{"entity":{"id":"kmt2d","kind":"target","name":"KMT2D","aka":["lysine methyltransferase 2D","Histone-lysine N-methyltransferase 2D","MLL4","CAGL114","TNRC21","MLL2"],"tldr":"KMT2D (Histone-lysine N-methyltransferase 2D) is a protein that switches other genes on and off. The public catalogues list it as a drug target, an oncogene driver, a tumour suppressor and a biomarker, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Lung cancer, Non-Hodgkin lymphoma, Bladder & urothelial cancer and 5 more.","summary":"Histone methyltransferase that catalyses methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4). Part of chromatin remodeling machinery predominantly forms H3K4me1 methylation marks at active chromatin sites where transcription and DNA repair take place. Acts as a coactivator for oestrogen receptor by being recruited by ESR1, thereby activating transcription.\n\nCIViC holds 15 clinical evidence items and 0 assertions across 3 variants, naming Immune Checkpoint Inhibitor, Afatinib, Gefitinib and Olaparib and others. Open Targets scores its association with cancer at 0.81 (direct and indirect evidence; datatypes affected pathway 0.54, literature 0.97, genetic association 0.18, somatic mutation 0.95, animal model 0.27). IntOGen calls it a driver in 91 cohorts (14 activating, 77 loss-of-function), covering Adenoid Cystic Carcinoma, Acute Lymphoblastic Leukaemia, Anal Squamous Cell Carcinoma, Basal Cell Carcinoma, Burkitt Lymphoma, Bladder/Urinary Tract and others.","asOf":"2026-09-23","links":[{"label":"HGNC HGNC:7133","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7133"},{"label":"UniProt O14686","url":"https://www.uniprot.org/uniprotkb/O14686/entry"},{"label":"NCBI Gene 8085","url":"https://www.ncbi.nlm.nih.gov/gene/8085"},{"label":"Ensembl ENSG00000167548","url":"https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000167548"},{"label":"Pasqualucci et al., Nature 2011: inactivating mutations of the acetyltransferase genes CREBBP and EP300 in B-cell lymphoma","url":"https://doi.org/10.1038/nature09730"},{"label":"Morin et al., Nature 2011: frequent mutation of histone-modifying genes in non-Hodgkin lymphoma","url":"https://doi.org/10.1038/nature10351"},{"label":"Pasqualucci et al., Nat Genet 2011: the coding genome of diffuse large B-cell lymphoma","url":"https://doi.org/10.1038/ng.892"}],"tags":["cancer-genes-wave"],"related":["civic","open-targets","intogen"],"cancers":["lung-cancer","non-hodgkin-lymphoma","urothelial","head-and-neck","colorectal","prostate","neuroendocrine","gastric"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Written by scripts/fetch-cancer-genes.ts from CIViC, Open Targets, IntOGen, HGNC and UniProt; the function text is UniProt's, condensed and in UK spelling. Roles: CIViC lists 11 therapies; IntOGen calls it an activating (Act) driver in 14 cohorts; IntOGen calls it a loss-of-function (LoF) driver in 77 cohorts; CIViC holds 15 clinical evidence items on its variants. Evidence tier \"clinical-evidence\" is the strongest of those signals.","Prevalence not recorded: none of the sources gives a positivity rate.","Diseases the sources name that have no OnCo cancer page yet, so they are not linked: Kabuki Syndrome; High-Grade Glioma, NOS.","Lymphoma, CREBBP, EP300 and the rest of the chromatin machinery: CREBBP and EP300 are acetyltransferases. Losing one allele lowers the dose of acetylation, which leaves BCL6 acetylated less often and therefore active more often, and leaves p53 acetylated less often and therefore working less well; the same lesion also turns down the enhancers that would let a germinal-centre cell present antigen to T cells. KMT2D, formerly MLL2, writes H3K4 monomethylation at enhancers and is the single most frequently mutated gene in follicular lymphoma. Frequency: Genomic deletion or somatic mutation removing or inactivating the acetyltransferase domain of CREBBP or, more rarely, EP300 in about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma, usually on one allele only (Pasqualucci 2011). KMT2D mutated in 32% of diffuse large B-cell lymphoma and 89% of follicular lymphoma in the discovery series, with MEF2B in 11.4% and 13.4% (Morin 2011); the coding genome of diffuse large B-cell lymphoma carries more than 30 clonally represented alterations per case (Pasqualucci 2011, Nat Genet). What it changes about treatment: Not yet. The pairing of CREBBP loss with HDAC3 dependency is the clearest synthetic-lethal hypothesis in B-cell lymphoma and is in trials; no approval depends on a CREBBP result."],"provenance":{"editedBy":"scripts/fetch-cancer-genes.ts (CIViC, Open Targets, IntOGen, HGNC, UniProt)","editedOn":"2026-09-23"},"symbol":"KMT2D","role":["drug-target","oncogene-driver","tumour-suppressor","biomarker"],"evidenceTier":"clinical-evidence","sources":[{"label":"HGNC HGNC:7133","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7133","note":"approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)"},{"label":"UniProt O14686","url":"https://www.uniprot.org/uniprotkb/O14686/entry","note":"protein name, function text, keywords and locations (REST API)"},{"label":"CIViC gene KMT2D","url":"https://civicdb.org/features/64","note":"15 evidence items, 0 assertions, 3 variants; diseases: Mantle Cell Lymphoma, Colorectal Adenocarcinoma, Melanoma, Lung Non-small Cell Carcinoma, Lung Adenocarcinoma and 7 more (GraphQL API, CC0)"},{"label":"Open Targets ENSG00000167548","url":"https://platform.opentargets.org/target/ENSG00000167548/associations","note":"association with cancer (MONDO_0004992) 0.81; per-cancer scores at or above 0.5: non-small cell lung carcinoma 0.57, colorectal cancer 0.65, gastric cancer 0.60, oesophageal cancer 0.59, prostate cancer 0.65, urinary bladder cancer 0.68 (GraphQL API, CC0)"},{"label":"IntOGen KMT2D","url":"https://www.intogen.org/search?gene=KMT2D","note":"driver in 91 cohorts (Act 14, LoF 77); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0"}],"specificity":"tumour-specific","distribution":"many-types","specificityNote":"Tumour-specific alteration: the catalogues call it an oncogene driver (IntOGen cohort analysis finds it activated more often than chance) and a tumour suppressor (IntOGen finds it knocked out more often than chance), so the direction differs between cohorts but the alteration is somatic either way; what a medicine would aim at or exploit is the altered form or its loss, absent from normal cells; no corpus medicine is aimed at it yet. HPA KMT2D: RNA low tissue specificity; high antibody staining in 4 normal tissues. Distribution: 8 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Lung cancer (all types), Lymphoma, Bladder & urothelial cancer, Head and neck squamous cell carcinoma, Colorectal cancer, Prostate cancer, Neuroendocrine tumours and more); Open Targets associates it with 7 specific cancer types at or above 0.5 (diffuse large B-cell lymphoma, head and neck squamous cell carcinoma, prostate adenocarcinoma, squamous cell lung carcinoma, medulloblastoma, urinary bladder cancer and more). (Rule 6 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"UniProt O14686","url":"https://www.uniprot.org/uniprotkb/O14686/entry","note":"protein name, function text, keywords and locations (REST API)"},{"label":"CIViC gene KMT2D","url":"https://civicdb.org/features/64","note":"15 evidence items, 0 assertions, 3 variants; diseases: Mantle Cell Lymphoma, Colorectal Adenocarcinoma, Melanoma, Lung Non-small Cell Carcinoma, Lung Adenocarcinoma and 7 more (GraphQL API, CC0)"},{"label":"IntOGen KMT2D","url":"https://www.intogen.org/search?gene=KMT2D","note":"driver in 91 cohorts (Act 14, LoF 77); Compendium_Cancer_Genes.tsv release 20240920, CC0 1.0"},{"label":"Human Protein Atlas KMT2D tissue","url":"https://www.proteinatlas.org/ENSG00000167548-KMT2D/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000167548 associations","url":"https://platform.opentargets.org/target/ENSG00000167548/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:7133","ensembl":"ENSG00000167548","uniprot":"O14686","entrez":"8085","firstDescribed":1997,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Prasad et al, Oncogene, 1997, \"Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/9247308/","biology":"Histone methyltransferase that catalyses methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4). Part of chromatin remodeling machinery predominantly forms H3K4me1 methylation marks at active chromatin sites where transcription and DNA repair take place. Acts as a coactivator for oestrogen receptor by being recruited by ESR1, thereby activating transcription. Location: Nucleus (UniProt). Locus 12q13.12 (HGNC).","whereFound":["Lung cancer: Open Targets association 0.75 with lung cancer (MONDO_0008903)","Non-Hodgkin lymphoma: Open Targets association 0.71 with non-Hodgkin lymphoma (MONDO_0018908); IntOGen driver in 3 cohorts (LNM, MLYM, NHL)","Bladder & urothelial cancer: Open Targets association 0.68 with urinary bladder cancer (MONDO_0001187); CIViC evidence names this disease","Head and neck squamous cell carcinoma: Open Targets association 0.66 with head and neck squamous cell carcinoma (MONDO_0010150); IntOGen driver in 6 cohorts (HNSC)","Colorectal cancer: Open Targets association 0.65 with colorectal cancer (MONDO_0005575); CIViC evidence names this disease","Prostate cancer: Open Targets association 0.65 with prostate cancer (MONDO_0008315); CIViC evidence names this disease"],"targetClass":"transcription","prevalence":[]},"route":"/targets/kmt2d/","neighbours":{"collection":[{"id":"civic","kind":"collection","name":"CIViC","route":"/collections/civic/"},{"id":"intogen","kind":"collection","name":"IntOGen","route":"/collections/intogen/"},{"id":"open-targets","kind":"collection","name":"Open Targets Platform","route":"/collections/open-targets/"}],"cancer":[{"id":"urothelial","kind":"cancer","name":"Bladder & urothelial cancer","route":"/cancers/urothelial/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"follicular-lymphoma","kind":"cancer","name":"Follicular lymphoma","route":"/cancers/follicular-lymphoma/"},{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"head-and-neck","kind":"cancer","name":"Head and neck squamous cell carcinoma","route":"/cancers/head-and-neck/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-lymphoma/"},{"id":"neuroendocrine","kind":"cancer","name":"Neuroendocrine tumours","route":"/cancers/neuroendocrine/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"pathway":[{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"germinal-centre-reaction","kind":"pathway","name":"The germinal centre reaction","route":"/pathways/germinal-centre-reaction/"}],"paper":[{"id":"paper-sausen-ctdna-pancreatic-resection-nat-commun-2015","kind":"paper","name":"Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients","route":"/key-papers/paper-sausen-ctdna-pancreatic-resection-nat-commun-2015/"},{"id":"paper-george-sclc-genomic-profiles-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung cancer","route":"/key-papers/paper-george-sclc-genomic-profiles-nature-2015/"},{"id":"paper-campbell-pan-lung-somatic-alterations-nat-genet-2016","kind":"paper","name":"Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas","route":"/key-papers/paper-campbell-pan-lung-somatic-alterations-nat-genet-2016/"},{"id":"paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018","kind":"paper","name":"The long tail of oncogenic drivers in prostate cancer","route":"/key-papers/paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018/"},{"id":"paper-grasso-mutational-landscape-lethal-crpc-nature-2012","kind":"paper","name":"The mutational landscape of lethal castration-resistant prostate cancer","route":"/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/"}]}}