KMT2A

Structure

The human KMT2A protein contains a total of 3,969 amino acid residues and contains the following motifs and domains (reading from the N-terminus to C-terminus):

KMT2A has over a dozen binding partners and is cleaved into two pieces, a larger N-terminal fragment, involved in gene repression, and a smaller C-terminal fragment, which is a transcriptional activator. The cleavage, followed by the association of the two fragments, is necessary for KMT2A to be fully active. Like many other methyltransferases, the KMT2 family members exist in multisubunit nuclear complexes (human COMPASS), where other subunits also mediate the enzymatic activity.

Function

Transcriptional regulation

KMT2A gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. Enriched in the nucleus, the KMT2A enzyme trimethylates H3K4 (H3K4me3). It also upregulates mono- and dimethylation of H3K4. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C (~180 kDa) and MLL-N (~320 kDa). These fragments then assemble into different multi-protein complexes that regulate the transcription of specific target genes, including many of the HOX genes.

Transcriptome profiling after deletion of KMT2A in cortical neurons revealed decreased promoter-bound H3K4me3 peaks at 318 genes, with 31 of these having significantly decreased expression and promoter binding. Among them were Meis2, a homeobox transcription factor critical for development of forebrain neurons and Satb2, a protein involved in neuronal differentiation.

Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.

Cognition and emotion

KMT2A has been shown to be an important epigenetic regulator of complex behaviors. Rodent models of MLL1 dysfunction in forebrain neurons showed that conditional deletion results in elevated anxiety and defective cognition. Prefrontal cortex-specific knockout of KMT2A results in the same phenotypes, as well as working memory deficits.

Stem cells

KMT2A has been found to be an important regulator of epiblast-derived stem cells, post-implantation epiblast derived stem cells which display pluripotency yet many recognizable differences from the traditional embryonic stem cells derived from inner cell mass prior to implantation. Suppression of KMT2A expression was shown to be adequate for inducing ESC-like morphology and behavior within 72 hours of treatment. It has been proposed that the small molecule inhibitor MM-401, which was used to inhibit KMT2A, changes the distribution of H3K4me1, the single methylation of the histone H3 lysine 4, to be significantly downregulated at KMT2A targets thus leading to decreased expression of KMT2A targets, rather than a direct regulation of pluripotency core markers.

Clinical significance

The dysregulation of the KMT2A gene underlies a broad spectrum of human disease from cancer to developmental abnormalities.

Cancer

KMT2A is one of the most significant genes in cancer. Chromosomal rearrangements generating KMT2A fusion proteins with more than 90 partners (most commonly AFF1, MLLT1, MLLT3, and MLLT10). KMT2A gene rearrangements drive acute myeloid and acute lymphoblastic leukemias. Nearly 80% of infant acute lymphoblastic leukemia cases contain KMT2A gene rearrangements and KMT2A rearrangements are strongly associated with poor outcomes.

Related alterations such as KMT2A gene duplication (increased dosage of otherwise-normal KMT2A) and KMT2A-PTD ( partial tandem gene duplication that produces a functionally abnormal protein) likewise confer poor prognosis in myelodysplastic syndrome and acute myeloid leukemia. Amplification linked to a median survival of only 2–3 months. Beyond leukemia, KMT2A alterations occur in high-grade B-cell lymphoma and various solid tumors including sarcomas, pancreatic cancer, and colorectal cancer.

These findings have motivated the development of targeted therapeutic strategies against KMT2A's protein partners and interactions, including menin inhibitors such as revumenib, DOT1L inhibitors such as pinometostat, and agents targeting BRD4, LSD1, and WDR5.

Developmental abnormalities

Mutations in KMT2A cause Wiedemann-Steiner syndrome. Germline loss-of-function mutations in KMT2A cause Wiedemann–Steiner syndrome, an autosomal dominant disorder marked by intellectual disability, developmental delay, hypotonia, short stature, and characteristic craniofacial and skeletal features.

Inflammation

KMT2A is required for the expression of senescence-associated secretory phenotype (SASP)-related genes and promotes increased inflammation.

Neurological disorders

Abnormal H3K4 trimethylation has been implicated in several neurological disorders such as autism. Humans with cognitive and neurodevelopmental disease often have dysregulation of H3K4 methylation in prefrontal cortex (PFC) neurons. It also may participate in the process of GAD67 downregulation in schizophrenia.

Interactions

MLL (gene) has been shown to interact with:

• ASH2L,
• CREBBP,
• CTBP1,
• HDAC1,
• HCFC1,
• MEN1,
• PPIE,
• PPP1R15A,
• RBBP5, and
• WDR5.