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SRX21479917: GSM7732640: D1063-7_MOLM14_FLT3i_IL3_Rep1; Homo sapiens; ATAC-seq
1 ILLUMINA (NextSeq 2000) run: 29M spots, 2.2G bases, 854.7Mb downloads

External Id: GSM7732640_r1
Submitted by: Institute for Cancer and Genomic Sciences, University of Birmingham
Study: Pharmaceutical inhibition of RAS overcomes cytokine mediated resistance to FLT3 inhibition in FLT3-ITD+ AML [ATAC-seq]
show Abstracthide Abstract
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. Overall design: ATAC-Seq of FLT3-ITD primary AML samples, and FLT3-ITD+ cell lines (MOLM14, MV411) before and after treatment with FLT3 inhibitors, RAS inhibitors and IL3 with replicates
Sample: D1063-7_MOLM14_FLT3i_IL3_Rep1
SAMN37144967 • SRS18712524 • All experiments • All runs
Organism: Homo sapiens
Library:
Name: GSM7732640
Instrument: NextSeq 2000
Strategy: ATAC-seq
Source: GENOMIC
Selection: other
Layout: SINGLE
Construction protocol: Cells were treated with inhibitors in the presence or absence of IL-3 for 24 h prior to harvest. Omni ATAC-seq was performed as in Corces et al. Briefly, cells were washed in ATAC resuspension buffer (RSB) (10mM Tris-HCl pH7.5, 10mM NaCl and 3mM MgCl2) and then lysed for 3 minutes on ice in RSB buffer with 0.1% NP-40, 0.1% Tween-20. Then the cells were washed with 1ml of ATAC wash buffer consisting of RSB with 0.1% Tween-20. Then the nuclear pellet was resuspended in ATAC transposition buffer consisting of 25μl TD buffer and a concentration of Tn5 transposase enzyme (Illumina) related to the number of input cells, 16.5 μl PBS, 5 μl water, 0.1% tween-20 and 0.01% digitonin and then incubated on a thermomixer at 37°C for 30 minutes. The transposed DNA was then amplified by PCR amplification up to ¼ of maximum amplification, as assessed by a qPCR side reaction. The library was purified using a QIAquick PCR cleanup kit (QIAGEN) followed by ampure (Beckman Coulter) and analysed on a Next Seq 2000 75 using a NextSeq 500/550 High output kit.
Runs: 1 run, 29M spots, 2.2G bases, 854.7Mb
Run# of Spots# of BasesSizePublished
SRR2575694828,952,5152.2G854.7Mb2024-05-01

ID:
28921007

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