• Open Access

AMD3100 is a potent antagonist at CXCR4R334X, a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome

Authors

  • David H. McDermott,

    Corresponding author
    1. Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Joseph Lopez,

    1. Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Francis Deng,

    1. Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Qian Liu,

    1. Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Teresa Ojode,

    1. Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Haoqian Chen,

    1. Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Jean Ulrick,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Nana Kwatemaa,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Corin Kelly,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Sandra Anaya-O’Brien,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Mary Garofalo,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Martha Marquesen,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Dianne Hilligoss,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Rosamma DeCastro,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Harry L. Malech,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Philip M. Murphy

    1. Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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David H. McDERMOTT, M.D.,
Bldg 10, Room 11N113, NIH,
Bethesda, MD 20892, USA.
Tel.: 301–496-8483
Fax: 301–402-4369
E-mail: dmcdermott@niaid.nih.gov

Abstract

WHIM is an acronym for a rare immunodeficiency syndrome (OMIM #193670) caused by autosomal dominant mutations truncating the C-terminus of the chemokine receptor CXC chemokine receptor 4 (CXCR4). WHIM mutations may potentiate CXCR4 signalling, suggesting that the United States Food and Drug Administration (FDA)-approved CXCR4 antagonist AnorMED3100 (AMD3100) (also known as Plerixafor) may be beneficial in WHIM syndrome. We have tested this at the preclinical level by comparing Chinese hamster ovary (CHO) and K562 cell lines matched for expression of recombinant wild-type CXCR4 (CXCR4WT) and the most common WHIM variant of CXCR4 (CXCR4R334X), as well as leucocytes from a WHIM patient with the CXCR4R334X mutation versus healthy controls. We found that CXCR4R334X mediated modestly increased signalling (∼2-fold) in all functional assays tested, but strongly resisted ligand-dependent down-regulation. AMD3100 was equipotent and equieffective as an antagonist at CXCR4R334X and CXCR4WT. Together, our data provide further evidence that CXCR4R334X is a gain-of-function mutation, and support clinical evaluation of AMD3100 as mechanism-based treatment in patients with WHIM syndrome.

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