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Mus musculus

ABSTRACT: Menin-MLL inhibitors block oncogenic transformation by MLL fusion proteins in a fusion partner independent manner

PROVIDER: PRJNA286308 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR2058770.fastq.gz	Fastqsanger.gz
	SRR2058780.fastq.gz	Fastqsanger.gz
	SRR2058771.fastq.gz	Fastqsanger.gz
	SRR2058781.fastq.gz	Fastqsanger.gz
	SRR2058772.fastq.gz	Fastqsanger.gz

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Menin-MLL inhibitors block oncogenic transformation by MLL fusion proteins in a fusion partner independent manner

Project description:Chromosomal rearrangements of the Mixed Lineage Leukemia (MLL) gene result in fusion proteins which retain the N-terminal portion of MLL fused with one of more than 70 different fusion partners. The high diversity of MLL fusion partners raises a question whether it is possible to develop a general therapeutic strategy to block the oncogenic activity of MLL fusion proteins in a fusion partner independent manner. We have demonstrated that blocking the menin-MLL interaction using small molecule inhibitor inhibits oncogenic activity of different MLL fusion proteins according to a mechanism that is independent on the fusion partner.

2018-06-09 | GSE69740 | GEO

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia [barcode-seq SG12]

Project description:Targeting the MYST acetyltransferases are an exciting therapeutic opportunity in acute myeloid leukaemia (AML). Here we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models showing that although KAT6A/B inhibition is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate oncogenic transcriptional programs. Focusing on MLL fusion oncoprotein (MLL-FP) AML, we show that inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of the MLL-FP. Combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Notably, KAT7 remains an important targetable dependency in acquired genetic/non-genetic resistance to Menin inhibition providing the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.

2025-07-01 | GSE300174 | GEO

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia [barcode-seq SG05]

2025-07-01 | GSE300173 | GEO

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia [ChiP-seq]

2025-07-01 | GSE300169 | GEO

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia [scRNA-Seq]

2025-07-01 | GSE301145 | GEO

Genetic deletion or small molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML

Project description:The hematological malignancies classified as Mixed Lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia (AML), here we show that genetic inactivation or small molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein driven transformation. Genome wide transcriptional analysis revealed that inhibition of PRMT5 methyltransferase activity overrides the differentiation block in leukemia cells without affecting the expression of MLL-fusion direct oncogenic targets. Furthermore, we find that this differentiation block is mediated by transcriptional silencing of the cyclin-dependent kinase inhibitor p21 (CDKN1a) gene in leukemia cells. Our study provides pre-clinical rationale for targeting PRMT5 using small molecule inhibitors in the treatment of leukemias harboring MLL-rearrangements.

2017-07-13 | GSE100820 | GEO

A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia [ChIP-seq]

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

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in acute myeloid leukaemia [human RNA-seq]

Project description:Understanding the molecular pathogenesis of MLL fusion oncoproteins (MLL-FP) has spawned epigenetic therapies that have improved clinical outcomes in this and other molecular subtypes of acute myeloid leukaemia (AML). Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases the therapeutic efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate the oncogenic transcriptional program. Focussing on MLL-FP AML, we show that inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of the MLL-FP. Consequently, combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Moreover, PF-9363 or genetic depletion reveals that KAT7 remains an important targetable dependency in acquired genetic/non-genetic resistance to Menin inhibition. These data provide the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.

2025-06-16 | GSE295647 | GEO

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in acute myeloid leukaemia [mouse RNA-seq]

2025-06-16 | GSE295646 | GEO

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in acute myeloid leukaemia [CUT&Tag]

2025-06-16 | GSE295645 | GEO