Abstract
Given its pleiotropic functions, including its prominent role in inflammation, immune responses and cancer, the C-X-C chemokine receptor type 4 (CXCR4) has gained significant attention in recent years and has become a relevant target in drug development. Although the signaling properties of CXCR4 have been extensively studied, several aspects deserve deeper investigations. Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome, a rare congenital immunodeficiency associated by chronic leukopenia. Similar mutations have also been recently identified in 30% of patients affected by Waldenstrom’s macroglobulinaemia, a B-cell neoplasia with bone marrow accumulation of malignant cells. An ample body of work has been generated to define the impact of WHIM mutations on CXCR4 signaling properties and evaluate their role on pathogenesis, diagnosis, and response to therapy, although the identity of disease-causing signaling pathways and their relevance for disease development in different genetic variants are still open questions. This review discusses the current knowledge on biochemical properties of CXCR4 mutations to identify their prototypic signaling profile potentially useful to highlighting novel opportunities for therapeutic intervention.
Highlights
The CXCL12 receptor CXCR4 is a G protein-coupled receptor (GPCR) identified for the first time in peripheral blood leukocytes [1], and initially described because of its role as a co-receptor for HIV [2]
These mutations act as gain-of-function mutations that turn CXCR4 into a truncated receptor with impaired internalization/desensitization and amplified signaling properties that dramatically impact on its biological functions, resulting in a “high-performance“ receptor associated with aberrant expression and activity, and with chemotherapy resistance in Waldenstrom’s macroglobulinaemia (WM)
CXCR4 genetic is a crucial hub for the pathogenesis of both WHIM syndrome and WM, and deciphering the aberrant signaling profile represents a fundamental element for the identification of relevant biomarkers and the development of precision therapy in both diseases
Summary
The CXCL12 receptor CXCR4 is a G protein-coupled receptor (GPCR) identified for the first time in peripheral blood leukocytes [1], and initially described because of its role as a co-receptor for HIV [2]. Aberrant CXCR4 signaling caused by heterogeneous mutations affecting the C-terminal (C-ter) region of the receptor has been reported in a rare primary immunodeficiency, the Warts, Hypogammaglobulinaemia, Infections and Myelokathexis (WHIM) syndrome [5], and more recently in Waldenstrom’s macroglobulinaemia (WM), an indolent form of B-cell non-Hodgkin lymphoma [6]. These mutations act as gain-of-function mutations that turn CXCR4 into a truncated receptor with impaired internalization/desensitization and amplified signaling properties that dramatically impact on its biological functions, resulting in a “high-performance“ receptor associated with aberrant expression and activity, and with chemotherapy resistance in WM patients [7]. We attempt a systematic description of WHIM mutations aimed at outlying the global organization of this group of mutations, drawing up a prototypic WHIM-mutated CXCR4 profile and identifying aspects deserving further investigation
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