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