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| Status |
Public on Jan 25, 2019 |
| Title |
Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Multiple myeloma (MM) is a hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs due to a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells exhibit cancer stem cell-like characteristics in MM; thus targeting these cells is a promising strategy to completely cure this malignancy. Here, we showed that SP cells expressed higher levels of enhancer of zeste (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1/2 are both potential therapeutic targets to eradicate myeloma stem cells. A novel EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including in a patient-derived xenograft model. Moreover, long-term continuous administration of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling, and over-activation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells. Our results demonstrate that dual inhibition of EZH1/2 is a promising therapeutic approach to eradicate myeloma stem cells, leading to significant advances in the treatment of MM.
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| |
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| Overall design |
Examination and comprison of transcriptomes of MM cells with or without OR-S1 treatment.
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| |
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| Contributor(s) |
Nakagawa M, Kitabayashi I |
| Citation(s) |
30343511 |
| |
| Submission date |
Jan 25, 2018 |
| Last update date |
Apr 26, 2019 |
| Contact name |
Makoto Nakagawa |
| E-mail(s) |
[email protected]
|
| Organization name |
Duke University
|
| Department |
Department of Orthopaedic Surgery
|
| Street address |
308 Research Drive
|
| City |
Durham |
| State/province |
NC |
| ZIP/Postal code |
27710 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (4)
|
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| This SubSeries is part of SuperSeries: |
| GSE109675 |
Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma |
|
| Relations |
| BioProject |
PRJNA431630 |
| SRA |
SRP131406 |
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