KMT2A

"HRX" redirects here. For the bank holding, see Hypo Real Estate. For a language, the ISO 639-3 code of which is hrx, see Riograndenser Hunsrückisch German.

Histone-lysine N-methyltransferase 2A also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia (MLL), or zinc finger protein HRX (HRX) is an enzyme that in humans is encoded by the KMT2A gene.

MLL is a histone methyltransferase deemed a positive global regulator of gene transcription. This protein belongs to the group of histone-modifying enzymes comprising transactivation domain 9aaTAD and is involved in the epigenetic maintenance of transcriptional memory.

Function

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. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. 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.

Structure

Gene

KMT2A gene has 37 exons and resides on chromosome 11 at q23.

Protein

KMT2A has over a dozen of 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. The 9aaTAD transactivation domains of E proteins and MLL are very similar and both bind to the KIX domain of general transcriptional mediator CBP.

Clinical significance

Rearrangements of the MLL gene are associated with aggressive acute leukemias, both lymphoblastic and myeloid. It also may participate in the process of GAD67 downregulation in schizophrenia.

Despite being an aggressive leukemia, the MLL rearranged sub-type had the lowest mutation rates reported for any cancer.

Mutations in MLL cause Wiedemann-Steiner syndrome and Acute lymphoblastic leukemia. The leukemia cells of up to 80 percent of infants with ALL have a chromosomal rearrangement that fuses the MLL gene to a gene on a different chromosome.

Interactions

MLL (gene) has been shown to interact with:

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

External links

• MLL OMIM Entry: MYELOID/LYMPHOID OR MIXED LINEAGE LEUKEMIA GENE; MLL
• MLL protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• Gene MLL on the Atlas of Genetics and Oncology