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Chronic Lymphocytic Leukemia

Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia

Leukemia volume 28, pages 2005–2015 (2014)Cite this article

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Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+CD19+ B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNα) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNα production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-β and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.

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Acknowledgements

We thank Professor Stephen Jane for critical appraisal of the manuscript, the AMREP flow cytometry team for technical assistance, Dr Meredith O’Keefe for technical suggestions, Dr Pohan Lukito for control BM samples, the AMREP Animal Service staff for colony health management and the ALLG Tissue Bank for provision of BM and PBL samples. We especially thank all patients involved in this study. SBT is supported by an NHMRC RD Wright Career Development Fellowship. This study was funded by the Association for International Cancer Research (AICR) UK and the National Health and Medical Research Council (NHMRC) of Australia.

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Authors and Affiliations

  1. Department of Immunology, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria, Australia

    D Saulep-Easton, F B Vincent, M Le Page & F Mackay

  2. Department of Haematology, The Alfred Hospital, 55 Commercial Road, Melbourne, Victoria, Australia

    A Wei & S B Ting

  3. Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria, Australia

    A Wei & S B Ting

  4. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, 460 West 12th Avenue, Columbus, OH, USA

    C M Croce

  5. Department of Haematology, Peter MacCallum Cancer Centre, St. Andrews’s Place, East Melbourne, Victoria, Australia

    C Tam

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Saulep-Easton, D., Vincent, F., Le Page, M. et al. Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia. Leukemia 28, 2005–2015 (2014). https://doi.org/10.1038/leu.2014.105

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