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Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes

ABSTRACT: Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes

PROVIDER: PRJNA753530 | ENA |

REPOSITORIES: ENA

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Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CUT&TAG]

Project description:Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and is frequently corrupted in cancer. By coupling a cell surface readout of bivalent MHC class I gene expression with whole genome CRISPR/Cas9 screens, we identify specific roles for MTF2-PRC2.1, PCGF1-PRC1.1 and Menin- KMT2A/B complexes in maintaining bivalency. Unexpectedly, genetic loss or pharmacological inhibition of Menin phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells. Whilst Menin and KMT2A/B contribute to H3K4me3 at active genes, a separate Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent genes. Release of KMT2A from active genes following Menin targeting alters the balance of polycomb and KMT2A at bivalent genes, facilitating gene activation. This functional partitioning of Menin-KMT2A/B complex components reveals novel therapeutic opportunities that can be leveraged through inhibition of Menin.

2023-01-13 | GSE222516 | GEO

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CRISPR]

Project description:Precise dynamic control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent gene promoters is essential for normal development and frequently corrupted in cancer. Using whole genome CRISPR/Cas9 screens we identify specific roles for MTF2-PRC2.1 and PCGF1-PRC1.1 polycomb complexes, and MLL1/2-COMPASS-like complex components in maintaining bivalency. Contrary to expectations, loss of Menin or inhibition of the Menin-MLL1/2 interaction, induces activation of bivalent genes via loss of polycomb-mediated repression and defines distinct roles for MLL1/2 and Menin in gene regulation. Whilst Menin and MLL1/2 contribute to maintenance H3K4me3 at active genes, a separate Menin-independent function of MLL1/2 opposes polycomb mediated repression at bivalent genes. MLL1/2 are essential for basal transcription and, although dispensable for transcription factor driven activation, facilitate transcriptional consistency during dynamic changes in gene expression. This functional partitioning of COMPASS complex components reveals therapeutic opportunities to target oncogenic and immunosuppressive functions of PRC2 through pharmacological inhibition of Menin.

2023-01-13 | GSE181818 | GEO

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [RNA-seq]

2023-01-13 | GSE181828 | GEO

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [ChIP-seq]

2023-01-13 | GSE181823 | GEO

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CRISPR]

Project description:Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CRISPR]

| PRJNA753522 | ENA

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [ChIP-seq]

Project description:Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [ChIP-seq]

| PRJNA753529 | ENA

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CUT&TAG]

Project description:Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CUT&TAG]

| PRJNA922457 | ENA

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [RNA-seq]

Project description:Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [RNA-seq]

| PRJNA753533 | ENA

Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-01-13 | GSE181829 | GEO

The menin inhibitor SNDX-5613 for KMT2A rearranged or NPM1 mutant leukemia

Project description:Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependency in acute leukaemia caused by either rearrangement of KMT2A or mutation in Nucleophosmin 1(NPM1). KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin–KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.

2023-03-01 | GSE216730 | GEO

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