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Dual Targeting of FLT3 and LSD1 Disrupts the MYC Super Enhancer Complex in Acute Myeloid Leukemia.

GSE190785 Homo sapiens (human) ChIP-seq / ATAC-seq (genome binding and open chromatin) 289 samples Submitted 2024/03/21 Platform GPL20301Platform GPL24676Platform GPL23227Platform GPL18573
At a glance

ChIP-seq / ATAC-seq (genome binding and open chromatin) · human · 289 samples

What it is
ChIP-seq / ATAC-seq (genome binding and open chromatin)Where proteins bind the genome, or which regions are open and active.
Organism
Homo sapiens (human)
Topic
Acute myeloid leukemiaThis series is part of our curated briefing on it.
Samples
289 samples: 100 conditions, mostly in triplicateGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid LeukemiaMolecular cancer research : MCR · 2023
Summary (written by the submitters)
Clinical responses to kinase inhibitor therapy in acute myeloid leukemia (AML) are limited by the inevitable development of resistance. A major contributor to resistance is early epigenetic adaptation, leading to persistence of a small number of leukemia cells. Here we show that inhibition of the epigenetic regulator lysine-specific deme-thylase 1 (LSD1) augments the response to inhibitors of the FLT3 kinase in AML.
Read the full summary ↓
We demonstrate that combined FLT3 and LSD1 inhibition results in synergistic cell death of FLT3-mutant AML cells via proliferative arrest and apoptosis. The drug combination synergistically activates a pro-differentiative epigenetic and transcriptional program while simultaneously suppressing the activity of MYC target genes. High resolution multi-modal epigenetic analyses revealed that combined FLT3 and LSD1 resulted in the suppression of MYC-bound promoters and the activation of PU.1-bound enhanc-ers. Forced expression of MYC partially abrogated the drug effect, and regulon en-richment analysis in primary AML samples nominated STAT5 as a putative regulator of MYC gene expression. STAT5 is highly bound to the MYC blood super-enhancer and inhibition of FLT3 results in a loss of STAT5 binding and a loss of super enhancer acti-vation. Furthermore, knockdown of STAT5 augments LSD1-inhibitor induced cell death. LSD1 inhibition also directly represses MYC target genes which show specific accumulation of the repressive LSD1 substrate H3K9me1. We validated these findings in 67 primary AML samples including 19 FLT3-ITD positive AML samples, with the vast majority demonstrating improved responses with the drug combination. High MYC regulon activity was a predictor of response to the drug combination and RNA-seq on drug treated AML samples revealed suppression of MYC target genes. Finally, single cell ATAC seq on primary AML blasts treated ex-vivo with combined FLT3 and LSD1 inhibition results in a shift from MYC super enhancer-high to a MYC super enhancer-low cell state. Collectively, these studies provide preclinical rationale for the investiga-tion of dual FLT3 and LSD1 inhibition in clinical trial.
Published in
Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Yashar WM, Curtiss BM, Coleman DJ et al. · Molecular cancer research : MCR 2023 · PMID 36976323 · doi:10.1158/1541-7786.MCR-22-0745
This dataset
Open GSE190785 in finder → Find more human RNA-seq datasets → Acute myeloid leukemia landscape →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE190785_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: Look for peak files (.bed, .narrowPeak) and signal tracks (.bigWig) among the supplementary files; the raw reads are on ENA.

Also filed as BioProject PRJNA788519 and SRA study SRP350696. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 36976323) ↗
Study design
100 conditions, mostly in triplicate
MOLM13 RNA-seq 24h DMSO ×3 MOLM13 RNA-seq 24h Quizartinib ×3 MOLM13 RNA-seq 24h GSK2879552 ×3 MOLM13 RNA-seq 24h Combination ×3 Primary AML Sample 2307 24h DMSO ×3 Primary AML Sample 2307 24h Quizartinib ×3 Primary AML Sample 2307 24h GSK2879552 ×3 Primary AML Sample 2307 24h Combination ×3 +103 more

Supports a between-group comparison across 278 samples.

How we read this: 100 replicated groups read from 289 sample titles; they account for 278 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study

+ 249 more — browse all 289 samples with per-sample file links →

More Acute myeloid leukemia datasets

Search all human RNA-seq datasets in GEO →

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Metadata from NCBI GEO, cached and refreshed periodically — the NCBI page above is authoritative. Downloads link straight to NCBI/ENA; nothing is proxied through BioTransfer.