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Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ChIP-seq II]

GSE256131 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 4 samples Submitted 2024/05/01 Platform GPL30173
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.
Published in
Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1
Coleman DJL, Keane P, Chin PS et al. · iScience 2024 · PMID 38638836 · doi:10.1016/j.isci.2024.109576
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Also filed as BioProject PRJNA1078309 and SRA study SRP490640. Searching any of these in the dataset finder brings you back here.

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