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 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.
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. dmcdermott@niaid.nih.gov
David H
DH
McDermott
Joseph
J
Lopez
Francis
F
Deng
Qian
Q
Liu
Teresa
T
Ojode
Haoqian
H
Chen
Jean
J
Ulrick
Nana
N
Kwatemaa
Corin
C
Kelly
Sandra
S
Anaya-O'Brien
Mary
M
Garofalo
Martha
M
Marquesen
Dianne
D
Hilligoss
Rosamma
R
DeCastro
Harry L
HL
Malech
Philip M
PM
Murphy
D000328:Adult; D000818:Animals; D001596:Benzylamines; D016466:CHO Cells; D006224:Cricetinae; D000080027:Cyclams; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D020014:K562 Cells; D000081207:Primary Immunodeficiency Diseases; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014860:Warts / Q000235:genetics*
D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor