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

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

ORGANISM(S): Mus musculus

PROVIDER: GSE249218 | 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 [PRO-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 | GSE249216 | GEO

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

2024-09-16 | GSE274479 | GEO

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

2024-09-16 | GSE249217 | GEO

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

The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML.

Project description:Translocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells. Menin-MLL1 inhibition upregulates markers of differentiation such as CD11b and downregulates expression of proleukemogenic transcription factors such as Meis1 in NUP98-fusion-transformed leukemia cells. We demonstrate that MLL1 and the NUP98 fusion protein itself are evicted from chromatin at a critical set of genes that are essential for the maintenance of the malignant phenotype. In addition to these in vitro studies, we established patient-derived xenograft (PDX) models of NUP98-fusion-driven AML to test the in vivo efficacy of menin-MLL1 inhibition. Treatment with VTP50469 significantly prolongs survival of mice engrafted with NUP98-NSD1 and NUP98-JARID1A leukemias. Gene expression analysis revealed that menin-MLL1 inhibition simultaneously suppresses a proleukemogenic gene expression program, including downregulation of the HOXa cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias.

| S-EPMC8832476 | biostudies-literature

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

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]