Spatial Organization and Early Signaling of the B-Cell Receptor in CLL

Chronic lymphocytic leukemia (CLL) is dichotomized into two groups based on the somatic hypermutation (SHM) status of the IGHV gene. IGHV-mutated CLL (M-CLL) is a slower progressive disease, while IGHV-unmutated CLL (U-CLL) is more aggressive. Most CLL clones express BcR of both IgM and IgD isotypes. However, a small proportion of cases, around 5-10%, express isotype-switched IgGs. Isotype-switched IgG+ CLL almost exclusively belong to the M-CLL subset. To characterize the gene expression of IgG class-switched versus IgM+ CLL we performed RNAseq analysis of eighteen CD19+ isolated CLL cell samples on Illumina sequencing platform. All IgG+ CLL samples in this analysis carried mutated IGHV4-34 gene rearrangements. After normalization, unsupervised clustering clearly separated the samples primarily according to IGHV gene SHM status and then by the IG subclass. Next, we directly compared (supervised analysis) the three different CLL subtypes/subclasses (IgM U-CLL, IgM M-CLL and IgG M-CLL). We showed distinct gene expression signatures between the three immunogenetic subgroups. The gene expression signature of IgG M-CLL was closely related to that of IgM M-CLL, while both were distinct from IgM U-CLL.