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| Status |
Public on May 01, 2024 |
| Title |
Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
AML is characterised by a variety of co-occurring driver mutations in genes associated with cell signallingand growth regulationsuch as the FLT3-ITD. Inhibitors targeting FLT3 (FLT3i) are beingused to treat FLT3-ITD+ patients but most relapse.By profiling the gene regulatory networks of samples from patients before and after FLT3i treatment weobservedan increase in AP-1 mediated and a loss of RUNX1 mediated connections in treatment resistant cells. Treatmentinducesupregulation of signalling pathway genesindicatingthat cytokines mediate resistance to FLT3i, with IL-3 playing a major role. IL3 rescues survival by counteracting FLT3i mediated globalRUNX1 degradation and adown-regulationof bindingof RUNX1 in chromatin.To identify inhibitors which bypass the RUNX1 barrier we inhibitedMAPK signalling with a novel pan-RAS inhibitor which overcomes cytokine mediated resistance.Our data show (I) that cytokinesinstructAML maintenance via the stabilisation of transcriptional regulators and (ii)pan-RAS drugs bypass thisbarrier, suggesting a novel approach to treatment of AML.
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| Overall design |
ChIP-Seq of FLT3-ITD cell lines (MV411, MOLM14) targeting cFOS and RUNX1 before and after treatment with FLT3i, RASi, Doxyclin inducible RAS antibody (RAS iDAB), IL3 and untreated
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| Contributor(s) |
Keane P, Coleman D, Cockerill P, Bonifer C |
| Citation(s) |
38638836 |
| |
| Submission date |
Aug 24, 2023 |
| Last update date |
May 02, 2024 |
| Contact name |
Peter Keane |
| E-mail(s) |
p.keane@bham.ac.uk
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| Organization name |
University of Birmingham
|
| Department |
Institute for Cancer and Genomic Sciences
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| Street address |
Vincent Drive
|
| City |
Birmingham |
| ZIP/Postal code |
B15 2TT |
| Country |
United Kingdom |
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| Platforms (1) |
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| Samples (13)
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| This SubSeries is part of SuperSeries: |
| GSE241650 |
Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML |
|
| Relations |
| BioProject |
PRJNA1009052 |
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