MGA deletion leads to Richter’s transformation via modulation of mitochondrial OXPHOS

Richter’s transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma.MGA(Max gene associated), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms ofMGAdeletion driving CLL to RT remain elusive. We established a novel RT mouse model by knockout ofMgain theSf3b1/MdrCLL model via CRISPR-Cas9 to determine the role ofMgain RT. Murine RT cells exhibit mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). We identifiedNme1(Nucleoside diphosphate kinase) as aMgatarget through RNA sequencing and functional characterization, which drives RT by modulating OXPHOS. AsNME1is also a known MYC target without targetable compounds, we found that concurrent inhibition of MYC and ETC complex II significantly prolongs the survival of RT micein vivo. Our results suggest thatMga-Nme1axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a novel therapeutic avenue for RT.Statement of SignificanceWe established a murine RT model through knockout ofMgain an existing CLL model based on co-expression ofSf3b1-K700E anddel(13q). We determined that theMGA/NME1regulatory axis is essential to the CLL-to-RT transition via modulation of mitochondrial OXPHOS, highlighting this pathway as a novel target for RT treatment.