Gene expression profile of IGLV3-21^R110 CLL. (A) UMAP representation of C1-CLL cases based on 825 DEGs between U-IGHV and M-IGHV cases (top). Projection of expression levels of these 825 genes from C2-CLL cases on previous UMAP embedding (bottom). C1-CLL565 carrying YDND motif is highlighted. (B) Heatmap representation of 64 DEGs between IGLV3-21^R110 and non–IGLV3-21^R110 cases. Genes are ordered based on their log2-transformed fold change. (C) Boxplots showing expression levels of WNT5A and WNT5B according to CLL subtype in C1-CLL (top) and C2-CLL (bottom). P values by Wilcoxon test. (D) Gene sets downregulated in IGLV3-21^R110 CLL are related to genes downregulated in aggressive CLL (top) and genes upregulated in M-IGHV tumors (middle and bottom). (E) Number of DEGs between subset 2 and non–subset 2 i-CLL cases carrying IGLV3-21^R110 as well as between i-CLL and m-CLL cases with M-IGHV and lacking IGLV3-21^R110. (F) Summary of findings: cases carrying IGLV3-21^R110 mutation have transcriptome mirroring that observed in n-CLL. Considering that most patients carrying IGLV3-21^R110 belong to i-CLL subtype, this illustration aims to highlight that IGLV3-21^R110 identifies a subset of i-CLL cases resembling n-CLL cases. In contrast, absence of this mutation is associated with phenotype typical of m-CLL tumors. P < .1, *P < .05, **P < .001, ***P < .0001. ns, not significant; TPM, gene-level transcripts per million.