deletion leads to Richter's transformation by modulating mitochondrial OXPHOS.

Abstract

Richter's transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma.(), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms ofdeletion that drive CLL to RT remain elusive. We established an RT mouse model by knockout ofin the/CLL model using CRISPR-Cas9 to determine the role ofin RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified(nucleoside diphosphate kinase) as antarget, which drives RT by modulating OXPHOS. Given thatis also a known MYC target without targetable compounds, we found that concurrent inhibition of MYC and electron transport chain complex II substantially prolongs the survival of RT mice in vivo. Our results suggest that theaxis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT.