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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181829 | GEO | 2023/01/13

REPOSITORIES: GEO

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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 [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 [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

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

| PRJNA753530 | ENA

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

Small Molecule Menin Inhibitors: Novel Therapeutic Agents Targeting Acute Myeloid Leukemia with KMT2A Rearrangement or NPM1 Mutation.

Project description:Recent advances have included insights into the clinical value of genomic abnormalities in acute myeloid leukemia (AML) and consequently the development of numerous targeted therapeutic agents that have improved clinical outcome. In this setting, various clinical trials have recently explored novel therapeutic agents either used alone or in combination with intensive chemotherapy or low-intensity treatments. Among them, menin inhibitors could represent a novel group of targeted therapies in AML driven by rearrangement of the lysine methyltransferase 2A (KMT2A) gene, previously known as mixed-lineage leukemia (MLL), or by mutation of the nucleophosmin 1 (NPM1) gene. Recent phase 1/2 clinical trials confirmed the efficacy of SNDX-5613 (revumenib) and KO-539 (ziftomenib) and their acceptable tolerability. Several small molecule menin inhibitors are currently being evaluated as a combination therapy with standard of care treatments. The current paper reviews the recent progress in exploring the inhibitors of menin-KMT2A interactions and their application prospects in the treatment of acute leukemias.

| S-EPMC10881917 | biostudies-literature

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