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

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

PROVIDER: PRJNA1047913 | ENA |

REPOSITORIES: ENA

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Non-Canonical PRC1.1 is required for the activity of Menin-MLL1 Inhibitors in NUP98-Rearranged AML [SLAM-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 | GSE249217 | GEO

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

2024-09-16 | GSE249216 | GEO

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

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

2024-09-16 | GSE249215 | GEO

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

2024-09-16 | GSE249214 | GEO

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

Project description:Non-Canonical PRC1.1 is required for the activity of Menin-MLL1 Inhibitors in NUP98-Rearranged AML

| PRJNA1047909 | ENA

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

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

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

| PRJNA1047911 | ENA

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

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

| PRJNA1047910 | ENA

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

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

| PRJNA1047912 | ENA