MGA deletion leads to Richter's transformation by modulating mitochondrial OXPHOS

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 that drive CLL to RT remain elusive. We established...

Full description

Saved in:
Bibliographic Details
Published in:Science translational medicine 2024-07, Vol.16 (758), p.eadg7915
Main Authors: Iyer, Prajish, Zhang, Bo, Liu, Tingting, Jin, Meiling, Hart, Kevyn, Zhang, Jibin, Siegert, Viola, Remke, Marianne, Wang, Xuesong, Yu, Lei, Song, Joo, Venkataraman, Girish, Chan, Wing C, Jia, Zhenyu, Buchner, Maike, Siddiqi, Tanya, Rosen, Steven T, Danilov, Alexey, Wang, Lili
Format: Article
Language:English
Subjects:
Animal models
Animals
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Chronic lymphocytic leukemia
CRISPR
Disease Models, Animal
Electron transport chain
Gene Deletion
Genetic transformation
Humans
Kinases
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Lymphoma
MAX gene
Mice
Mitochondria - metabolism
Molecular modelling
Myc protein
Nucleoside-diphosphate kinase
Oxidative Phosphorylation
Phosphorylation
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 that drive CLL to RT remain elusive. We established an RT mouse model by knockout of in the / CLL model using CRISPR-Cas9 to determine the role of in RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified (nucleoside diphosphate kinase) as an target, which drives RT by modulating OXPHOS. Given that 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 axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT.
ISSN:1946-6234
1946-6242
1946-6242
1946-3242
DOI:10.1126/scitranslmed.adg7915