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| Status |
Public on Aug 15, 2024 |
| Title |
Genome-wide CRISPR screen of MOLM13 cells after Idasanutlin treatment |
| Organisms |
Homo sapiens; synthetic construct |
| Experiment type |
Other
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| Summary |
Targeting MDM2 is an attractive therapeutic approach for TP53 wild-type (WT) tumors, including the majority of de novo acute myeloid leukemia (AML) cases. However, patients with WT TP53 have shown variable responses to MDM2 inhibitors in clinical trials, highlighting the need to identify additional biomarkers to maximize the chances of clinical success. We performed CRISPR-Cas9 knockout screens to identify genes that confer resistance to an MDM2 inhibitor idasanutlin. We did not find recurrent sgRNA hits or mutations in p53 downstream targets, such as CDKN1A, BAX, PMIAP1, and BBC3, apart from TP53. This was consistent with the results of individual knockout validation experiments and exome sequencing data from idasanutlin resistant cell lines generated form long-term exposure to low doses of idasanutlin. RNA-seq differential expression analysis revealed that major p53 downstream targets were upregulated in both idasanutlin-sensitive MOLM13 and resistant OCIAML3 cell lines after idasanutlin treatment. These findings highlight the pleiotropic functions of TP53 and suggest that the loss of individual downstream targets of TP53 does not significantly contribute to MDM2 inhibitor resistance.
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| Overall design |
MOLM13 cells constitutively expressing Cas9 and were transduced with a CRISPR library virus and puromycin-selected and then treated with Idasanutlin or DMSO control for 14 days.
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| Contributor(s) |
Ryabinin P, Bottomly D, McWeeney S, Zhang H, Allen B, Savoy L, Wang A |
| Citation missing |
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| |
| Submission date |
Aug 16, 2023 |
| Last update date |
Aug 15, 2024 |
| Contact name |
Peter Ryabinin |
| E-mail(s) |
[email protected]
|
| Organization name |
Oregon Health and Science University
|
| Street address |
3181 SW Sam Jackson Park Rd
|
| City |
Portland |
| State/province |
OR |
| ZIP/Postal code |
97239 |
| Country |
USA |
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| Platforms (2) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL19604 |
Illumina HiSeq 2500 (synthetic construct) |
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| Samples (6)
|
| GSM7713302 |
MOLM13 Idasanutlin 200nM D14 Replicate 1 |
| GSM7713303 |
MOLM13 Idasanutlin 200nM D14 Replicate 2 |
| GSM7713304 |
MOLM13 Idasanutlin 50nM D14 Replicate 1 |
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| This SubSeries is part of SuperSeries: |
| GSE241674 |
Immune signature and monocytic leukemia cells are resistant to MDM2 inhibition |
|
| Relations |
| BioProject |
PRJNA1005974 |
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