# KMT2D

Source: https://onco.cc/targets/kmt2d/  
OnCo record `kmt2d` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

CIViC 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.

## Fields

- Kind: Target
- Last checked: 2026-09-23
- Also known as: lysine methyltransferase 2D; Histone-lysine N-methyltransferase 2D; MLL4; CAGL114; TNRC21; MLL2
- Tags: cancer-genes-wave
- Symbol: KMT2D
- Class: transcription
- 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).
- Where found: 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

## 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.

## Sources

- HGNC HGNC:7133: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7133
- UniProt O14686: https://www.uniprot.org/uniprotkb/O14686/entry
- NCBI Gene 8085: https://www.ncbi.nlm.nih.gov/gene/8085
- Ensembl ENSG00000167548: https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000167548
- Pasqualucci et al., Nature 2011: inactivating mutations of the acetyltransferase genes CREBBP and EP300 in B-cell lymphoma: https://doi.org/10.1038/nature09730
- Morin et al., Nature 2011: frequent mutation of histone-modifying genes in non-Hodgkin lymphoma: https://doi.org/10.1038/nature10351
- Pasqualucci et al., Nat Genet 2011: the coding genome of diffuse large B-cell lymphoma: https://doi.org/10.1038/ng.892

## Connected records

- collections: [CIViC](https://onco.cc/collections/civic/), [IntOGen](https://onco.cc/collections/intogen/), [Open Targets Platform](https://onco.cc/collections/open-targets/)
- cancers: [Bladder & urothelial cancer](https://onco.cc/cancers/urothelial/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Follicular lymphoma](https://onco.cc/cancers/follicular-lymphoma/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [Head and neck squamous cell carcinoma](https://onco.cc/cancers/head-and-neck/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Neuroendocrine tumours](https://onco.cc/cancers/neuroendocrine/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [The germinal centre reaction](https://onco.cc/pathways/germinal-centre-reaction/)
- key papers: [Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients](https://onco.cc/key-papers/paper-sausen-ctdna-pancreatic-resection-nat-commun-2015/), [Comprehensive genomic profiles of small cell lung cancer](https://onco.cc/key-papers/paper-george-sclc-genomic-profiles-nature-2015/), [Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas](https://onco.cc/key-papers/paper-campbell-pan-lung-somatic-alterations-nat-genet-2016/), [The long tail of oncogenic drivers in prostate cancer](https://onco.cc/key-papers/paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018/), [The mutational landscape of lethal castration-resistant prostate cancer](https://onco.cc/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/)

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JSON: https://onco.cc/api/v1/entities/kmt2d.json