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| Status |
Public on Apr 03, 2013 |
| Title |
Engineering ABT-737 Resistance in MYC-driven Lymphomas Identifies DHX9 as a Drug Response Modifier |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
Many traditional cytotoxic agents used in the treatment of cancer function by eliciting an apoptotic response in tumor cells. However, evasion of apoptosis by BCL-2 family members is often deregulated prior to therapeutic intervention leading to treatment failure. To address this, ABT-737 was rationally designed to target BCL-2-like family members and has shown promising results against tumor cells dependent on BCL-2 for their survival. One shortcoming is that MCL-1, a member of the BCL-2 family is poorly inhibited by ABT-737 and is a major cause of resistance. To gain insight into biological pathways that could circumvent this resistance, we designed an shRNA screen to identify novel sensitizers to ABT-737 by engineering MYC driven lymphomas that were resistant to ABT-737 due to endogenous MCL-1 expression. Utilizing this model, we performed a shRNA drop-out screen and identified Dhx9 as a target whose suppression sensitizes cells to ABT-737. DHX9 loss lead to replicative stress signaling, which in turn potently induced the BH3-only proteins, NOXA and PUMA, in a p53-dependent manner to curtail MCL-1 activity. Induction of NOXA is essential for ABT-737 sensitization. Our results ascribe a novel role for DHX9 in the replicative stress pathway and link DHX9 activity to p53 function in vivo.
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| Overall design |
Comparison of Arf-/-Eu-myc/Bcl-2 lymphomas expressing either control Rluc.713 or Dhx9 shRNA, Dhx9.1241
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| |
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| Contributor(s) |
Larsson O |
| Citation(s) |
23440244 |
| |
| Submission date |
Mar 29, 2012 |
| Last update date |
Jul 22, 2013 |
| Contact name |
Ola Larsson |
| E-mail(s) |
ola.larsson@ki.se
|
| Phone |
+46 (0)8 517 73280
|
| Organization name |
Karolinska Institutet
|
| Department |
Department of oncology-pathology
|
| Street address |
CCK, R8:01
|
| City |
Stockholm |
| ZIP/Postal code |
171 76 |
| Country |
Sweden |
| |
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| Platforms (1) |
| GPL11078 |
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [CDF: MoGene10stv1_Mm_ENTREZG_13] |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA157127 |
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