Warts, Hypogammaglobulinemia, Infections, And Myelokathexis Research Articles

WHIM syndrome and oral squamous cell carcinoma

WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is an autosomal dominant disease related to a mutation in the chemokine receptor CXCR4 resulting in altered immune function. An increased susceptibility in these patients to human papillomavirus (HPV) manifests as cutaneous warts and, in women, cervical dysplasia and squamous carcinoma. HPV-related squamous carcinoma in other sites has not been documented. We report the occurrence of HPV-related squamous cell carcinoma of the oral cavity in 2 siblings with WHIM syndrome, whose pedigree has previously been described.

Separate elements are required for ligand‐dependent and ‐independent internalization of metastatic potentiator CXCR4

The C-terminal cytoplasmic domain of the metastatic potentiator CXCR4 regulates its function and spatiotemporal expression. However, little is known about the mechanism underlying constitutive internalization of CXCR4 compared to internalization mediated by its ligand, stromal cell-derived factor-1 alpha (SDF-1alpha)/CXCL12. We established a system to analyze the role of the CXCR4 cytoplasmic tail in steady-state internalization using the NP2 cell line, which lacks endogenous CXCR4 and SDF-1alpha. Deleting more than six amino acids from the C-terminus dramatically reduced constitutive internalization of CXCR4. Alanine substitution mutations revealed that three of those amino acids Ser(344) Glu(345) Ser(346) are essential for efficient steady-state internalization of CXCR4. Mutating Glu(345) to Asp did not disrupt internalization, suggesting that the steady-state internalization motif is S(E/D)S. When responses to SDF-1alpha were tested, cells expressing CXCR4 mutants lacking the C-terminal 10, 14, 22, 31 or 44 amino acids did not show downregulation of cell surface CXCR4 or the cell migration induced by SDF-1alpha. Interestingly, however, we identified two mutants, one with E344A mutation and the other lacking the C-terminal 17 amino acids, that were defective in constitutive internalization but competent in ligand-promoted internalization and cell migration. These data demonstrate that ligand-dependent and -independent internalization is genetically separable and that, between amino acids 336 and 342, there is a negative regulatory element for ligand-promoted internalization. Potential involvement of this novel motif in cancer metastasis and other CXCR4-associated disorders such as warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome is discussed.

WHIM syndrome: A defect in CXCR4 signaling

The study of inherited immunodeficiencies has proven valuable in elucidating molecular signaling cascades underlying the developmental and functional regulation of the human immune system. The first example of a human immunologic disease caused by mutation of a chemokine receptor was provided by WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, a rare, combined immunodeficiency featuring an unusual form of neutropenia. Subsequent studies following the initial description of mutations in the CXCR4 gene have revealed a striking concordance in the types of mutations observed, suggesting that impaired regulation of receptor signaling by truncation of the cytoplasmic tail domain is an essential aspect in disease pathogenesis. Biochemical studies have provided support for the model that impaired receptor downregulation leads to the characteristic immunologic and hematologic disturbances. Interestingly, these genetic studies have also identified phenocopies with the same clinical features but without mutation of CXCR4, suggesting that mutations in as yet uncharacterized downstream regulators of the receptor may be involved in a proportion of cases.