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| Status |
Public on Apr 01, 2024 |
| Title |
Orthogonal proteogenomic approaches identify the druggable PA2G4-MYC axis in 3q26 AML |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens, we identified selective and pan-histone deacetylase inhibitors (HDACis) as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, we dissected the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstituted the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogated EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACi-based combination therapies in patients with 3q26 AML.
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| Overall design |
Human CD45+ leukemia cells were isolated through cell sorting from PDLX mice model after 4 weeks of treatment with Vehicle, azacitidine (Aza), entinostat (Ent), or a combination of azacitidine and entinostat (Ent_Aza)
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| Contributor(s) |
Roti G, Marchesini M, Gherli A, Montanaro A, Simoncini E, Moron dalla Tor L |
| Citation(s) |
38834613 |
| |
| Submission date |
Feb 19, 2024 |
| Last update date |
Jun 26, 2024 |
| Contact name |
Matteo Marchesini |
| Organization name |
IRCSS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" (IRST)
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| Street address |
via Piero Maroncelli 40
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| City |
Meldola |
| State/province |
FC |
| ZIP/Postal code |
47014 |
| Country |
Italy |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA1078002 |
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