<i>MGA</i> 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. <i>MGA</i> (<i>Max gene associated</i>), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms of <i>MGA</i> deletion that drive CLL to RT remain elusive. We established an RT mouse model by knockout of <i>Mga</i> in the <i>Sf3b1</i>/<i>Mdr</i> CLL model using CRISPR-Cas9 to determine the role of <i>Mga</i> in RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified <i>Nme1</i> (nucleoside diphosphate kinase) as an <i>Mga</i> target, which drives RT by modulating OXPHOS. Given that <i>NME1</i> is 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 the <i>Mga-Nme1</i> axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT.