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| Status |
Public on Jan 19, 2022 |
| Title |
Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax [RNA-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The prognosis for B cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however lack of sufficient responses in pre-clinical models and possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in patient derived xenograft model leads to downregulation of particular p53-related genes. Interestingly, addition of auranofin, a thioredoxin system inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently on the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of NOXA-encoding gene (PMAIP1) by chromatin remodeling and increased transcriptional accessibility. Altogether, these results present novel, promising drug combination that could be exploited for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.
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| Overall design |
RNA-seq in MLL-AF4+ patient derived xenograft ALL cells isolated from control (n=3) and venetoclax-treated (n=3) NSG mice
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| Contributor(s) |
Fidyt K, Harman JR, Madzio J, Pastorczak A, Milne TA, Firczuk M |
| Citation(s) |
35091682 |
| |
| Submission date |
Dec 15, 2020 |
| Last update date |
Jan 31, 2022 |
| Contact name |
Malgorzata Firczuk |
| E-mail(s) |
[email protected]
|
| Organization name |
Medical University of Warsaw
|
| Department |
Department of Immunology
|
| Street address |
Nielubowicza 5 Street
|
| City |
Warsaw |
| State/province |
masovian |
| ZIP/Postal code |
02-097 |
| Country |
Poland |
| |
|
| Platforms (1) |
|
| Samples (6)
|
| GSM4975373 |
RNA-seq in MLL-AF4 patient derived xenograft cells - control_1 |
| GSM4975374 |
RNA-seq in MLL-AF4 patient derived xenograft cells - control_2 |
| GSM4975375 |
RNA-seq in MLL-AF4 patient derived xenograft cells - control_3 |
| GSM4975376 |
RNA-seq in MLL-AF4 patient derived xenograft cells - VEN_1 |
| GSM4975377 |
RNA-seq in MLL-AF4 patient derived xenograft cells - VEN_2 |
| GSM4975378 |
RNA-seq in MLL-AF4 patient derived xenograft cells - VEN_3 |
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| This SubSeries is part of SuperSeries: |
| GSE163229 |
Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax |
|
| Relations |
| BioProject |
PRJNA685404 |
| SRA |
SRP297999 |
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