deletion leads to Richter's transformation via modulation of mitochondrial OXPHOS.

UNLABELLED

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 of deletion driving CLL to RT remain elusive. We established a novel RT mouse model by knockout of in the / CLL model via CRISPR-Cas9 to determine the role of in RT. Murine RT cells exhibit mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). We identified (Nucleoside diphosphate kinase) as a target through RNA sequencing and functional characterization, which drives RT by modulating OXPHOS. As is 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 mice . Our results suggest that axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a novel therapeutic avenue for RT.

STATEMENT OF SIGNIFICANCE

We established a murine RT model through knockout of in an existing CLL model based on co-expression of -K700E and ( ). We determined that the regulatory axis is essential to the CLL-to-RT transition via modulation of mitochondrial OXPHOS, highlighting this pathway as a novel target for RT treatment.