{"entity":{"id":"kmt2a","kind":"target","name":"KMT2A (MLL) rearrangement","aka":["KMT2A rearrangement","KMT2A-rearranged","KMT2A-r","KMT2Ar","KMT2A fusion","MLL-rearranged","MLL rearrangement","MLLr","MLL-r","11q23 rearrangement","KMT2A partner gene"],"tldr":"A gene fusion that drives an aggressive leukaemia in infants and adults. It cannot be blocked directly, but the scaffold protein it depends on (menin) can.","summary":"KMT2A (formerly MLL) rearrangements with >80 partner genes occur in ~5-10% of adult AML (higher in therapy-related AML), ~80% of infant ALL, and a subset of adult B-ALL. The fusion protein needs menin to bind chromatin and sustain HOXA9/MEIS1 expression. Menin inhibitors revumenib (approved 2024) and ziftomenib (in trials for KMT2Ar) release the differentiation block. Resistance emerges through MEN1 mutations at the drug-binding site.","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/KMT2A","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/KMT2A"}],"tags":["driver","fusion"],"related":["menin"],"cancers":["aml","all-leukemia"],"sections":[],"technologies":[],"targets":[],"drugs":["revumenib","ziftomenib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"symbol":"KMT2A","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"one-type","specificityNote":"Broadly expressed or essential: HPA finds the RNA at low tissue specificity; the 3 medicines aimed at it (Revumenib, Ziftomenib, Etoposide) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA KMT2A: RNA low tissue specificity; high antibody staining in 2 normal tissues; highest cancer staining head and neck cancer (2 of 4 high). Distribution: 1 cancer family in the corpus carries a prevalence row, label threshold or catalogue link for it (Leukaemia); approvals of single-target medicines aimed at it also list Testicular germ cell tumours, Lung cancer (all types), Sarcomas (soft tissue, bone, GIST), Lymphoma and more, not counted; Open Targets associates it with 0 specific cancer types at or above 0.5. (Rule 7 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas KMT2A tissue","url":"https://www.proteinatlas.org/ENSG00000118058-KMT2A/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000118058 associations","url":"https://platform.opentargets.org/target/ENSG00000118058/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:7132","ensembl":"ENSG00000118058","uniprot":"Q03164","entrez":"4297","firstDescribed":1992,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Tkachuk D.C. et al, Cell, 1992, \"Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/1423624/","biology":"Histone H3K4 methyltransferase; fusions lose the SET domain and gain partner-driven transcriptional elongation activity. Menin binds the N-terminus and is required for leukaemogenesis.","whereFound":["Infant ALL (~80%)","Adult AML (5-10%; therapy-related after topoisomerase II inhibitors)","Adult B-ALL (KMT2A::AFF1)","Mixed-phenotype acute leukaemia"],"targetClass":"transcription","prevalence":[{"cancerId":"aml","pct":"5-10","measure":"rearrangement","note":"Higher in therapy-related AML"},{"cancerId":"all-leukemia","pct":"~80 in infants; 5-10 in adults","measure":"rearrangement"}]},"route":"/targets/kmt2a/","neighbours":{"target":[{"id":"hoxa9","kind":"target","name":"HOXA9","route":"/targets/hoxa9/"},{"id":"meis1","kind":"target","name":"MEIS1","route":"/targets/meis1/"},{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/"}],"cancer":[{"id":"all-leukemia","kind":"cancer","name":"Acute lymphoblastic leukaemia","route":"/cancers/all-leukemia/"},{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"aml-paediatric","kind":"cancer","name":"Acute myeloid leukaemia in children","route":"/cancers/aml-paediatric/"},{"id":"all-infant","kind":"cancer","name":"Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year)","route":"/cancers/all-infant/"},{"id":"aml-npm1-kmt2a","kind":"cancer","name":"NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia","route":"/cancers/aml-npm1-kmt2a/"}],"drug":[{"id":"etoposide","kind":"drug","name":"Etoposide","route":"/drugs/etoposide/"},{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"ziftomenib","kind":"drug","name":"Ziftomenib","route":"/drugs/ziftomenib/"}],"term":[{"id":"b-all-cytogenetic-risk","kind":"term","name":"B-ALL risk groups (NCI criteria, ETV6::RUNX1, hyperdiploidy, hypodiploidy, iAMP21, IKZF1, CNS status)","route":"/terms/b-all-cytogenetic-risk/"},{"id":"eln-risk","kind":"term","name":"ELN 2022 risk classification","route":"/terms/eln-risk/"}],"trial":[{"id":"augment-101","kind":"trial","name":"AUGMENT-101","route":"/trials/augment-101/"},{"id":"interfant-06","kind":"trial","name":"Interfant-06","route":"/trials/interfant-06/"}],"pairing":[{"id":"menin-plus-venetoclax-hma","kind":"pairing","name":"Menin inhibitor + venetoclax + azacitidine","route":"/pairings/menin-plus-venetoclax-hma/"}],"idea":[{"id":"idea-bio2-mechanism-defined-baskets","kind":"idea","name":"Group trials by broken mechanism, not by organ or single mutation","route":"/ideas/idea-bio2-mechanism-defined-baskets/"},{"id":"idea-menin-infant-all","kind":"idea","name":"Menin inhibitors for infant KMT2A-rearranged ALL","route":"/ideas/idea-menin-infant-all/"}],"bottleneck":[{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"pathway":[{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}],"paper":[{"id":"paper-augment-101-revumenib-menin-nature-2023","kind":"paper","name":"AUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutation","route":"/key-papers/paper-augment-101-revumenib-menin-nature-2023/"}]}}