CXCR4 WHIM-like mutations identified as second driver and ibrutinib resistance factor

Hunter et al. (2014) discovered activating CXCR4 mutations (homologous to WHIM syndrome variants) in 30-40% of WM patients. CXCR4 mutations confer relative ibrutinib resistance by sustaining AKT and ERK survival signaling, and are associated with higher IgM levels, symptomatic hyperviscosity, and slower treatment response. CXCR4 genotyping now guides treatment selection.