Enhanced function with decreased internalization of carboxy-terminus truncated CXCR4 responsible for WHIM syndrome

WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus–truncated CXCR4

“…13,20 Filtered vector supernatant was collected from confluent FLYRD18 producer cultures. After concentration of the vector by centrifugation (18 600g for 3 hours at 4°C), RD114-MFGS vectors were applied for transduction.…”

“…In particular, we previously reported that transduction of the R334X WHIM variant into healthy human CD34 ϩ peripheral blood mobilized stem cells (PBSCs) results in enhanced chemotactic and calcium flux responses of the cells to SDF-1, and found that this effect was associated with and presumably caused by a failure of the mutant receptor to downregulate and internalize, leading to prolongation of activation. 13 In the current study we explore the mechanism of myelokathexis in WHIM syndrome using the NOD.CB17-Prkdc scid /J mouse (nonobese diabetic/severe combined immunodeficiency [NOD/SCID] mouse) xenotransplantation model engrafted with healthy human mobilized CD34 ϩ PBSCs that had been transduced with internal ribosome entry site (IRES)-containing bifunctional retrovirus vectors encoding mutated CXCR4 or wild-type (wt) CXCR4 together with a green fluorescent protein (GFP) construct or with vector-encoding GFP construct only. We will demonstrate that expression of mutated CXCR4 does not itself induce apoptosis in transduced myeloid cells differentiated in culture from the transduced PBSCs, but does result in a WHIM-type myelokathexis pattern of the transduced human cells in the in vivo xenotransplantation model (myeloid apoptosis in marrow and decreased release of cells from the marrow to the circulation).…”

How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome

“…As the CXCR4 chemokine receptor is more sensitive to CXCL12 activation in WHIM syndrome cells, [5][6][7] the pharmaceutical exposition of the receptor to an antagonist may restore normal CXCR4 chemokine receptor function and thereby reestablish a physiological pathway. Plerixafor is a selective reversible antagonist that blocks the capacity of the chemokine CXCL12 to sustain the permanent activation of CXCR4.…”

“…Plerixafor is a selective reversible antagonist that blocks the capacity of the chemokine CXCL12 to sustain the permanent activation of CXCR4. [5][6][7] Consequently, treatment with a CXCR4 antagonist has the potential to restore normal circulating blood cells levels (the levels of both neutrophils and lymphocytes) 29,30 and might impact the efficacy of the treatment of HPV infection. Indeed, the first human trial shows promising short-term effects: in ;1 week, the therapy with plerixafor dramatically restored neutrophil and lymphocyte counts in a total of 9 patients.…”

“…Heterozygous mutations of CXCR4 result in an impaired internalization and prolonged response of the receptor to CXCL12 and neutrophil accumulation in the bone marrow ( Figure 1). 3,[5][6][7] The purpose of the present article is to discuss the treatment approach and review the clinical, immunological, and molecular phenotypes of the syndrome. Where evidence is available, it is cited; suggestions are otherwise based on our experience and opinions.…”