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

ABSTRACT: 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. The, genetic models and molecular mechanisms of MGA deletion driving CLL to RT remain elusive. We established a RT mouse model by knockout of Mga in the Sf3b1/Mdr CLL model via CRISPR-Cas9. Murine RT cells exhibit mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). We identified Nme1 (Nucleoside diphosphate kinase) as a Mga target through RNA sequencing and functional characterization, which drives RT by modulating OXPHOS. As NME1 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 in vivo. Our results suggest that Mga-Nme1 axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a novel therapeutic avenue for RT.

ORGANISM(S): Mus musculus

PROVIDER: GSE263238 | GEO | 2024/06/27

REPOSITORIES: GEO

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