KMT2A

Lysine (K)-specific methyltransferase 2A
PDB rendering based on 2j2s.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2AGH​, 2J2S​, 2JYI​, 2KKF​, 2KU7​, 2KYU​, 2LXS​, 2LXT​, 2MSR​, 2MTN​, 2W5Y​, 2W5Z​, 3EG6​, 3EMH​, 3LQH​, 3LQI​, 3LQJ​, 3P4F​, 3U85​, 3U88​, 4ESG​, 4GQ6​, 4NW3​
Identifiers
Symbols	KMT2A ; ALL-1; CXXC7; HRX; HTRX1; MLL; MLL-AF9; MLL/GAS7; MLL1; MLL1A; TET1-MLL; TRX1; WDSTS
External IDs	OMIM: 159555 MGI: 96995 HomoloGene: 4338 ChEMBL: 1293299 GeneCards: KMT2A Gene
EC number	2.1.1.43
Gene ontology Molecular function • core promoter sequence-specific DNA binding • AT DNA binding • chromatin binding • transcription factor activity, sequence-specific DNA binding • protein binding • zinc ion binding • histone methyltransferase activity (H3-K4 specific) • identical protein binding • protein homodimerization activity • transcription regulatory region DNA binding • unmethylated CpG binding • lysine-acetylated histone binding Cellular component • nucleus • nucleoplasm • cytoplasm • histone methyltransferase complex • MLL1 complex Biological process • DNA methylation • chromatin organization • transcription from RNA polymerase II promoter • protein complex assembly • apoptotic process • negative regulation of cell proliferation • anterior/posterior pattern specification • positive regulation of transporter activity • circadian regulation of gene expression • embryonic hemopoiesis • response to potassium ion • histone H4-K16 acetylation • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • histone H3-K4 methylation • positive regulation of histone H3-K4 methylation • membrane depolarization • definitive hemopoiesis • regulation of histone H3-K14 acetylation • histone H3-K4 trimethylation • regulation of histone H3-K9 acetylation • positive regulation of cellular response to drug Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4297	214162
Ensembl	ENSG00000118058	ENSMUSG00000002028
UniProt	Q03164	P55200
RefSeq (mRNA)	NM_001197104	NM_001081049
RefSeq (protein)	NP_001184033	NP_001074518
Location (UCSC)	Chr 11: 118.44 – 118.53 Mb	Chr 9: 44.8 – 44.88 Mb
PubMed search

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.^[1]

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^[2] 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.^[3]

Structure

Gene

KMT2A gene has 37 exons and resides on chromosome 11 at q23.^[3]

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.^[4] 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.^[5]

Clinical significance

Rearrangements of the MLL gene are associated with aggressive acute leukemias, both lymphoblastic and myeloid.^[6] It also may participate in the process of GAD67 downregulation in schizophrenia.^[7]

Despite being an aggressive leukemia, the MLL rearranged sub-type had the lowest mutation rates reported for any cancer.^[8]

Mutations in MLL cause Wiedemann-Steiner syndrome and Acute lymphoblastic leukemia.^[9] 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.^[8]

Interactions

MLL (gene) has been shown to interact with:

• ASH2L,^[10]
• CREBBP,^[11][12]
• CTBP1,^[13]
• HDAC1,^[13]
• HCFC1,^[10]
• MEN1,^[10]
• PPIE,^[14]
• PPP1R15A,^[15]
• RBBP5,^[10] and
• WDR5.^[10]

References

1. Ziemin-van der Poel S, McCabe NR, Gill HJ, Espinosa R, Patel Y, Harden A, Rubinelli P, Smith SD, LeBeau MM, Rowley JD (January 1992). "Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias". Proc Natl Acad Sci U S A 88 (23): 10735–9. doi:10.1073/pnas.88.23.10735. PMC 53005. PMID 1720549.
2. Piskacek S, Gregor M, Nemethova M, Grabner M, Kovarik P, Piskacek M (June 2007). "Nine-amino-acid transactivation domain: establishment and prediction utilities". Genomics 89 (6): 756–68. doi:10.1016/j.ygeno.2007.02.003. PMID 17467953.; Piskacek M (November 2009). "Common Transactivation Motif 9aaTAD recruits multiple general co-activators TAF9, MED15, CBP and p300". Nature Precedings: Prepublication research and preliminary findings. doi:10.1038/npre.2009.3488.2.; Piskacek M (November 2009). "9aaTADs mimic DNA to interact with a pseudo-DNA Binding Domain KIX of Med15 (Molecular Chameleons)". Nature Precedings: Prepublication research and preliminary findings. doi:10.1038/npre.2009.3939.1.; Goto NK, Zor T, Martinez-Yamout M, Dyson HJ, Wright PE (November 2002). "Cooperativity in transcription factor binding to the coactivator CREB-binding protein (CBP). The mixed lineage leukemia protein (MLL) activation domain binds to an allosteric site on the KIX domain". J. Biol. Chem. 277 (45): 43168–74. doi:10.1074/jbc.M207660200. PMID 12205094.; Prasad R, Yano T, Sorio C, Nakamura T, Rallapalli R, Gu Y, Leshkowitz D, Croce CM, Canaani E (December 1995). "Domains with transcriptional regulatory activity within the ALL1 and AF4 proteins involved in acute leukemia". Proc. Natl. Acad. Sci. U.S.A. 92 (26): 12160–4. doi:10.1073/pnas.92.26.12160. PMC 40316. PMID 8618864.; Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ (April 2001). "MLL and CREB Bind Cooperatively to the Nuclear Coactivator CREB-Binding Protein". Mol. Cell. Biol. 21 (7): 2249–58. doi:10.1128/MCB.21.7.2249-2258.2001. PMC 86859. PMID 11259575.
3. "Entrez Gene: KMT2A lysine (K)-specific methyltransferase 2A".
4. Yokoyama A, Kitabayashi I, Ayton PM, Cleary ML, Ohki M (Nov 2002). "Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties". Blood 100 (10): 3710–8. doi:10.1182/blood-2002-04-1015. PMID 12393701.
5. Mohan M, Herz HM, Shilatifard A (Apr 2012). "SnapShot: Histone lysine methylase complexes". Cell 149 (2): 498–498.e1. doi:10.1016/j.cell.2012.03.025. PMID 22500810.
6. Guenther MG, Jenner RG, Chevalier B, Nakamura T, Croce CM, Canaani E, Young RA (June 2005). "Global and Hox-specific roles for the MLL1 methyltransferase". Proc. Natl. Acad. Sci. U.S.A. 102 (24): 8603–8. doi:10.1073/pnas.0503072102. PMC 1150839. PMID 15941828.
7. Huang HS, Matevossian A, Whittle C, Kim SY, Schumacher A, Baker SP, Akbarian S (October 2007). "Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters". J. Neurosci. 27 (42): 11254–62. doi:10.1523/JNEUROSCI.3272-07.2007. PMID 17942719.
8. Andersson AK, Ma J, Wang J, Chen X, Gedman AL, Dang J, Nakitandwe J, Holmfeldt L, Parker M, Easton J, Huether R, Kriwacki R, Rusch M, Wu G, Li Y, Mulder H, Raimondi S, Pounds S, Kang G, Shi L, Becksfort J, Gupta P, Payne-Turner D, Vadodaria B, Boggs K, Yergeau D, Manne J, Song G, Edmonson M, Nagahawatte P, Wei L, Cheng C, Pei D, Sutton R, Venn NC, Chetcuti A, Rush A, Catchpoole D, Heldrup J, Fioretos T, Lu C, Ding L, Pui CH, Shurtleff S, Mullighan CG, Mardis ER, Wilson RK, Gruber TA, Zhang J, Downing JR (2015). "The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias". Nat. Genet. 47: 330–7. doi:10.1038/ng.3230. PMID 25730765. Lay summary – SciGuru Science News.
9. Mendelsohn BA, Pronold M, Long R, Smaoui N, Slavotinek AM (2014). "Advanced bone age in a girl with Wiedemann-Steiner syndrome and an exonic deletion in KMT2A (MLL)". American Journal of Medical Genetics Part A 164 (8): n/a. doi:10.1002/ajmg.a.36590. PMID 24818805.
10. Yokoyama A, Wang Z, Wysocka J, Sanyal M, Aufiero DJ, Kitabayashi I, Herr W, Cleary ML (July 2004). "Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression". Mol. Cell. Biol. 24 (13): 5639–49. doi:10.1128/MCB.24.13.5639-5649.2004. PMC 480881. PMID 15199122.
11. Goto NK, Zor T, Martinez-Yamout M, Dyson HJ, Wright PE (November 2002). "Cooperativity in transcription factor binding to the coactivator CREB-binding protein (CBP). The mixed lineage leukemia protein (MLL) activation domain binds to an allosteric site on the KIX domain". J. Biol. Chem. 277 (45): 43168–74. doi:10.1074/jbc.M207660200. PMID 12205094.
12. Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ (April 2001). "MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein". Mol. Cell. Biol. 21 (7): 2249–58. doi:10.1128/MCB.21.7.2249-2258.2001. PMC 86859. PMID 11259575.
13. Xia ZB, Anderson M, Diaz MO, Zeleznik-Le NJ (July 2003). "MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein". Proc. Natl. Acad. Sci. U.S.A. 100 (14): 8342–7. doi:10.1073/pnas.1436338100. PMC 166231. PMID 12829790.
14. Fair K, Anderson M, Bulanova E, Mi H, Tropschug M, Diaz MO (May 2001). "Protein interactions of the MLL PHD fingers modulate MLL target gene regulation in human cells". Mol. Cell. Biol. 21 (10): 3589–97. doi:10.1128/MCB.21.10.3589-3597.2001. PMC 100280. PMID 11313484.
15. Adler HT, Chinery R, Wu DY, Kussick SJ, Payne JM, Fornace AJ, Tkachuk DC (October 1999). "Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins". Mol. Cell. Biol. 19 (10): 7050–60. PMC 84700. PMID 10490642.

Further reading

• Marschalek R, Nilson I, Löchner K, Greim R, Siegler G, Greil J, Beck JD, Fey GH (1998). "The structure of the human ALL-1/MLL/HRX gene". Leuk. Lymphoma 27 (5–6): 417–28. doi:10.3109/10428199709058308. PMID 9477123.
• Eguchi M, Eguchi-Ishimae M, Greaves M (2004). "The role of the MLL gene in infant leukemia". Int. J. Hematol. 78 (5): 390–401. doi:10.1007/BF02983811. PMID 14704031.
• Daser A, Rabbitts TH (2004). "Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis". Genes Dev. 18 (9): 965–74. doi:10.1101/gad.1195504. PMID 15132992.
• Li ZY, Liu DP, Liang CC (2005). "New insight into the molecular mechanisms of MLL-associated leukemia". Leukemia 19 (2): 183–90. doi:10.1038/sj.leu.2403602. PMID 15618964.
• Douet-Guilbert N, Morel F, Le Bris MJ, Sassolas B, Giroux JD, De Braekeleer M (2005). "Rearrangement of MLL in a patient with congenital acute monoblastic leukemia and granulocytic sarcoma associated with a t(1;11)(p36;q23) translocation". Leuk. Lymphoma 46 (1): 143–6. doi:10.1080/104281904000010783. PMID 15621793.

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