This study used single-cell RNA sequencing with B-cell receptor (BCR) sequencing, single-cell ATAC sequencing, and whole-genome sequencing to characterize tumor B-cell clones and their genomic, transcriptomic, and epigenetic features across 12 patients with IgM MGUS, smoldering WM (SWM), and symptomatic WM (134,040 cells analyzed).
IgM MGUS and low/intermediate-risk SWM showed oligoclonal B-cell landscapes (multiple clones), while symptomatic WM was dominated by a single clone; the dominant clone (C1) was defined by CD9, JCHAIN, RASSF6, and DUSP22 expression and high POU2F2 chromatin activity, and 6q deletion—found in high-risk patients—conferred a metabolic fitness advantage with enriched OXPHOS signatures in del6q vs. copy-neutral C1 cells (4,309 vs. 7,144 cells compared).
Small cohort (12 patients, 16 samples) limits generalizability; single-cell RNA-based mutation calling has low sensitivity for low-expressed genes (e.g., MYD88); CXCR4 indels could not be assessed at single-cell resolution; longitudinal cases are too few to draw firm conclusions about clonal stability over time.
CD9, JCHAIN, and DUSP22 mark the dominant tumor clone in WM and may serve as targets or biomarkers, but CD9 expression is context-dependent (absent in some treated/relapsed cases) and requires protein-level validation in larger cohorts before clinical use. The 6q deletion appears to be a late, fitness-conferring event in high-risk patients and warrants prospective tracking as a progression marker.
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