|
| Status |
Public on May 01, 2017 |
| Title |
Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Multiple Myeloma (MM) is a frequently incurable hematological cancer in which over activity of MYC plays a central role, notably through upregulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small molecule library for anti-MM activity. The most potent hits identified were rocaglate-scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, our most promising rocaglate. Proteome-wide, reversion correlated with selective depletion of short-lived proteins key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates.
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| |
|
| Overall design |
RNA sequencing of 5 cell lines (NCI-H929, NAMALWA, U266, MM1S and OPM2) treated with CMLD010509 or vehicle control (DMSO)
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| |
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| Contributor(s) |
Manier S, Ghobrial IM |
| Citation(s) |
28490664 |
| |
| Submission date |
Feb 13, 2017 |
| Last update date |
Jul 09, 2019 |
| Contact name |
Irene Ghobrial |
| E-mail(s) |
irene_ghobrial@dfci.harvard.edu
|
| Phone |
6176326777
|
| Organization name |
Dana-Farber Cancer Institute
|
| Department |
Medical Oncology
|
| Lab |
Ghobrial Lab
|
| Street address |
4 Blackfan Circle, 2nd Floor, Suite 240
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
|
| Samples (10)
|
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| Relations |
| BioProject |
PRJNA374537 |
| SRA |
SRP099436 |
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