Transcriptome profiling of HepG2 cells upon treatment of the menin-MLL inhibitor MI-503 or DMSO
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE103327 | GEO | 2018/02/16
REPOSITORIES: GEO
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Project description:MLL1 translocations encode fusion proteins retaining the N-terminus of MLL1, which interacts with the tumor suppressor, menin. This interaction is essential for leukemogenesis, thus is a promising drug target. However, wild-type MLL1 plays a critical role in sustaining hematopoietic stem cells (HSCs), therefore disruption of an essential MLL1 cofactor would be expected to obliterate normal hematopoiesis. Here we show that rather than working together as a complex, menin and MLL1 regulate distinct pathways during normal hematopoiesis, particularly in HSCs and B-cells. We demonstrate the lack of genetic interaction between menin and MLL1 in steady-state or regenerative hematopoiesis and in B-cell differentiation despite the fact that MLL1 is critical for these processes. In B-cells, menin- or MLL1-regulated genes can be classified into three categories: 1) a relatively small group of co-regulated genes including previously described targets Hoxa9 and Meis1 but also Mecom and Eya1, and much larger groups of 2) exclusively menin-regulated and 3) exclusively MLL1-regulated genes. Our results highlight the large degree of independence of these two proteins and demonstrate that menin is not a requisite cofactor for MLL1 during normal hematopoiesis. Furthermore, our data support the development of menin-MLL1 disrupting drugs as safe and selective leukemia targeting agents. We performed gene expression analysis to determine the genes deregulated in B-cell progenitors upon loss of menin. Fraction B pro-B cells (defined as B220+CD43+HSA+BP-1- BM cells) were sorted from four MenF/F and four Rag1-cre;MenF/F mice of three weeks old. Total RNA was amplified once, labeled, fragmented and hybridized to Affymerix GeneChip Mouse Genome 430 2.0 array.
2013-08-05 | E-GEOD-49120 | biostudies-arrayexpress
Project description:MLL1 translocations encode fusion proteins retaining the N-terminus of MLL1, which interacts with the tumor suppressor, menin. This interaction is essential for leukemogenesis, thus is a promising drug target. However, wild-type MLL1 plays a critical role in sustaining hematopoietic stem cells (HSCs), therefore disruption of an essential MLL1 cofactor would be expected to obliterate normal hematopoiesis. Here we show that rather than working together as a complex, menin and MLL1 regulate distinct pathways during normal hematopoiesis, particularly in HSCs and B-cells. We demonstrate the lack of genetic interaction between menin and MLL1 in steady-state or regenerative hematopoiesis and in B-cell differentiation despite the fact that MLL1 is critical for these processes. In B-cells, menin- or MLL1-regulated genes can be classified into three categories: 1) a relatively small group of co-regulated genes including previously described targets Hoxa9 and Meis1 but also Mecom and Eya1, and much larger groups of 2) exclusively menin-regulated and 3) exclusively MLL1-regulated genes. Our results highlight the large degree of independence of these two proteins and demonstrate that menin is not a requisite cofactor for MLL1 during normal hematopoiesis. Furthermore, our data support the development of menin-MLL1 disrupting drugs as safe and selective leukemia targeting agents. We performed gene expression analysis to determine the genes deregulated in B-cell progenitors upon loss of menin.
2013-08-05 | GSE49120 | GEO
Project description:Multiple endocrine neoplasia type I (MEN1) is a familial cancer syndrome characterized primarily by tumors of multiple endocrine glands. The gene for MEN1 encodes a ubiquitously expressed tumor suppressor protein called menin. Menin was recently shown to interact with several components of a trithorax family histone methyltransferase complex including ASH2, Rbbp5, WDR5, and the leukemia proto-oncoprotein MLL. To elucidate menin's role as a tumor suppressor and gain insights into the endocrine-specific tumor phenotype in MEN1, we mapped the genomic binding sites of menin, MLL1, and Rbbp5, to approximately 20,000 promoters in HeLa S3, HepG2, and pancreatic islet cells using the strategy of chromatin-immunoprecipitation coupled with microarray analysis. We found that menin, MLL1, and Rbbp5 localize to the promoters of thousands of human genes but do not always bind together. These data suggest that menin functions as a general regulator of transcription. Keywords: ChIP/chip NHGRI Menin ChIP-Chip
2006-07-24 | E-GEOD-5357 | biostudies-arrayexpress
Project description:Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes in the nucleus. We identified three missense mutations, R52G, E255K and E359K, which display predominant reduction in interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions.
2022-10-14 | PXD031928 | Pride
Project description:Precise dynamic control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent gene promoters is essential for normal development and frequently corrupted in cancer. Using whole genome CRISPR/Cas9 screens we identify specific roles for MTF2-PRC2.1 and PCGF1-PRC1.1 polycomb complexes, and MLL1/2-COMPASS-like complex components in maintaining bivalency. Contrary to expectations, loss of Menin or inhibition of the Menin-MLL1/2 interaction, induces activation of bivalent genes via loss of polycomb-mediated repression and defines distinct roles for MLL1/2 and Menin in gene regulation. Whilst Menin and MLL1/2 contribute to maintenance H3K4me3 at active genes, a separate Menin-independent function of MLL1/2 opposes polycomb mediated repression at bivalent genes. MLL1/2 are essential for basal transcription and, although dispensable for transcription factor driven activation, facilitate transcriptional consistency during dynamic changes in gene expression. This functional partitioning of COMPASS complex components reveals therapeutic opportunities to target oncogenic and immunosuppressive functions of PRC2 through pharmacological inhibition of Menin.
2023-01-13 | GSE181818 | GEO
Project description:Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, is the most common form of acute leukemia in adults. MLL rearrangements (MLL-r) are observed in approximately 10% of AML and are associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusions recruit KDM4C to mediate epigenetic reprogramming, which is required for maintenance of MLL-r leukemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI-503, a potent Menin-MLL inhibitor, induced synergistically enhanced apoptosis in MLL-r leukemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI-503 significantly prolongs survival in AML xenograft models. Differential Gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-target therapy for MLL-r AML.
2024-12-01 | GSE252057 | GEO
Project description:Precise dynamic control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent gene promoters is essential for normal development and frequently corrupted in cancer. Using whole genome CRISPR/Cas9 screens we identify specific roles for MTF2-PRC2.1 and PCGF1-PRC1.1 polycomb complexes, and MLL1/2-COMPASS-like complex components in maintaining bivalency. Contrary to expectations, loss of Menin or inhibition of the Menin-MLL1/2 interaction, induces activation of bivalent genes via loss of polycomb-mediated repression and defines distinct roles for MLL1/2 and Menin in gene regulation. Whilst Menin and MLL1/2 contribute to maintenance H3K4me3 at active genes, a separate Menin-independent function of MLL1/2 opposes polycomb mediated repression at bivalent genes. MLL1/2 are essential for basal transcription and, although dispensable for transcription factor driven activation, facilitate transcriptional consistency during dynamic changes in gene expression. This functional partitioning of COMPASS complex components reveals therapeutic opportunities to target oncogenic and immunosuppressive functions of PRC2 through pharmacological inhibition of Menin.
2023-01-13 | GSE181823 | GEO
Project description:Precise dynamic control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent gene promoters is essential for normal development and frequently corrupted in cancer. Using whole genome CRISPR/Cas9 screens we identify specific roles for MTF2-PRC2.1 and PCGF1-PRC1.1 polycomb complexes, and MLL1/2-COMPASS-like complex components in maintaining bivalency. Contrary to expectations, loss of Menin or inhibition of the Menin-MLL1/2 interaction, induces activation of bivalent genes via loss of polycomb-mediated repression and defines distinct roles for MLL1/2 and Menin in gene regulation. Whilst Menin and MLL1/2 contribute to maintenance H3K4me3 at active genes, a separate Menin-independent function of MLL1/2 opposes polycomb mediated repression at bivalent genes. MLL1/2 are essential for basal transcription and, although dispensable for transcription factor driven activation, facilitate transcriptional consistency during dynamic changes in gene expression. This functional partitioning of COMPASS complex components reveals therapeutic opportunities to target oncogenic and immunosuppressive functions of PRC2 through pharmacological inhibition of Menin.
2023-01-13 | GSE181828 | GEO
Project description:The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1-rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. Here, we delineate a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that Menin safeguards leukemia cell fitness by impeding binding of the histone demethylase UTX at a subset of non-canonical target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of genes with tumor suppressive function. We show that this epigenetic mechanism is operative in murine and human models of AML, and clinical responses to Menin-MLL inhibition in primary human leukemia are accompanied by induction of tumor suppressive gene expression at Menin-UTX targets. These findings shed light on the context-dependent and often antagonistic roles that chromatin regulators exhibit in development and disease and provide mechanistic insight for rational design of targeted epigenetic therapies.
2022-11-16 | GSE186709 | GEO
Project description:The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1-rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. Here, we delineate a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that Menin safeguards leukemia cell fitness by impeding binding of the histone demethylase UTX at a subset of non-canonical target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of genes with tumor suppressive function. We show that this epigenetic mechanism is operative in murine and human models of AML, and clinical responses to Menin-MLL inhibition in primary human leukemia are accompanied by induction of tumor suppressive gene expression at Menin-UTX targets. These findings shed light on the context-dependent and often antagonistic roles that chromatin regulators exhibit in development and disease and provide mechanistic insight for rational design of targeted epigenetic therapies.
2022-11-16 | GSE186695 | GEO