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Non-Canonical PRC1.1 is required for the activity of Menin-MLL1 Inhibitors in NUP98-Rearranged AML [SLAM-Seq]

ABSTRACT: Translocations involving the Nucleoporin 98 (NUP98) gene predict a poor prognosis for patients with acute myeloid leukemia. These translocations generate NUP98-fusion proteins which interact with the mixed-lineage leukemia (MLL1/KMT2A) chromatin modifying enzyme and its binding partner Menin. The mechanisms by which the NUP98-fusion proteins maintain gene expression remain unclear. We demonstrate that the NUP98-fusion-Menin-KMT2A complex is essential for maintenance of H3K27Ac and active transcription at key loci such as Meis1 and the Hox cluster, among others. However, eviction of the complex from chromatin is insufficient to completely silence gene expression. Accumulation of the PRC1.1 complex and deposition of H2aK119Ub and H3K27Me3 is required to transition to a transcriptionally repressive chromatin state. Furthermore, we demonstrate that loss of PRC1.1 function leads to resistance to small molecule Menin inhibitors. Therefore, a critical function of the NUP98-fusion-Menin-KMT2A complex is to antagonize repressive chromatin complexes. These same mechanisms are critical for efficacy of newly developed therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE249217 | GEO | 2024/09/16

REPOSITORIES: GEO

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Non-Canonical PRC1.1 is required for the activity of Menin-MLL1 Inhibitors in NUP98-Rearranged AML [ChIP-Seq]

Project description:Translocations involving the Nucleoporin 98 (NUP98) gene predict a poor prognosis for patients with acute myeloid leukemia. These translocations generate NUP98-fusion proteins which interact with the mixed-lineage leukemia (MLL1/KMT2A) chromatin modifying enzyme and its binding partner Menin. The mechanisms by which the NUP98-fusion proteins maintain gene expression remain unclear. We demonstrate that the NUP98-fusion-Menin-KMT2A complex is essential for maintenance of H3K27Ac and active transcription at key loci such as Meis1 and the Hox cluster, among others. However, eviction of the complex from chromatin is insufficient to completely silence gene expression. Accumulation of the PRC1.1 complex and deposition of H2aK119Ub and H3K27Me3 is required to transition to a transcriptionally repressive chromatin state. Furthermore, we demonstrate that loss of PRC1.1 function leads to resistance to small molecule Menin inhibitors. Therefore, a critical function of the NUP98-fusion-Menin-KMT2A complex is to antagonize repressive chromatin complexes. These same mechanisms are critical for efficacy of newly developed therapeutics.

2024-09-16 | GSE249215 | GEO

Non-Canonical PRC1.1 is required for the activity of Menin-MLL1 Inhibitors in NUP98-Rearranged AML [PRO-Seq]

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Non-Canonical PRC1.1 is required for the activity of Menin-MLL1 Inhibitors in NUP98-Rearranged AML [CRISPR-Seq]

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Combination of menin and kinase inhibitors as a novel treatment for NUP98-rearranged leukemia

Project description:Chromosomal translocations involving the nucleoporin 98 (NUP98) gene at chromosome 11p15 are found in pediatric and adult Acute Myeloid Leukemia (AML) patients, representing one of the most common genetic alterations in pediatric AMLs found in ~10% of these patients. Previous studies demonstrated that NUP98 fusion proteins interact with MLL1 (Mixed Lineage Leukemia 1 also known as KMT2A) protein complex, and colocalize with MLL1 on Hoxa/b cluster genes, supporting MLL1 as a molecular dependency in the NUP98-r leukemia. Importantly, recent work has validated an important role of the scaffold protein menin, which directly interacts with the N-terminus of MLL1, in the NUP98-r leukemia. Here, we explored the effect of combining our menin inhibitor MI-3454 with CDK6 or FLT3 kinase inhibitors in the NUP98-r leukemia models as a possible way to enhance the anti-leukemic effect.

2024-10-30 | GSE246783 | 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

The SS18-SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma [ATAC-seq]

Project description:Gene fusions arising from chromosomal translocations are key oncogenic drivers in soft tissue sarcomas but little is known about how they exert their oncogenic effects. Our study explores the molecular mechanisms by which the SS18-SSX fusion oncoprotein subverts epigenetic mechanisms of gene regulation to drive synovial sarcoma. Using functional genomics, we identify KDM2B – a histone demethylase and core component of a non-canonical Polycomb Repressive Complex 1 (PRC1.1) – as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands genome-wide. Via KDM2B, SS18-SSX binds and aberrantly activates expression of a series of developmentally regulated transcription factors that would otherwise be targets of polycomb-mediated repression, which is restored upon KDM2B depletion leading to irreversible mesenchymal differentiation. Thus, SS18-SSX de-regulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression.

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The SS18-SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma [ChIP-seq]

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The SS18-SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma [RNA-seq]

2018-03-01 | GSE108928 | GEO

Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability

Project description:The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of the mSWI/SNF (BAF) complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the ability of SS18-SSX to occupy H2AK119ub1-rich regions is an intrinsic property of its SSX C terminus, which can be exploited by fusion to transcriptional regulators beyond SS18. Accordingly, SS18-SSX recruitment occurs in a manner that is independent of the core components and catalytic activity of BAF. Alternative SSX fusions are also recruited to H2AK119ub1-rich chromatin and reproduce the expression signatures of SS18-SSX by engaging with transcriptional activators. Variant Polycomb repressive complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C terminus not only depends on H2AK119ub1 for localization, but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results uncover a critical role for SSX-C in mediating gene deregulation in synovial sarcoma by providing specificity to chromatin and further enabling oncofusion binding by enhancing PRC1.1 stability and H2AK119ub1 deposition.

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