MGA deletion leads to Richter's transformation by modulating mitochondrial OXPHOS.
Sci Transl Med
; 16(758): eadg7915, 2024 Jul 31.
Article
in En
| MEDLINE
| ID: mdl-39083585
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. However, genetic models and molecular mechanisms of MGA deletion that drive CLL to RT remain elusive. We established an RT mouse model by knockout of Mga in the Sf3b1/Mdr CLL model using CRISPR-Cas9 to determine the role of Mga in RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified Nme1 (nucleoside diphosphate kinase) as an Mga target, which drives RT by modulating OXPHOS. Given that NME1 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 Mga-Nme1 axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oxidative Phosphorylation
/
Leukemia, Lymphocytic, Chronic, B-Cell
/
Mitochondria
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci Transl Med
Journal subject:
CIENCIA
/
MEDICINA
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: