Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA949262 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23984603_1.fastq.gz | Fastqsanger.gz | |||
| SRR23984603_2.fastq.gz | Fastqsanger.gz | |||
| SRR23984604_1.fastq.gz | Fastqsanger.gz | |||
| SRR23984604_2.fastq.gz | Fastqsanger.gz | |||
| SRR23984605_1.fastq.gz | Fastqsanger.gz |
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Project description:Treatment with Menin inhibitor (MI) disrupts interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, majority of patients with AML with MLLr or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin, or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in cell line or PD AML cell xenografts harboring MLL1r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLLr AML cells expressing FLT3 mutation, also CRISPR edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1r or mtNPM1.
2022-03-12 | GSE190719 | GEO
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.
2023-04-19 | GSE228322 | GEO
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.
2023-04-19 | GSE228325 | GEO
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.
2023-04-19 | GSE228323 | GEO
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.
2023-04-19 | GSE228321 | GEO
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:Menin inhibitors have demonstrated profound preclinical activity in MLL1-rearranged and NPM1 mutated AML and in this context, ziftomenib is a novel compound currently assessed in a clinical phase I/II trials. We assessed preclinical effects of ziftomenib and demonstrate profound synergy in combination with compounds targeting chromatin regulation and apoptosis including the BCL2 inhibitor venetoclax which was validated in primary AML samples and an MLL-r and NPM1 mutated AML xenograft model.
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Project description:Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1. [ChIP-Seq]
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Project description:Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1. [scRNA-Seq]
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Project description:Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1. [scATAC-Seq]
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