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

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

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE175597 | GEO | 2022/06/01

REPOSITORIES: GEO

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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

The MLL-Menin Interaction is a Therapeutic Vulnerability in <i>NUP98</i>-rearranged AML.

Project description:Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin-MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors.

| S-EPMC10378738 | biostudies-literature

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 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: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

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