Determine differences in chromatin accessibility in primary human AML samples by ATAC-seq.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE150868 | GEO | 2022/02/06
REPOSITORIES: GEO
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Project description:Determine differences in chromatin accessibility in primary human AML samples by ATAC-seq.
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Project description:ATAC-seq of 79 primary samples obtained from human acute leukemias, namely AML, T-ALL and mixed myeloid/lymphoid leukemias with CpG Island Methylator Phenotype (CIMP). Moreover, ATAC-seq of CD34+ HSPCs from 3 healthy donors are included. ATAC-seq was performed as described (Buenrostro et al., 2013) with a modification in the lysis buffer to reduce mitochondrial DNA contamination. Due to patient confidentiality considerations, the raw data files for this dataset have been deposited to the EGA controlled-access archive under the accession numbers EGAS00001007094 (study); EGAD00001011050 (dataset).
2023-08-31 | E-MTAB-13118 | biostudies-arrayexpress
Project description:For ATAC-seq data processing, we used the ENCODE ATAC-seq pipeline (https://www.encodeproject.org/atac-seq/). In detail, for each sample, ATAC-seq reads were first checked for adaptor contamination. Then, adaptor trimmed reads were aligned to hg19 using Bowtie2 under paired-end mode with parameter “-X2000”, which permits 2000 bp for the maximum allowable insert size between two paired ends of each read. Using the ENCODE ATAC-seq pipeline, duplicated reads were properly filtered out. ATAC-seq enriched peaks were called using MACS2 (Zhang et al., 2008) based on remaining unique reads with parameters “-f BAMPE -q 0.05 --nomodel”. In total, we collected 45,569 peaks for the ARID1AWT sample and 27,480 peaks for the ARID1AKO sample.
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Project description:Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single cell RNA-Seq, ChiP-Seq, concordant perturbations in ATAC-Seq and RNA-Seq peaks, RPPA and CyTOF analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. MI-mediated genome-wide, concordant, log2 fold-perturbations (up or down-regulation) in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. scRNA-Seq analysis of bone marrow aspirate (BMA) cells harboring MLL1-FP and FLT3 mutation revealed enrichment of gene-sets of TNFα, interferon α/γ, inflammatory response and apoptosis gene-sets, but negative enrichment of the gene-set of MYC targets. Notably, MI treatment reduced the number of cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy and could potentially prevent therapy-refractory relapse of AML with MLL1-r or mtNPM1.
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Project description:Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single cell RNA-Seq, ChiP-Seq, concordant perturbations in ATAC-Seq and RNA-Seq peaks, RPPA and CyTOF analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. MI-mediated genome-wide, concordant, log2 fold-perturbations (up or down-regulation) in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. scRNA-Seq analysis of bone marrow aspirate (BMA) cells harboring MLL1-FP and FLT3 mutation revealed enrichment of gene-sets of TNFα, interferon α/γ, inflammatory response and apoptosis gene-sets, but negative enrichment of the gene-set of MYC targets. Notably, MI treatment reduced the number of cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy and could potentially prevent therapy-refractory relapse of AML with MLL1-r or mtNPM1.
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Project description:Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single cell RNA-Seq, ChiP-Seq, concordant perturbations in ATAC-Seq and RNA-Seq peaks, RPPA and CyTOF analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. MI-mediated genome-wide, concordant, log2 fold-perturbations (up or down-regulation) in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. scRNA-Seq analysis of bone marrow aspirate (BMA) cells harboring MLL1-FP and FLT3 mutation revealed enrichment of gene-sets of TNFα, interferon α/γ, inflammatory response and apoptosis gene-sets, but negative enrichment of the gene-set of MYC targets. Notably, MI treatment reduced the number of cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy and could potentially prevent therapy-refractory relapse of AML with MLL1-r or mtNPM1.
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Project description:Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single cell RNA-Seq, ChiP-Seq, concordant perturbations in ATAC-Seq and RNA-Seq peaks, RPPA and CyTOF analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. MI-mediated genome-wide, concordant, log2 fold-perturbations (up or down-regulation) in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. scRNA-Seq analysis of bone marrow aspirate (BMA) cells harboring MLL1-FP and FLT3 mutation revealed enrichment of gene-sets of TNFα, interferon α/γ, inflammatory response and apoptosis gene-sets, but negative enrichment of the gene-set of MYC targets. Notably, MI treatment reduced the number of cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy and could potentially prevent therapy-refractory relapse of AML with MLL1-r or mtNPM1.
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Project description:Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single cell RNA-Seq, ChiP-Seq, concordant perturbations in ATAC-Seq and RNA-Seq peaks, RPPA and CyTOF analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. MI-mediated genome-wide, concordant, log2 fold-perturbations (up or down-regulation) in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. scRNA-Seq analysis of bone marrow aspirate (BMA) cells harboring MLL1-FP and FLT3 mutation revealed enrichment of gene-sets of TNFα, interferon α/γ, inflammatory response and apoptosis gene-sets, but negative enrichment of the gene-set of MYC targets. Notably, MI treatment reduced the number of cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy and could potentially prevent therapy-refractory relapse of AML with MLL1-r or mtNPM1.
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