Gene
CXCR4
1 variant(s) documented across Waldenström's Macroglobulinemia
Variants
| Variant | Type | Frequency in disease | Significance | Also found in |
|---|---|---|---|---|
| WHIM-like mutations (most commonly S338X) | somatic | ~30-40% | Second most common somatic event in WM. Over 40 different mutations described, both nonsense and frameshift. Mutations cause sustained CXCR4 signaling and enhanced bone marrow homing via CXCL12. | WHIM syndrome (~100% (germline)) |
Clinical implications
WHIM-like mutations (most commonly S338X)
Associated with higher IgM levels, greater bone marrow involvement, increased hyperviscosity risk, and reduced/delayed response to BTK inhibitors. Nonsense mutations (especially S338X) confer more aggressive phenotype than frameshift mutations.
Testing: Sanger sequencing, next-generation sequencing, allele-specific PCR
Related molecules in pathway
CXCR4established
Chemokine receptor driving bone marrow homing — WHIM-like mutations in ~30-40%
Related hypotheses
CXCR4 WHIM-like mutations act as secondary drivers affecting bone marrow homing and drug resistance
78leading·40 studies
A two-hit model where MYD88 L265P provides the founding event and secondary mutations (CXCR4, ARID1A, TP53) shape disease phenotype
75leading·30 studies
Sources (4)
DetailsHunter ZR et al. (2014) The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis.DOI ↗