Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXH4DDG)

• DOT Name: Protein AF-9 (MLLT3)
• Synonyms: ALL1-fused gene from chromosome 9 protein; Myeloid/lymphoid or mixed-lineage leukemia translocated to chromosome 3 protein; YEATS domain-containing protein 3
• Gene Name: MLLT3
• Related Disease:
  Acute leukaemia
  Acute lymphocytic leukaemia
  Acute megakaryoblastic leukemia
  Adult acute monocytic leukemia
  Alzheimer disease
  Bipolar disorder
  Childhood acute lymphoblastic leukemia
  Chromosomal disorder
  Chronic inflammatory demyelinating polyneuropathy
  Epilepsy
  leukaemia
  Leukemia
  Myelodysplastic syndrome
  Neoplasm
  Oral cavity squamous cell carcinoma
  Schizophrenia
  Advanced cancer
  Diabetic kidney disease
  Endolymphatic hydrops
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Asthma
  Nasopharyngeal carcinoma
• UniProt ID: AF9_HUMAN
• PDB ID: 2LM0; 2MV7; 2N4Q; 2NDF; 2NDG; 4TMP; 5HJB; 5HJD; 5YYF; 6B7G; 6L5Z; 6LS6; 6MIL; 6MIM; 7EIC; 7EID; 7VKG; 7VKH; 8PJ7
• Pfam ID: PF17793 ; PF03366
• Sequence:
  MASSCAVQVKLELGHRAQVRKKPTVEGFTHDWMVFVRGPEHSNIQHFVEKVVFHLHESFP
  RPKRVCKDPPYKVEESGYAGFILPIEVYFKNKEEPRKVRFDYDLFLHLEGHPPVNHLRCE
  KLTFNNPTEDFRRKLLKAGGDPNRSIHTSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSS
  SSSSSSSSSSTSFSKPHKLMKEHKEKPSKDSREHKSAFKEPSRDHNKSSKESSKKPKENK
  PLKEEKIVPKMAFKEPKPMSKEPKPDSNLLTITSGQDKKAPSKRPPISDSEELSAKKRKK
  SSSEALFKSFSSAPPLILTCSADKKQIKDKSHVKMGKVKIESETSEKKKSTLPPFDDIVD
  PNDSDVEENISSKSDSEQPSPASSSSSSSSSFTPSQTRQQGPLRSIMKDLHSDDNEEESD
  EVEDNDNDSEMERPVNRGGSRSRRVSLSDGSDSESSSASSPLHHEPPPPLLKTNNNQILE
  VKSPIKQSKSDKQIKNGECDKAYLDELVELHRRLMTLRERHILQQIVNLIEETGHFHITN
  TTFDFDLCSLDKTTVRKLQSYLETSGTS
• Function: Chromatin reader component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. Specifically recognizes and binds acylated histone H3, with a preference for histone H3 that is crotonylated. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. Recognizes and binds histone H3 crotonylated at 'Lys-9' (H3K9cr), and with slightly lower affinity histone H3 crotonylated at 'Lys-18' (H3K18cr). Also recognizes and binds histone H3 acetylated and butyrylated at 'Lys-9' (H3K9ac and H3K9bu, respectively), but with lower affinity than crotonylated histone H3. In the SEC complex, MLLT3 is required to recruit the complex to crotonylated histones. Recruitment of the SEC complex to crotonylated histones promotes recruitment of DOT1L on active chromatin to deposit histone H3 'Lys-79' methylation (H3K79me). Plays a key role in hematopoietic stem cell (HSC) maintenance by preserving, rather than conferring, HSC stemness. Acts by binding to the transcription start site of active genes in HSCs and sustaining level of H3K79me2, probably by recruiting DOT1L.
• Tissue Specificity: Enriched in undifferentiated hematopoietic stem cells in fetal liver, cord blood and bone marrow.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[2]
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Genetic Variation	[3]
Adult acute monocytic leukemia	DISG6BLX	Strong	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[6]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[7]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[8]
Chronic inflammatory demyelinating polyneuropathy	DISNGBLD	Strong	Biomarker	[9]
Epilepsy	DISBB28L	Strong	Genetic Variation	[10]
leukaemia	DISS7D1V	Strong	Biomarker	[11]
Leukemia	DISNAKFL	Strong	Genetic Variation	[11]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[13]
Oral cavity squamous cell carcinoma	DISQVJVA	Strong	Altered Expression	[13]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
Diabetic kidney disease	DISJMWEY	Disputed	Therapeutic	[14]
Endolymphatic hydrops	DISUPJBC	Disputed	Biomarker	[15]
Acute monocytic leukemia	DIS28NEL	Limited	Altered Expression	[16]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[17]
Asthma	DISW9QNS	Limited	Genetic Variation	[18]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Genetic Variation	[19]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein AF-9 (MLLT3).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein AF-9 (MLLT3).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein AF-9 (MLLT3).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein AF-9 (MLLT3).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein AF-9 (MLLT3).	[24]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Protein AF-9 (MLLT3).	[25]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein AF-9 (MLLT3).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein AF-9 (MLLT3).	[27]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Protein AF-9 (MLLT3).	[28]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein AF-9 (MLLT3).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein AF-9 (MLLT3).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein AF-9 (MLLT3).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein AF-9 (MLLT3).	[32]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein AF-9 (MLLT3).	[31]

References

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• [2] Bile acids at neutral and acidic pH induce apoptosis and gene cleavages in nasopharyngeal epithelial cells: implications in chromosome rearrangement.BMC Cancer. 2018 Apr 12;18(1):409. doi: 10.1186/s12885-018-4327-4.
• [3] Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study.Blood. 2015 Sep 24;126(13):1575-84. doi: 10.1182/blood-2015-02-629204. Epub 2015 Jul 27.
• [4] MLLT3 gene on 9p22 involved in t(9;11) leukemia encodes a serine/proline rich protein homologous to MLLT1 on 19p13.Oncogene. 1993 Nov;8(11):3085-92.
• [5] Genotype-based association test for general pedigrees: the genotype-PDT.Genet Epidemiol. 2003 Nov;25(3):203-13. doi: 10.1002/gepi.10258.
• [6] Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder.Neuropathol Appl Neurobiol. 2011 Feb;37(2):206-19. doi: 10.1111/j.1365-2990.2010.01128.x.
• [7] Molecular studies reveal a MLL-MLLT3 gene fusion displaced in a case of childhood acute lymphoblastic leukemia with complex karyotype.Cancer Genet. 2015 Apr;208(4):143-7. doi: 10.1016/j.cancergen.2015.02.002. Epub 2015 Feb 19.
• [8] Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs.Proc Natl Acad Sci U S A. 1993 May 15;90(10):4631-5. doi: 10.1073/pnas.90.10.4631.
• [9] Differential gene expression in chronic inflammatory demyelinating polyneuropathy (CIDP) skin biopsies.J Neurol Sci. 2010 Mar 15;290(1-2):115-22. doi: 10.1016/j.jns.2009.10.006. Epub 2009 Nov 17.
• [10] Loss-of-function mutation of the AF9/MLLT3 gene in a girl with neuromotor development delay, cerebellar ataxia, and epilepsy.Hum Genet. 2005 Oct;118(1):76-81. doi: 10.1007/s00439-005-0004-1. Epub 2005 Oct 28.
• [11] De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.Nat Commun. 2018 May 2;9(1):1770. doi: 10.1038/s41467-018-04180-1.
• [12] MicroRNA?43 increases cell apoptosis in myelodysplastic syndrome through the Fas/FasL pathway both invitro and invivo.Int J Oncol. 2018 Nov;53(5):2191-2199. doi: 10.3892/ijo.2018.4534. Epub 2018 Aug 22.
• [13] Characterization of Copy Number Variations in Oral Cavity Squamous Cell Carcinoma Reveals a Novel Role for MLLT3 in Cell Invasiveness.Oncologist. 2019 Dec;24(12):e1388-e1400. doi: 10.1634/theoncologist.2019-0063. Epub 2019 Jul 4.
• [14] Spironolactone rescues Dot1a-Af9-mediated repression of endothelin-1 and improves kidney injury in streptozotocin-induced diabetic rats.PLoS One. 2012;7(10):e47360. doi: 10.1371/journal.pone.0047360. Epub 2012 Oct 15.
• [15] Effect of aldosterone on cochlear Af9 expression and hearing in guinea pig.Acta Otolaryngol. 2017 Sep;137(9):903-909. doi: 10.1080/00016489.2017.1309681. Epub 2017 Apr 11.
• [16] C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation.Leukemia. 2018 Mar;32(3):828-836. doi: 10.1038/leu.2017.280. Epub 2017 Sep 5.
• [17] Integrated transcriptomic and epigenetic data analysis identifiesaberrant expression of genes in acute myeloid leukemia with MLLAF9 translocation.Mol Med Rep. 2020 Feb;21(2):883-893. doi: 10.3892/mmr.2019.10849. Epub 2019 Nov 26.
• [18] Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma.PLoS One. 2015 Jun 17;10(6):e0129385. doi: 10.1371/journal.pone.0129385. eCollection 2015.
• [19] Matrix association region/scaffold attachment region: the crucial player in defining the positions of chromosome breaks mediated by bile acid-induced apoptosis in nasopharyngeal epithelial cells.BMC Med Genomics. 2019 Jan 15;12(1):9. doi: 10.1186/s12920-018-0465-4.
• [20] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [21] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [22] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [23] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [24] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [25] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [26] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [27] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [28] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [29] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [30] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [31] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [32] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.