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Protein / target

Histone-lysine N-methyltransferase 2A

Encoded byKMT2AQ03164Homo sapiensSwiss-Prot
UniProt: Q03164Ensembl: ENSG00000118058HGNC: HGNC:7132NCBI Gene: 4297
Clinical-stage
Therapeutic maturity
2
Clinical candidates
Small-molecule tractable
Druggability
Phase 1 Clinical
1
Research papers

Protein at a glance

Biological role

Minor groove of adenine-thymine-rich DNA binding

Strongest disease association

Genetic Diseases, Inborn

Via encoding gene KMT2A · Genetic evidence · score 0.91

Therapeutic position

Clinically advancing target

Small molecules

Research activity

Emerging research

1 papers · latest 2016

Derived from structured UniProt, Open Targets and literature data on this page.

Protein profile

UniProt 2026_02

Canonical identity and biological annotation from UniProt.

Function overview

Histone methyltransferase that plays an essential role in early development and hematopoiesis.

View complete UniProt function annotation

Histone methyltransferase that plays an essential role in early development and hematopoiesis (PubMed:12453419, PubMed:15960975, PubMed:19187761, PubMed:19556245, PubMed:20677832, PubMed:21220120, PubMed:26886794). Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac) (PubMed:12453419, PubMed:15960975, PubMed:19187761, PubMed:19556245, PubMed:20677832, PubMed:21220120, PubMed:24235145, PubMed:26886794). Catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) via a non-processive mechanism. Part of chromatin remodeling machinery predominantly forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:12453419, PubMed:15960975, PubMed:19187761, PubMed:19556245, PubMed:20677832, PubMed:21220120, PubMed:25561738, PubMed:26886794). Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity (PubMed:19187761, PubMed:26886794). Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9' (PubMed:19187761). Binds to unmethylated CpG elements in the promoter of target genes and helps maintain them in the nonmethylated state (PubMed:20010842). Required for transcriptional activation of HOXA9 (PubMed:12453419, PubMed:20010842, PubMed:20677832). Promotes PPP1R15A-induced apoptosis (PubMed:10490642). Plays a critical role in the control of circadian gene expression and is essential for the transcriptional activation mediated by the CLOCK-BMAL1 heterodimer (By similarity). Establishes a permissive chromatin state for circadian transcription by mediating a rhythmic methylation of 'Lys-4' of histone H3 (H3K4me) and this histone modification directs the circadian acetylation at H3K9 and H3K14 allowing the recruitment of CLOCK-BMAL1 to chromatin (By similarity). Also has auto-methylation activity on Cys-3882 in absence of histone H3 substrate (PubMed:24235145)

Subcellular location

Nucleus
Domains and Gene Ontology detail (34)

Domains & features

BromoFYR N-terminalFYR C-terminalSETPost-SET

Gene Ontology

  • Ccytosol
  • Chistone methyltransferase complex
  • CMLL1 complex
  • Cnucleoplasm
  • Cnucleus
  • Fchromatin binding
  • Fhistone H3K4 methyltransferase activity
  • Fhistone H3K4 monomethyltransferase activity
  • Fhistone H3K4 trimethyltransferase activity
  • Fidentical protein binding
  • Fminor groove of adenine-thymine-rich DNA binding
  • Fprotein homodimerization activity

3969 aa · 432 kDa · 3 isoforms

Biological roles

What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.

Metabolic enzyme activityUniProt · GOTranscriptional regulationUniProt · GO
View supporting evidence

Metabolic enzyme activity

  • ·Histone methyltransferase that plays an essential role in early development and hematopo…
  • ·histone H3K4 methyltransferase activity
  • ·histone H3K4 monomethyltransferase activity
  • ·histone H3K4 trimethyltransferase activity

Transcriptional regulation

  • ·Histone methyltransferase that plays an essential role in early development and hematopo…
  • ·circadian regulation of gene expression
  • ·positive regulation of DNA-templated transcription
  • ·positive regulation of transcription by RNA polymerase II

Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.

Translational evidence

Open Targets 26

Why this target matters therapeutically, strongest evidence first. Disease associations are gene-level (via the gene that encodes this protein) and open into the full confidence synthesis; the development universe, tractability and safety annotations are target-level, from Open Targets.

Strongest disease associations · via encoding gene KMT2A

Gene-level evidence surfaced through the gene KMT2A that encodes this protein — not a direct protein–disease relationship. Ranked by Forefront's causal-directness weighting, so genetically- and clinically-evidenced diseases lead over ones that merely share the literature.

Genetic Diseases, Inborn
0.91Well supported

Genetic evidence dominant · Open Targets 0.56

Leukemia, Myeloid, Acute
0.76Well supported

Clinical evidence dominant · Open Targets 0.46

Microcephaly
0.66Moderately supported

Genetic evidence dominant · Open Targets 0.40

Precursor Cell Lymphoblastic Leukemia-Lymphoma
0.66Moderately supported

Somatic mutation evidence dominant · Open Targets 0.44

Urinary Bladder Neoplasms
0.47Limited support

Somatic mutation evidence dominant · Open Targets 0.41

View evidence synthesis (5)
Genetic Diseases, InbornWell supported
0.91
agreement 0.77–1.00
Genetic99%Literature1%

Open Targets aggregate 0.56 · 2 independent evidence families

Leukemia, Myeloid, AcuteWell supported
0.76
agreement 0.65–0.87
Clinical36%Pathway26%Somatic mutation25%Literature13%

Open Targets aggregate 0.46 · 4 independent evidence families

MicrocephalyModerately supported
0.66
agreement 0.52–0.80
Genetic98%Literature2%

Open Targets aggregate 0.40 · 2 independent evidence families

Precursor Cell Lymphoblastic Leukemia-LymphomaModerately supported
0.66
agreement 0.55–0.76
Somatic mutation44%Pathway27%Literature17%Clinical13%

Open Targets aggregate 0.44 · 4 independent evidence families

Urinary Bladder NeoplasmsLimited support
0.47
agreement 0.31–0.63
Somatic mutation81%Literature19%

Open Targets aggregate 0.41 · 2 independent evidence families

The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the per-type scores above show the calculation.

Show all associations
Genetic Diseases, Inborn0.56
Leukemia, Myeloid, Acute0.46
Precursor Cell Lymphoblastic Leukemia-Lymphoma0.44
Urinary Bladder Neoplasms0.41
Microcephaly0.40
Melanoma0.39

Drug development

2 compounds recorded · 2 in clinical development

Open Targets' development universe — every compound recorded against the target at any stage, not all approved medicines.

View all recorded compounds (2)
REVUMENIB SESQUIFUMARATEPhase 1 2
REVUMENIBPhase 3

Open Targets known-drugs universe. Drug name and highest clinical stage only — the disease relationship is NOT read from this slice (it carries trial-context noise); approved indications come from the canonical graph above.

Tractability

Small molecules — Supported

Phase 1 Clinical and Structure with Ligand support this modality.

Protein degraders — Emerging

Feasibility evidence (uniprot ubiquitination and database ubiquitination) — no clinical-stage drug of this modality recorded.

View underlying tractability evidence (8)
SM · Phase 1 ClinicalSM · Structure with LigandSM · High-Quality LigandSM · Druggable FamilyPR · UniProt UbiquitinationPR · Database UbiquitinationPR · Half-life DataPR · Small Molecule Binder

Raw Open Targets tractability assessment buckets, by modality.

Research activity

1 papers · to 2016

Papers linked directly to this protein. This is the protein's own literature — descriptor-derived papers are kept separate below.

Most cited

Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy.596 cites

Gardner R · Blood · 2016

Recent

Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy.

Gardner R · Blood · 2016

Europe PMC papers linked directly to this protein.