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AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome

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 Administ...

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Autores principales: McDermott, David H, Lopez, Joseph, Deng, Francis, Liu, Qian, Ojode, Teresa, Chen, Haoqian, Ulrick, Jean, Kwatemaa, Nana, Kelly, Corin, Anaya-O’Brien, Sandra, Garofalo, Mary, Marquesen, Martha, Hilligoss, Dianne, DeCastro, Rosamma, Malech, Harry L, Murphy, Philip M
Formato: Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071896/
https://www.ncbi.nlm.nih.gov/pubmed/21070597
http://dx.doi.org/10.1111/j.1582-4934.2010.01210.x
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author McDermott, David H
Lopez, Joseph
Deng, Francis
Liu, Qian
Ojode, Teresa
Chen, Haoqian
Ulrick, Jean
Kwatemaa, Nana
Kelly, Corin
Anaya-O’Brien, Sandra
Garofalo, Mary
Marquesen, Martha
Hilligoss, Dianne
DeCastro, Rosamma
Malech, Harry L
Murphy, Philip M
author_facet McDermott, David H
Lopez, Joseph
Deng, Francis
Liu, Qian
Ojode, Teresa
Chen, Haoqian
Ulrick, Jean
Kwatemaa, Nana
Kelly, Corin
Anaya-O’Brien, Sandra
Garofalo, Mary
Marquesen, Martha
Hilligoss, Dianne
DeCastro, Rosamma
Malech, Harry L
Murphy, Philip M
author_sort McDermott, David H
collection PubMed
description 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 (CXCR4(WT)) and the most common WHIM variant of CXCR4 (CXCR4(R334X)), as well as leucocytes from a WHIM patient with the CXCR4(R334X) mutation versus healthy controls. We found that CXCR4(R334X) 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 CXCR4(R334X) and CXCR4(WT). Together, our data provide further evidence that CXCR4(R334X) 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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spelling pubmed-30718962012-10-01 AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome McDermott, David H Lopez, Joseph Deng, Francis Liu, Qian Ojode, Teresa Chen, Haoqian Ulrick, Jean Kwatemaa, Nana Kelly, Corin Anaya-O’Brien, Sandra Garofalo, Mary Marquesen, Martha Hilligoss, Dianne DeCastro, Rosamma Malech, Harry L Murphy, Philip M J Cell Mol Med Articles 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 (CXCR4(WT)) and the most common WHIM variant of CXCR4 (CXCR4(R334X)), as well as leucocytes from a WHIM patient with the CXCR4(R334X) mutation versus healthy controls. We found that CXCR4(R334X) 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 CXCR4(R334X) and CXCR4(WT). Together, our data provide further evidence that CXCR4(R334X) is a gain-of-function mutation, and support clinical evaluation of AMD3100 as mechanism-based treatment in patients with WHIM syndrome. Blackwell Publishing Ltd 2011-10 2011-09-26 /pmc/articles/PMC3071896/ /pubmed/21070597 http://dx.doi.org/10.1111/j.1582-4934.2010.01210.x Text en © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
spellingShingle Articles
McDermott, David H
Lopez, Joseph
Deng, Francis
Liu, Qian
Ojode, Teresa
Chen, Haoqian
Ulrick, Jean
Kwatemaa, Nana
Kelly, Corin
Anaya-O’Brien, Sandra
Garofalo, Mary
Marquesen, Martha
Hilligoss, Dianne
DeCastro, Rosamma
Malech, Harry L
Murphy, Philip M
AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome
title AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome
title_full AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome
title_fullStr AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome
title_full_unstemmed AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome
title_short AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome
title_sort amd3100 is a potent antagonist at cxcr4(r334x), a hyperfunctional mutant chemokine receptor and cause of whim syndrome
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071896/
https://www.ncbi.nlm.nih.gov/pubmed/21070597
http://dx.doi.org/10.1111/j.1582-4934.2010.01210.x
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