Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia

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.

Case Report: A Novel CXCR4 Mutation in a Chinese Child With Kawasaki Disease Causing WHIM Syndrome

“…To date, all the twelve known heterozygous gain-of-function CXCR4 WHIM mutations are in the genomic region that encodes the C-terminal domain of the receptor ( Figure 1A ). And c.1000C> T (p. Arg334Ter, also written informally as R334X) is the most frequent ( Figure 1B ), which is consistent with a previous review ( 18 , 19 ). The nucleotide changes, mutation types, amino acid changes and the proportion of WHIM patients with CXCR4 mutation are also summarized ( Figure 1B ) ( 17 ).…”

Shared genomic segment analysis in a large high-risk chronic lymphocytic leukemia pedigree implicates CXCR4 in inherited risk

“…A small case-control gene-panel sequencing study of sporadic CLL included CXCR4, and identified a common variant in CXCR4 (rs2228014, MAF = 0.04) that was increased in CLL cases (uncorrected P = 0.0015) [50] . The association of this variant with CLL was not replicated in a second, larger case-control study (P = 0.84) [51] . However, one rare truncating variant and one missense variant were observed in CXCR4 in two CLL cases with positive family history which was absent from controls (not statistically significant) [51] .…”

“…The association of this variant with CLL was not replicated in a second, larger case-control study (P = 0.84) [51] . However, one rare truncating variant and one missense variant were observed in CXCR4 in two CLL cases with positive family history which was absent from controls (not statistically significant) [51] .…”

“…However, one rare truncating variant and one missense variant were observed in CXCR4 in two CLL cases with positive family history which was absent from controls (not statistically significant) [ 51 ] . Truncating germline mutations in the C-terminus of CXCR4 have been shown to act as gain-of-function mutations and cause WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), and Waldenström’s macroglobulinemia [ 52 ] .…”

Genome-wide association study on 13,167 individuals identifies regulators of hematopoietic stem and progenitor cell levels in human blood

“…Of note, some of the candidate genes underlie autosomal-dominant blood disorders characterized by aberrant HSPC function. Gain-of-function mutations in CXCR4 cause the Warts, Hypogammaglobulinemia, Immunodeficiency and Myelokathexis (WHIM) syndrome, marked by impaired egression of HSPCs and other white blood cells out of the bone marrow 23,24 . CEBPA mutations cause familial acute myeloid leukemia 25 .…”