol 2017; 35: 175–184.

    Article  CAS  PubMed  Google Scholar 

  5. Yeung DT, Tang C, Vidovic L, White DL, Branford S, Hughes TP et al. KIR2DL5B genotype predicts outcomes in CML patients treated with response-directed sequential imatinib/nilotinib strategy. Blood 2015; 126: 2720–2723.

    Article  CAS  PubMed  Google Scholar 

  6. Schutz C, Inselmann S, Sausslele S, Dietz CT, Mu Ller MC, Eigendorff E et al. Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. Leukemia 2017; 31: 829–836.

    Article  CAS  PubMed  Google Scholar 

  7. Ilander M, Olsson-Stromberg U, Schlums H, Guilhot J, Bruck O, Lahteenmaki H et al. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia 2017; 31: 1108–1116.

    Article  CAS  PubMed  Google Scholar 

  8. Hochhaus A, Rosti G, Cross NC, Steegmann JL, le Coutre P, Ossenkoppele G et al. Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study. Leukemia 2015; 30: 57–64.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Schonberg K, Rudolph J, Vonnahme M, Parampalli Yajnanarayana S, Cornez I, Hejazi M et al. JAK inhibition impairs NK cell function in myeloproliferative neoplasms. Cancer Res 2015; 75: 2187–2199.

    Article  PubMed  Google Scholar 

  10. Kumagai T, Matsuki E, Inokuchi K, Ohashi K, Shinagawa A, Takeuchi J et al. Relative increase in lymphocytes from as early as 1 month predicts improved response to dasatinib in chronic-phase chronic myelogenous leukemia. Int J Hematol 2014; 99: 41–52.

    Article  CAS  PubMed  Google Scholar 

  11. Chen CI, Koschmieder S, Kerstiens L, Schemionek M, Altvater B, Pscherer S et al. NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR-ABL-positive mice. Leukemia 2012; 26: 465–474.

    Article  CAS  PubMed  Google Scholar 

  12. Nakajima H, Zhao R, Lund TC, Ward J, Dolan M, Hirsch B et al. The BCR/ABL transgene causes abnormal NK cell differentiation and can be found in circulating NK cells of advanced phase chronic myelogenous leukemia patients. J Immunol 2002; 168: 643–650.

    Article  CAS  PubMed  Google Scholar 

  13. Takahashi N, Miura I, Saitoh K, Miura AB . Lineage involvement of stem cells bearing the philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. Blood 1998; 92: 4758–4763.

    CAS  PubMed  Google Scholar 

  14. Cho EK, Heo DS, Seol JG, Seo EJ, Chi HS, Kim ES et al. Ontogeny of natural killer cells and T cells by analysis of BCR-ABL rearrangement from patients with chronic myelogenous leukaemia. Br J Haematol 2000; 111: 216–222.

    Article  CAS  PubMed  Google Scholar 

  15. Min CK, Yang IH, Kim DW, Lee JW, Han CW, Min WS et al. Detection of the BCR-ABL fusion gene in natural killer cells in patients with chronic myelogenous leukemia. Acta Haematol 2000; 104: 135–138.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all patients contributing to the success of this study. This work is supported by the EUTOS program for CML 2016, Novartis and the Jubiläumsfonds of the Österreichische Nationalbank (No 14781).

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, Medical University Innsbruck, Innsbruck, Austria

    S Sopper & D Wolf

  2. Tyrolean Cancer Research Institute, Innsbruck, Austria

    S Sopper & D Wolf

  3. University of Helsinki and Department of Hematology, Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland

    S Mustjoki & K Porkka

  4. Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland

    S Mustjoki

  5. Institute of Medicine, Hematology Section, University of Bergen, Bergen, Norway

    B T Gjertsen

  6. NMDTI, Northwestern University, Chicago, USA

    F Giles

  7. Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    A Hochhaus

  8. Department of Hematology, VU University Medical Center, Amsterdam, Netherlands

    J J W M Janssen

  9. Department of Hematology, Oncology, Immunoncology and Rheumatology, Center of Integrated Oncology Cologne Bonn, University Hospital of Bonn, Bonn, Germany

    D Wolf

Authors
  1. S Sopper
    View author publications

    Search author on:PubMed Google Scholar

  2. S Mustjoki
    View author publications

    Search author on:PubMed Google Scholar

  3. B T Gjertsen
    View author publications

    Search author on:PubMed Google Scholar

  4. F Giles
    View author publications

    Search author on:PubMed Google Scholar

  5. A Hochhaus
    View author publications

    Search author on:PubMed Google Scholar

  6. J J W M Janssen
    View author publications

    Search author on:PubMed Google Scholar

  7. K Porkka
    View author publications

    Search author on:PubMed Google Scholar

  8. D Wolf
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to S Sopper or D Wolf.

Ethics declarations

Competing interests

All authors received research support from Novartis.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sopper, S., Mustjoki, S., Gjertsen, B. et al. NK cell dynamics and association with molecular response in early chronic phase chronic myelogenous leukemia (CML-CP) patients treated with nilotinib. Leukemia 31, 2264–2267 (2017). https://doi.org/10.1038/leu.2017.235

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/leu.2017.235

This article is cited by

Search

Advanced search

Quick links