Pan-Cancer MLL3 Mutational Landscape and Its Association with Immunotherapy
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PROVIDER: PRJNA1314211 | ENA |
REPOSITORIES: ENA
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Project description:Translocation-linked Mixed Lineage Leukemia (MLL) genes were discovered ~ 30 years ago and are homologs of Trithorax in Drosophila. MLL3 is a histone methyltransferase catalyzing the monomethylation of histone H3 lysine 4 (H3K4me1), a hallmark for gene enhancers. Although recurrent mutations of MLL3 are reported across a broad spectrum of cancers and MLL3 represents one of the most commonly mutated cancer genes, a pan-cancer-wide portrait of this high-frequency mutational event is still lacking. We report here a comprehensive analysis of MLL3 mutation and its association with molecular, cellular, and clinical features in 33 cancer types. The genetic alterations of MLL3 are primarily driven by point mutations or small INDELs rather than large-scale chromosomal perturbations and exhibit lineage-specific variations, which spontaneously yet heterogeneously impinge on the clinical behaviors of cancers and are intrinsically linked to hot tumor microenvironments, especially in uterine corpus endometrial carcinoma (UCEC) and colon adenocarcinoma (COAD), where MLL3 aberrances surprisingly predict better overall survivals and favorable responses to immunochemotherapy. Concurrent mutation of MLL3 and POLE in UCEC is associated with high immune cell infiltration and immune checkpoint gene expression, endowing the applicability of immune checkpoint inhibitors in these patients. Mouse models with Mll3-ablated colon cancer validate the immunostimulatory trait of Mll3 aberration. Our study provides a pan-cancer spectrum of the MLL3 mutational event and will contribute to the understanding of the genetic evolution and disease management of cancers, especially COAD and UCEC.
2025-09-07 | GSE307073 | GEO
Project description:Immune checkpoint inhibitors are used to restore or augment antitumor immune response and show great promise in treatment of melanoma and other types of cancers. However, only a relatively small percentage of patients are fully responsive to immune checkpoint inhibition, mostly due to tumor heterogeneity and primary resistance to therapy. Both of these features are largely driven by accumulation of patient-specific mutations, pointing to the need for personalized approaches in diagnostics and immunotherapy. Proteogenomics integrates patient-specific genomic and proteomic data to study cancer development and resistance mechanisms, as well as tumor heterogeneity in individual patients. Here, we use a proteogenomic approach to characterize the mutational landscape of samples derived from four clinical melanoma patients at the genomic, proteomic and phosphoproteomic level. Integration of datasets enabled identification and quantification of an extensive number of sample-specific amino acid variants, among them many were not previously reported in melanoma. We detected a disproportional number of alternate peptides between treated and untreated (naïve) samples with a high potential to influence signal transduction. This is one of the first proteogenomic study designed to study the mutational landscape of patient-derived melanoma tissue samples in response to immunotherapy.
2022-02-16 | PXD028700 | Pride
Project description:Chromatin association sites of KSHV and RRV PAN RNA
| PRJNA496580 | ENA
Project description:FOXA1 is a pioneer factor that is important in hormone dependent cancer cells to stabilise nuclear receptors, such as estrogen receptor (ER) to chromatin. FOXA1 binds to enhancers regions that are enriched in H3K4mono- and dimethylation (H3K4me1, H3K4me2) histone marks and evidence suggests that these marks are requisite events for FOXA1 to associate with enhancers to initate subsequent gene expression events. However, exogenous expression of FOXA1 has been shown to induce H3K4me1 and H3K4me2 signal at enhancer elements and the order of events and the functional importance of these events is not clear. We performed a FOXA1 Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) screen in ERα-positive MCF-7 breast cancer cells in order to identify FOXA1 interacting partners and we found histone-lysine N-methyltransferase (MLL3) as the top FOXA1 interacting protein. MLL3 is typically thought to induce H3K4me3 at promoter regions, but recent findings suggest it may contribute to H3K4me1 deposition, in line with our observation that MLL3 associates with an enhancer specific protein. We performed MLL3 ChIP-seq in breast cancer cells and unexpectedly found that MLL3 binds mostly at non-promoter regions enhancers, in contrast to the prevailing hypothesis. MLL3 was shown to occupy regions marked by FOXA1 occupancy and as expected, H3K4me1 and H3K4me2. MLL3 binding was dependent on FOXA1, indicating that FOXA1 recruits MLL3 to chromatin. Motif analysis and subsequent genomic mapping revealed a role for Grainy head like protein-2 (GRHL2) which was shown to co-occupy regions of the chromatin with MLL3. Regions occupied by all three factors, namely FOXA1, MLL3 and GRHL2, were most enriched in H3K4me1. MLL3 silencing decreased H3K4me1 at enhancer elements, but had no appreciable impact on H3K4me3 at enhancer elements. We identify a complex relationship between FOXA1, MLL3 and H3K4me1 at enhancers in breast cancer and propose a mechanism whereby the pioneer factor FOXA1 can interact with a chromatin modifier MLL3, recruiting it to chromatin to facilitate the deposition of H3K4me1 histone marks, subsequently demarcating active enhancer elements.
2016-12-12 | PXD005253 | Pride
Project description:Despite substantial investments, tuberculosis remains one of the biggest challenges in public health. DNA-immunotherapy is increasingly being suggested as a possibility to assist conventional treatment of tuberculosis. This strategy could allow treatment to be more efficient, faster and with advantages and modulate the host immune response, as demonstrated by our group with DNAhsp65 vaccine (Silva, Bonato et al., Gene Therapy, 2005). Based on this evidences, we performed a microarray assay to stydy the functional effects of DNAhsp65 immunotherapy associated with conventional chemotherapy in murine experimental tuberculosis. Briefly, we used a murine model of tuberculosis treatment compost by DNAhsp65 vaccine, or rifampicin and isoniazid or both therapies combined and performed a comprehensive analysis of its effects on gene expression of hostM-bM-^@M-^Ys lung . Female BALB/c mice,8 weeks old, were inoculated with 1.0 M-CM-^W 10e5 viable bacilli of Mycobacterium tuberculosis H37Rv strain by the intra-tracheal route in a level III bio-safety room facility (day 0). They were segregated in four groups, described below, with three animals each one. Control M-bM-^@M-^S just infected and not treated. Immunotherapy - Thirty days after challenge, 50 M-NM-<g of plasmid with DNA-insert (DNAhsp65) was administered by intramuscular injection in 50 M-NM-<L of 25% saccharose solution in saline into each quadriceps muscle, in four occasions, and at 10-days intervals, performing a final dose of 400 M-NM-<g of plasmid DNAhsp65 per animal. Control infected mice received saline. Chemotherapy - Thirty days after infection, animals were treated with water solution of isoniazid (25 mg/Kg, Sigma-Aldrich, St. Louis, MO, USA) and rifampicin (20 mg/Kg, Sigma-Aldrich, St. Louis, MO, USA) daily, during 30 days, by gavage. Control infected mice received the same volume of water. Association - The therapeutical association consists of the both therapeutical approaches, as described above. Ten days after the end of treatments, mice were killed by cervical dislocation under mild anesthesia, and lungs were removed to RNA extraction.
2013-04-08 | E-GEOD-44825 | biostudies-arrayexpress
Project description:During lytic replication of Kaposi’s sarcoma-associated herpesvirus (KSHV), a nuclear viral long noncoding RNA known as PAN RNA becomes the most abundant polyadenylated transcript in the cell. Knockout or knockdown of KSHV PAN RNA results in loss of late lytic viral gene expression and, consequently, reduction of progeny virion release from the cell. We studied KSHV and RRV PAN RNA homologs using capture hybridization analysis of RNA targets (CHART) and observed their reproducible associations with host chromatin, but the loci differ between PAN RNA homologs.
2018-10-17 | GSE121268 | GEO
Project description:MLL3 inactivation mutations occurs frequently in human breast cancer. To understand the function of MLL3 inactivation, we compared the gene expression profiles of the vector control (WT) and Mll3-knockout MCF7 cells generated by CRISPR-CAS9. Affymetrix human Gene 2.0ST arrays were used for microarray.
2022-10-08 | GSE171445 | GEO
Project description:MLL3 inactivation mutations occurs frequently in human breast cancer. To understand the function of MLL3 inactivation, we compared the gene expression profiles of the vector control (WT) and Mll3-null mouse mammary stem cells generated by CRISPR. Affymetrix mouse Gene 2.0ST ships were used for microarray.
2016-09-19 | GSE79946 | GEO
Project description:To determine the effect of Mll3 deletion on H3K4me3 Chip signals in intestinal stem cell populations. This data has been described in the following article : Discovery of candidate disease genes in ENU-induced mouse mutants by large-scale sequencing, including a splice-site mutation in nucleoredoxin. Boles MK et al PLoS Genet. 2009 Dec;5(12) and its further analysis can be freely submitted for publication. For information on the proper use of data shared by the Wellcome Trust Sanger Institute (including information on acknowledgement), please see http://www.sanger.ac.uk/datasharing/ Abstract: Briefly we wanted to determine the effect of Mll3 deletion on H3K4me3 binding in cells of the intestine and to compare these to the H3K4me3 pattern found in wildtype animals.
2011-12-15 | E-ERAD-42 | biostudies-arrayexpress
Project description:a.Background Cancer resequencing studies have revealed epigenetic enzymes as common targets for recurrent mutations. The monomethyltransferase MLL3 is among the most recurrently mutated enzymes in ER+ breast cancer. The H3K4me1 marks created by MLL3 can define enhancers. In ER+ breast cancer, ERα genome binding sites are primarily distal enhancers. Thus, we hypothesize that mutation of MLL3 will alter the genomic binding and transcriptional regulatory activity of ERα. b.Methods We investigated the genomic consequences of knocking down MLL3 in an MLL3/PIK3CA WT ER+ breast cancer cell line. c. Results Loss of MLL3 led to large loss of H3K4me1 across the genome, and a shift in ERα binding sites, which was accompanied by a re-organization of the breast cancer transcriptome. Enrichment analyses of ERα binding sites in MLL3 KD identified endocrine therapy resistance terms, and we show that MLL3 KD cells are resistant to tamoxifen and fulvestrant. Many differentially expressed genes are controlled by new locations of H3K4me1 deposition and ERα binding, suggesting that loss of functional MLL3 leads to new transcriptional regulation of essential genes. Motif analysis of RNA-seq and ChIP-seq data highlighted SP1 as a critical transcription factor in the MLL3 KD cells. Loss of ERα binding is accompanied by a massive increase in SP1 binding at differentially expressed genes. d.Conclusions Our data show that loss of functional MLL3 leads to endocrine therapy resistance. This highlights the importance of genotyping patient tumor samples for MLL3 mutation upon initial resection, prior to deciding upon treatment plans.
2020-12-16 | GSE163264 | GEO