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The MLL – Menin interaction is a therapeutic vulnerability in NUP98-rearranged AML

ABSTRACT: The MLL – Menin interaction is a therapeutic vulnerability in NUP98-rearranged AML

PROVIDER: PRJNA970807 | ENA |

REPOSITORIES: ENA

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The MLL – Menin interaction is a therapeutic vulnerability in NUP98-rearranged AML

Project description:To investigate the effect of Menin inhibitor on patient-derived NUP98-r AML. We treated primary AML cells with Menin inhibitor in a Mesenchymal stem cell co-Culture platform. Then we charachterized global gene expression in treated AML cells upon treatment in two different time points, day7 and day12.

2023-05-14 | GSE232091 | GEO

The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML [RNA-Seq]

Project description:Using mouse and human models of NUP98-rearrranged leukemia, we demonstrate that inhibition of MLL-Menin impairs leukemogenic gene expression and disrupts chromatin binding of MLL1 and NUP98 fusion proteins at a critical subset of genes that is essential for sustaining the undifferentiated leukemia phenotype.

2022-06-01 | GSE175596 | GEO

The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML [ChIP-Seq]

2022-06-01 | GSE175595 | GEO

The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML [BioChIP-seq]

2022-06-01 | GSE175594 | GEO

The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML

Project description:The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML

| PRJNA733040 | ENA

The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML [BioChIP-seq]

Project description:The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML [BioChIP-seq]

| PRJNA733037 | ENA

The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML [RNA-Seq]

Project description:The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML [RNA-Seq]

| PRJNA733041 | ENA

The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML [ChIP-Seq]

Project description:The MLL-Menin interaction is a molecular dependency in NUP98-rearranged AML [ChIP-Seq]

| PRJNA733042 | ENA

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

Project description:Inhibition of the Menin (encoded by MEN1) and MLL1 (KMT2A) protein-protein interaction has been proposed as a potential targeted therapeutic strategy for MLL-rearranged (MLL-r) leukemia. We sought to develop more potent and selective Menin-MLL1 interaction inhibitors that are effective in vitro and in vivo to directly assess potential therapeutic opportunities. Structure-based design yielded the potent, highly selective and orally-bioavailable small molecule inhibitor VTP-50469. Human cell lines carrying MLL-rearrangements were highly sensitive and selectively responsive to treatment with VTP-50469. VTP-50469 displaced Menin from high molecular weight protein complexes and inhibited chromatin occupancy of MLL1 at select target genes. Loss of MLL1 binding led to specific changes in gene expression, cellular differentiation, and apoptosis. Mice engrafted with leukemia cells isolated from patients with either MLL-r AML or MLL-r ALL showed dramatic reductions of leukemia burden and prolonged survival when treated with VTP-50469. Remarkably, multiple mice engrafted with MLL-r ALL remained disease free greater than 1 year following cessation of treatment. Therefore, inhibition of the Menin-MLL1 interaction with VTP-50469 is highly effective in patient-derived xenograft (PDX) models of human MLL-r AML and MLL-r ALL which supports rapid translation of this approach to clinical trials. This submission represents the scRNAseq component of the study.

2019-02-28 | GSE127298 | GEO

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

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