| Autor: |
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 |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 7/31/2024, Vol. 16 Issue 758, p1-12, 12p |
| Abstrakt: |
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. Editor's summary: Richter's transformation (RT) involves the progression of chronic lymphocytic leukemia (CLL) to a more aggressive lymphoma with poor outcomes. Understanding the transition into RT is key to more targeted therapeutic strategies. Iyer et al. examined the role of the MYC suppressor MGA, which is differentially expressed in RT, in an in vivo CLL model with MGA dysfunction. MGA loss resulted in increased mitochondrial function and reactive oxygen species and led to aberrant cell morphology and up-regulated MYC as commonly observed in patients. Combined inhibition of MYC and mitochondrial respiration prolonged in vivo survival in this model, highlighting potential therapeutic strategies for RT with this genetic profile. —Catherine Charneski [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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