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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 molecular dependency in NUP98-rearranged AML [BioChIP-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 | GSE175594 | GEO

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

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

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 [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 [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 [RNA-Seq]

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

| PRJNA733041 | ENA

Molecular pathogenesis of disease progression in MLL-rearranged AML.

Project description:Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N?=?96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P?<?0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P?=?0.007) and associated with earlier leukemia onset (P?=?0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P?<?0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P?<?0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.

| S-EPMC6462875 | biostudies-literature

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