The function of Men1 and kmt2a gene in lung of mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE302950 | GEO | 2025/09/01
REPOSITORIES: GEO
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Project description:To explore the target genes of Men1 in macrophage, we isolated the peritoneal cavity macrophage from WT and Men1 knockout mouse and performed gene expression profiling analysis by RNA-seq.
2024-12-25 | GSE230855 | GEO
Project description:The function of Men1 and kmt2a gene in lung of mice
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Project description:In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro. Functional genomic screens in 2D cell culture are of limited use for identifying therapeutic targets that modulate tumor cell-microenvironment cell interactions. By comparing targeted CRISPR-Cas9 screens in 2D culture of A549 lung cancer cells versus xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential effects in vitro and in vivo. Knockout of MEN1 in multiple solid cancer types does not impact cell proliferation in vitro, but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, knockout of MEN1 leads to increased chromatin interaction of its interaction partner MLL1 (KMT2A), a histone methyltransferase, to repetitive genomic regions, where it activates expression of double-stranded RNA. This results in MARV and cGAS-STING dependent activation of viral mimicry response, which induces infiltration of neutrophils and CD8+ T cells in immunodeficient and immunocompetent mice respectively. Consistently, multiple immune cell infiltrations are negatively correlated with MEN1 abundance and positively correlated with that of MLL1 in patient tumors of a broad range of cancer types. Pharmacological inhibition of MEN1-MLL interaction reduces tumor growth in CD8+ T cell dependent manner, with enhanced activity in combination with anti-PD-1 treatment. These findings reveal tumor microenvironment dependent oncogenic and tumor suppressive functions of MEN1 and provide rationale for therapeutic targeting of MEN1 alone or in combination with immunotherapy in multiple solid cancer types.
2022-11-03 | GSE194350 | GEO
Project description:Multiple endocrine neoplasia type 1 (MEN1) syndrome is the result of mutations in the MEN1 gene and results in tumor formation via mechanisms that are not well understood. Using a novel genome-wide methylation analysis, we studied tissues from patients with MEN1-parathyroid tumors, tissues from Men1 knockout (KO) mouse models, and mouse Men1 null mouse embryonic fibroblast (MEF) cell lines. Tissues from KO mice were used to confirm and assess the findings from the MEN1 clinical samples and further explore the molecular mechanisms of global epigenetic changes following the inactivation of menin. We demonstrated that the inactivation of menin results in enhanced activity of DNA (cytosine-5)-methyltransferase 1 (DNMT1) by retinoblastoma-binding protein 5 (Rbbp5) activation in MEN1 tumor tissues. The increased activity of DNMT1 mediated global DNA hypermethylation, which in turn resulted in aberrant activation of the Wnt/β-catenin signaling pathway through inactivation of Sox regulatory genes. Our study provides important insights into the possible regulatory role of menin in DNA methylation and its impact on the pathogenesis of MEN1 tumor development. Global DNA methylation in tissues from patients with MEN1-parathyroid tumors. Thirty-eight human parathyroid specimens were used: 13 sporadic (non-MEN1) parathyroid adenomas, 12 MEN1-parathyroid tumors, 4 parathyroid carcinomas, and 9 normal parathyroids.
2015-12-22 | E-GEOD-64412 | biostudies-arrayexpress
Project description:Functional genomic screen in 2D cell culture is limited in identifying therapeutic targets that modulates tumor-microenvironment interaction. Through comparison of targeted CRISPR-Cas9 screens in 2D cell culture and cell line derived xenografts of lung cancer A549, we identified MEN1 as the top hit that confers differential essentialities in vitro and in vivo. Knockout of MEN1 in multiple solid cancer types does not impact cell proliferation in vitro, but significantly promotes and inhibits tumor growth in immunodeficient and immunocompetent mice, respectively. Mechanistically, knockout of MEN1 leads to redistribution of its interaction partner MLL1, a histone methyltransferase, to repetitive genomic regions that produce double stranded RNA. This resulted in MARV and cGAS-STING dependent activation of viral mimicry response, which induces tumor promoting neutrophil and tumor suppressing CD8+ T cell infiltrations in immunodeficient and immunocompetent mice, respectively. Consistently, multiple immune cell infiltrations are negatively correlated with MEN1 abundance and positively correlated with that of MLL1 in patient tumors of a broad range of cancer types. Pharmacological inhibition of MEN1-MLL1 interaction reduces tumor growth in CD8+ T cell dependent manner, and synergizes with anti-PD-L1 treatment. These findings reveal tumor microenvironment dependent oncogenic and tumor suppressive function of MEN1 and provide rationale for therapeutic targeting of MEN1 alone or in combination with immunotherapy in multiple solid cancer types.
2024-06-30 | GSE197595 | GEO
Project description:Menin inhibitors have entered clinical trials for KMT2A-rearranged and NPM1 mutant acute leukemias and are demonstrating promising activity. CRISPR-Cas9 base editor screening previously predicted several MEN1 mutations that have arisen in patients receiving SNDX-5613 and confer menin inhibitor resistance. The extent to which MEN1 mutations will impact each menin inhibitor is currently unknown. We leveraged advances in CRISPR-Cas9 base editing technology to predict the MEN1 mutation profile that will impact five different menin inhibitors in clinical trials. We found key similarities (M327) and differences (C334, E368, V372) in the profile of MEN1 mutations that affect each compound. The co-crystal structure of menin bound to each compound suggests resistance mechanisms related to how each menin inhibitor binds in the KMT2A binding pocket of menin. Our in vitro and in vivo validation suggests that the MEN1 mutations identified and validated with this approach are likely to arise and impact all menin inhibitors.
2025-11-30 | GSE294624 | GEO
Project description:Menin inhibitors have entered clinical trials for KMT2A-rearranged and NPM1 mutant acute leukemias and are demonstrating promising activity. CRISPR-Cas9 base editor screening previously predicted several MEN1 mutations that have arisen in patients receiving SNDX-5613 and confer menin inhibitor resistance. The extent to which MEN1 mutations will impact each menin inhibitor is currently unknown. We leveraged advances in CRISPR-Cas9 base editing technology to predict the MEN1 mutation profile that will impact five different menin inhibitors in clinical trials. We found key similarities (M327) and differences (C334, E368, V372) in the profile of MEN1 mutations that affect each compound. The co-crystal structure of menin bound to each compound suggests resistance mechanisms related to how each menin inhibitor binds in the KMT2A binding pocket of menin. Our in vitro and in vivo validation suggests that the MEN1 mutations identified and validated with this approach are likely to arise and impact all menin inhibitors.
2025-11-30 | GSE294623 | GEO
Project description:Multiple endocrine neoplasia type1 (MEN1), an inherited autosomal dominant syndrome characterized by the development of endocrine tumors including NETs, results from mutation in the MEN1 gene that encodes the protein menin. In mouse models, heterozygous loss of Men1 leads to multiple endocrine tumors with loss of heterozygocity at the Men1 locus. Men1 interacts with several partners to regulate cellular processes and gene expression through regulating histone modification. We used microarrays to detail the global gene expression change in Men1 knockout MEFs and identified up-regulated genes during this process.
2017-08-22 | GSE87733 | GEO
Project description:Multiple endocrine neoplasia type 1 (MEN1) syndrome is the result of mutations in the MEN1 gene and results in tumor formation via mechanisms that are not well understood. Using a novel genome-wide methylation analysis, we studied tissues from patients with MEN1-parathyroid tumors, tissues from Men1 knockout (KO) mouse models, and Men1 null mouse embryonic fibroblast (MEF) cell lines. We demonstrated that the inactivation of menin (the protein product of MEN1) results in increased activity of DNA (cytosine-5)-methyltransferase 1 (DNMT1) by retinoblastoma-binding protein 5 (Rbbp5) activation in MEN1 tumor tissues. The increased activity of DNMT1 mediated global DNA hypermethylation, which in turn resulted in aberrant activation of the Wnt/β-catenin signaling pathway through inactivation of Sox regulatory genes. Our study provides important insights into the possible regulatory role of menin in DNA methylation and its impact on the pathogenesis of MEN1 tumor development.
2015-12-22 | GSE64412 | GEO
Project description:The chromatin adaptor protein Menin (MEN1) is required by acute leukemias driven by mixed lineage leukemia 1 gene rearrangements (KMT2A-r) for sustained leukemogenesis. Menin inhibitors (MIs), which disrupt the Menin-KMT2A interface leading to downregulation of Menin-KMT2A oncogenic transcriptional programs, have shown promising results in recent clinical trials treating acute myeloid leukemia (AML). Decreased Menin protein stability has been observed following treatment with several MIs though proteasomal degradation, though the biological mechanisms that control Menin stability are not well understood. Here we interrogate and compare five clinical MIs and two pre-clinical compounds to characterize the mechanism by which MIs induce Menin degradation and demonstrate that the loss of the Menin-KMT2A interaction results in decreased protein stability of Menin and KMT2A. We have identified the HECT E3 ubiquitin ligase UBR5 as a regulator of Menin protein stability and demonstrate that UBR5 binds to similar sites as the Menin/KMT2A complex on chromatin. Loss of UBR5 leads to transcriptional rescue of Menin-KMT2A target genes leading to decreased sensitivity to all MIs. Thus, we present UBR5 as an important regulator of Menin/KMT2A complex stability and Menin destabilization/subcellular localization as a designable feature of Menin inhibition targeting KMT2A-r leukemias.
2025-08-01 | GSE299103 | GEO