[Integrated analyses of mature B-cell neoplasms in mice triggered by Utx loss and Braf V600E mutation].

In multiple myeloma, inactive somatic mutations of UTX, a histone H3K27 demethylase and a component of the COMPASS complex, and activating BRAF V600E mutations have been reported. We generated a new mouse model in which Utx knock-out and Braf V600E knock-in were induced only in post-germinal center B cells including plasma cells. Compound mice with both mutations developed mature B-cell neoplasms such as B-cell lymphomas and myeloma-like plasma cell tumors as they aged. Analyses of malignant plasma cells revealed that the expression of Myc and myeloma-related genes was significantly increased and that epigenetic reprogramming progressed before the onset of disease. Furthermore, we proved that the function of UTX as a tumor suppressor was independent of its H3K27me3 demethylase activity. In addition, we found that CD8+PD-1+Tim-3+/- exhausted T cells were increased in tumor sites of mature B-cell neoplasms and that the prevention of excessive exhaustion could be a therapeutic option. This mouse model is a useful tool for understanding the pathogenesis of human diseases and developing novel therapeutics.