Workflow of the single-cell WGS analysis. Schematic representation of the steps followed for the analysis of the study. WGS was performed in 22 whole-genome amplified single-cells (13 MYD88^mut/CXCR4^mut and 9 MYD88^mut/CXCR4^wt) and the bulk tumor sample from a patient with WM. Variants called in the bulk sample were used as a matrix for the unsupervised clustering of the 22 cells. As cells did not cluster together according to CXCR4 mutation, we intentionally searched for variants significantly present in one group vs the other, by applying the Fisher’s exact test, and selected a list of 14. We validated them by Sanger sequencing on the bulk sample and on the 22 single cells. Next, we looked for mutations on these genes in a series of patients with whole-genome sequencing data to see whether they were predominant in CXCR4-mutated (mut) or wild-type (wt) cases. In addition, differential gene expression analysis based on CXCR4 was conducted in an independent set of patients, and results were cross-referenced with our list of variants. Finally, copy number alterations were compared between both groups. DGEA, differential gene expression analysis; NMF, nonnegative matrix factorization.