IGHV1 usage is associated with lymphadenopathy and aggressive disease in the TCL1 mouse model for chronic lymphocytic leukemia

Abstract

Abstract TCL1 mice are the most commonly used preclinical model for chronic lymphocytic leukemia (CLL), a B-cell malignancy characterized by clonal CD5 + B-lymphocyte accumulation. B-cell receptor (BCR) sequencing identifies two important risk markers, immunoglobulin heavy chain variable region (IGHV) mutational status and receptor stereotypy. Despite its clinical relevance in patients, comprehensive examinations of endogenous BCR repertoires in TCL1 mice remain limited. We analysed BCR repertoires of 85 TCL1 mice, primarily comprising CLL clones using IGHV1 and IGHV11 (27.3 and 49.1% of CLL clones, respectively). Interestingly, TCL1 mice with dominant IGHV1 CLL clones showed significantly higher levels of CD4 + T-cells, and increased exhaustion levels (PD-1) on splenic CD8 + T-cells compared to IGHV11 CLL clones. Cancer related pathways (p53, MTORC and KRAS) were distinctly regulated in IGHV1 CLL clones. These clones occurred more frequently in female mice, characterized by short survival times (hazard ratio 2.6). Additionally, mice with dominant IGHV1 CLL clones displayed an almost twofold inguinal lymph node enlargement. In conclusion, we identified molecular, phenotypical and immunological differences between IGHV1 and IGHV11 CLL clones, which are key to consider for preclinical studies using the TCL1 mouse model. Furthermore, our data suggests that IGHV1 CLL clones model the nodal form of human CLL.