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| Status |
Public on Jun 27, 2024 |
| Title |
MGA deletion leads to Richter's transformation via modulation of mitochondrial OXPHOS |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
To investigate the role of MGA in mouse CLL and Richters transformation. We adoptively transfer in-vitro edited via sgRNA-Mga/control early LSK (Lin-Sca1+ Kit+) progenitors (CD19-Cre+/--Mdrfl/+-Sf3B1fl/+-Cas9fl/+) in the recepient mice and followed the mice by serial bleeding for the development of CLL by flow cytometry for 22 months. After the mice developed CLL, we subsequenlty transplanted the CLL cells in other recepient mice and developed RT. We isolated the donor splenic B cells from Mga deleted mouse CLL and RT having SF3B1 K700E mutation and 13q(MDR) deletion and performed RNA seq on the donor splenic B cells.
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| Web link |
https://pubmed.ncbi.nlm.nih.gov/36798339/
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| Contributor(s) |
Wang L |
| Citation(s) |
36798339 |
| |
| Submission date |
Apr 04, 2024 |
| Last update date |
Sep 26, 2024 |
| Contact name |
Lili Wang |
| E-mail(s) |
lilwang@coh.org
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| Organization name |
City of Hope
|
| Department |
Systems biology
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| Lab |
Wang's Lab
|
| Street address |
1218 South Fifth Ave.
|
| City |
Monrovia |
| State/province |
CALIFORNIA |
| ZIP/Postal code |
91016 |
| Country |
USA |
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| Platforms (1) |
| GPL15103 |
Illumina HiSeq 1000 (Mus musculus) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA1096330 |
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