A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition [ChIP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA775615 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16598500.fastq.gz | Fastqsanger.gz | |||
| SRR16598501.fastq.gz | Fastqsanger.gz | |||
| SRR16598502.fastq.gz | Fastqsanger.gz | |||
| SRR16598503.fastq.gz | Fastqsanger.gz | |||
| SRR16598504.fastq.gz | Fastqsanger.gz |
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Project description:The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1-rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. Here, we delineate a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that Menin safeguards leukemia cell fitness by impeding binding of the histone demethylase UTX at a subset of non-canonical target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of genes with tumor suppressive function. We show that this epigenetic mechanism is operative in murine and human models of AML, and clinical responses to Menin-MLL inhibition in primary human leukemia are accompanied by induction of tumor suppressive gene expression at Menin-UTX targets. These findings shed light on the context-dependent and often antagonistic roles that chromatin regulators exhibit in development and disease and provide mechanistic insight for rational design of targeted epigenetic therapies.
2022-11-16 | GSE186709 | GEO
Project description:The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1-rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. Here, we delineate a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that Menin safeguards leukemia cell fitness by impeding binding of the histone demethylase UTX at a subset of non-canonical target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of genes with tumor suppressive function. We show that this epigenetic mechanism is operative in murine and human models of AML, and clinical responses to Menin-MLL inhibition in primary human leukemia are accompanied by induction of tumor suppressive gene expression at Menin-UTX targets. These findings shed light on the context-dependent and often antagonistic roles that chromatin regulators exhibit in development and disease and provide mechanistic insight for rational design of targeted epigenetic therapies.
2022-11-16 | GSE186695 | GEO
Project description:A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition
| PRJNA775621 | ENA
Project description:A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition [RNA-seq]
| PRJNA775622 | ENA
Project description:Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin-modifying complexes that dictates response to Menin-MLL inhibitors. MLL1-Menin safeguards leukemia survival by impeding the binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the Menin-MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin inhibitors. These findings shed light on novel functions of evolutionarily conserved epigenetic mediators like MLL1-Menin and MLL3/4-UTX and are relevant to understand and target molecular pathways determining therapeutic responses in ongoing clinical trials.SignificanceMenin-MLL inhibitors silence a canonical HOX- and MEIS1-dependent oncogenic gene expression program in leukemia. We discovered a parallel, noncanonical transcriptional program involving tumor suppressor genes that are repressed in Menin-MLL inhibitor-resistant leukemia cells but that can be reactivated upon combinatorial treatment with CDK4/6 inhibitors to augment therapy responses. This article is highlighted in the In This Issue feature, p. 1.
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Project description:Gastrointestinal stromal tumor (GIST) is commonly characterized by activating mutations in the receptor tyrosine kinase KIT. Tyrosine kinase inhibitors are the only approved therapy for GIST, and other complementary treatment strategies are urgently needed. As GIST both lacks oncogene amplification and relies upon an established network of transcription factors, we hypothesized that unique chromatin modifying enzymes are essential in orchestrating the GIST epigenome. Here, we identified through genome-wide CRISPR screening that MOZ and Menin-MLL chromatin regulatory complexes are cooperative and unique dependencies in GIST. These complexes were enriched at GIST-relevant genes and regulated their transcription. Inhibition of MOZ and Menin-MLL complexes decreased GIST cell proliferation by disrupting interactions with transcriptional regulators, such as DOT1L. Menin inhibition caused significant reductions in tumor burden in xenograft models, with superior effects observed in combination with imatinib. These results define unique chromatin regulatory dependencies in GIST and identify therapeutic strategies for clinical application.
2022-05-02 | GSE172153 | GEO
Project description:Treatment of cells carrying MLL-rearrangements with VTP-50469 (specific Menin-MLL1 inhibitor) displaces Menin from high molecular weight complexes and chromatin genome-wide. Since VTP-50469 block Menin interaction with MLL1 we tested using chip-seq if treatment with VTP-50469 also displaces MLL1 or MLL-fusions from chromatin. We found that the VTP-50469 treatment displaced MLL-fusions from only a subset of MLL-fusion binding sites. Since DOT1L is associated with MLL-AF9 we then tested if displacement of MLL1 also leads to loss of DOT1L association with chromatin on MLL-AF9 binding sites. We found that DOT1L binds to thousands of genes, treatment with VTP-50469 leads to genome wide loss of DOT1L binding including the same subset of MLL-fusion binding sites.
2019-11-06 | GSE127507 | GEO
Project description:Identification of new therapeutic targets in liver cancer remains critical. Chromatin regulating complexes are frequently mutated in liver cancer suggesting dysregulation of chromatin environments is a key feature driving liver cancer. We applied a focused CRISPR library targeting all genes involved in chromatin regulation to determine if the altered chromatin state of hepatocellular carcinoma cells could be targeted. The focused approach allowed us to test multiple cell lines in both 2D and 3D growth conditions which revealed striking differences in the essentiality of genes involved in ubiquitination and uncovered multiple chromatin regulators that are essential in 2D but whose loss promotes growth in 3D. We found the menin-MLL complex as among the strongest essential genes in all screens and deeply characterized the mechanism menin-MLL uses to promote hepatocellular carcinoma growth. Inhibition of menin-MLL led to global changes in occupancy of the complex and concomitant decreases in H3K4me3 and gene expression. A surprising increase in chromatin accessibility at sites not bound by menin-MLL was associated with recruitment of the pioneer transcription factor complex NF-Y. A screen of chromatin regulators in the presence of the menin-MLL inhibitor SNDX-5613 revealed a synergy between NF-YB loss and menin-MLL inhibition. Together these data show that menin-MLL is necessary for cell survival in HCC and cooperates with NF-Y to regulate transcription.
2025-04-07 | GSE293690 | GEO
Project description:Gastrointestinal stromal tumor (GIST) is commonly characterized by activating mutations in the receptor tyrosine kinase KIT. Tyrosine kinase inhibitors are the only approved therapy for GIST, and other complementary treatment strategies are urgently needed. As GIST both lacks oncogene amplification and relies upon an established network of transcription factors, we hypothesized that unique chromatin modifying enzymes are essential in orchestrating the GIST epigenome. Here, we identified through genome-wide CRISPR screening that MOZ and Menin-MLL chromatin regulatory complexes are cooperative and unique dependencies in GIST. These complexes were enriched at GIST-relevant genes and regulated their transcription. Inhibition of MOZ and Menin-MLL complexes decreased GIST cell proliferation by disrupting interactions with transcriptional regulators, such as DOT1L. Menin inhibition caused significant reductions in tumor burden in xenograft models, with superior effects observed in combination with imatinib. These results define unique chromatin regulatory dependencies in GIST and identify therapeutic strategies for clinical application.
2022-05-02 | GSE172152 | GEO
Project description:Identification of new therapeutic targets in liver cancer remains critical. Chromatin regulating complexes are frequently mutated in liver cancer suggesting dysregulation of chromatin environments is a key feature driving liver cancer. We applied a focused CRISPR library targeting all genes involved in chromatin regulation to determine if the altered chromatin state of hepatocellular carcinoma cells could be targeted. The focused approach allowed us to test multiple cell lines in both 2D and 3D growth conditions which revealed striking differences in the essentiality of genes involved in ubiquitination and uncovered multiple chromatin regulators that are essential in 2D but whose loss promotes growth in 3D. We found the menin-MLL complex as among the strongest essential genes in all screens and deeply characterized the mechanism menin-MLL uses to promote hepatocellular carcinoma growth. Inhibition of menin-MLL led to global changes in occupancy of the complex and concomitant decreases in H3K4me3 and gene expression. A surprising increase in chromatin accessibility at sites not bound by menin-MLL was associated with recruitment of the pioneer transcription factor complex NF-Y. A screen of chromatin regulators in the presence of the menin-MLL inhibitor SNDX-5613 revealed a synergy between NF-YB loss and menin-MLL inhibition. Together these data show that menin-MLL is necessary for cell survival in HCC and cooperates with NF-Y to regulate transcription.
2025-04-07 | GSE293693 | GEO