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| Status |
Public on Mar 10, 2022 |
| Title |
Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML [RNAseq IFNAR KO tumor cells] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Pharmacological inhibition of epigenetic enzymes can have therapeutic benefit against hematological malignancies. Apart from affecting tumor cell growth and proliferation, these epigenetic agents may mediate anti-tumor immunity. Here we discovered a novel immuno-regulatory mechanism through inhibition of histone deacetylases (HDACs). In models of AML, leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDCs) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated activation of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, while combined treatment of panobinostat and IFN improved outcomes in mouse and human models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances anti-tumor immunity, opening the possibility of exploiting this population for immunotherapies. profiling by high throughput sequencing.
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| Overall design |
Following three days of treatment with panobinostat or vehicle, leukemia tumor cells (GFP+) were sorted, using propidium iodide (PI) as a viability marker (3 replicates per group).
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| Contributor(s) |
Dominguez PM, Todorovski I, Vervoort SJ |
| Citation(s) |
35311997 |
| |
| Submission date |
Mar 07, 2022 |
| Last update date |
Jun 09, 2022 |
| Contact name |
Izabela Todorovski |
| E-mail(s) |
izabela.todorovski@petermac.org
|
| Organization name |
Peter MacCallum Centre
|
| Department |
Cancer Research Division
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| Lab |
Gene Regulation
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| Street address |
305 Grattan Street
|
| City |
Melbourne |
| State/province |
VIC |
| ZIP/Postal code |
3000 |
| Country |
Australia |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (6)
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| GSM5939240 |
A/E9a;NRASG12D;Ifnar1-/- vehicle_rep1_RNAseq |
| GSM5939241 |
A/E9a;NRASG12D;Ifnar1-/- vehicle_rep2_RNAseq |
| GSM5939242 |
A/E9a;NRASG12D;Ifnar1-/- vehicle_rep3_RNAseq |
| GSM5939243 |
A/E9a;NRASG12D;Ifnar1-/- pano_rep1_RNAseq |
| GSM5939244 |
A/E9a;NRASG12D;Ifnar1-/- pano_rep2_RNAseq |
| GSM5939245 |
A/E9a;NRASG12D;Ifnar1-/- pano_rep3_RNAseq |
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| This SubSeries is part of SuperSeries: |
| GSE198119 |
Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML |
|
| Relations |
| BioProject |
PRJNA813680 |
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