Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTURMDV7)

• DOT Name: Protein AF-10 (MLLT10)
• Synonyms: ALL1-fused gene from chromosome 10 protein
• Gene Name: MLLT10
• Related Disease:
  Acute leukaemia
  Acute lymphocytic leukaemia
  Acute megakaryoblastic leukemia
  Advanced cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Glioma
  Intracranial meningioma
  Melanoma
  Mixed phenotype acute leukemia
  Monocytic leukemia
  Papillary renal cell carcinoma
  Renal cell carcinoma
  T-cell acute lymphoblastic leukaemia
  Lymphoma
  Meningioma
  Neoplasm
  Myeloid leukaemia
  Acute monocytic leukemia
  Childhood acute lymphoblastic leukemia
  Chromosomal disorder
  Metastatic malignant neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Ovarian serous adenocarcinoma
• UniProt ID: AF10_HUMAN
• PDB ID: 5DAG; 5DAH; 6CKN; 6CKO; 6JN2; 7MJU
• Pfam ID: PF13831 ; PF13832
• Sequence:
  MVSSDRPVSLEDEVSHSMKEMIGGCCVCSDERGWAENPLVYCDGHGCSVAVHQACYGIVQ
  VPTGPWFCRKCESQERAARVRCELCPHKDGALKRTDNGGWAHVVCALYIPEVQFANVSTM
  EPIVLQSVPHDRYNKTCYICDEQGRESKAATGACMTCNKHGCRQAFHVTCAQFAGLLCEE
  EGNGADNVQYCGYCKYHFSKLKKSKRGSNRSYDQSLSDSSSHSQDKHHEKEKKKYKEKDK
  HKQKHKKQPEPSPALVPSLTVTTEKTYTSTSNNSISGSLKRLEDTTARFTNANFQEVSAH
  TSSGKDVSETRGSEGKGKKSSAHSSGQRGRKPGGGRNPGTTVSAASPFPQGSFSGTPGSV
  KSSSGSSVQSPQDFLSFTDSDLRNDSYSHSQQSSATKDVHKGESGSQEGGVNSFSTLIGL
  PSTSAVTSQPKSFENSPGDLGNSSLPTAGYKRAQTSGIEEETVKEKKRKGNKQSKHGPGR
  PKGNKNQENVSHLSVSSASPTSSVASAAGSITSSSLQKSPTLLRNGSLQSLSVGSSPVGS
  EISMQYRHDGACPTTTFSELLNAIHNGIYNSNDVAVSFPNVVSGSGSSTPVSSSHLPQQS
  SGHLQQVGALSPSAVSSAAPAVATTQANTLSGSSLSQAPSHMYGNRSNSSMAALIAQSEN
  NQTDQDLGDNSRNLVGRGSSPRGSLSPRSPVSSLQIRYDQPGNSSLENLPPVAASIEQLL
  ERQWSEGQQFLLEQGTPSDILGMLKSLHQLQVENRRLEEQIKNLTAKKERLQLLNAQLSV
  PFPTITANPSPSHQIHTFSAQTAPTTDSLNSSKSPHIGNSFLPDNSLPVLNQDLTSSGQS
  TSSSSALSTPPPAGQSPAQQGSGVSGVQQVNGVTVGALASGMQPVTSTIPAVSAVGGIIG
  ALPGNQLAINGIVGALNGVMQTPVTMSQNPTPLTHTTVPPNATHPMPATLTNSASGLGLL
  SDQQRQILIHQQQFQQLLNSQQLTPEQHQAFLYQLMQHHHQQHHQPELQQLQIPGPTQIP
  INNLLAGTQAPPLHTATTNPFLTIHGDNASQKVARLSDKTGPVAQEKS
• Function: Probably involved in transcriptional regulation. In vitro or as fusion protein with KMT2A/MLL1 has transactivation activity. Binds to cruciform DNA. In cells, binding to unmodified histone H3 regulates DOT1L functions including histone H3 'Lys-79' dimethylation (H3K79me2) and gene activation.
• Tissue Specificity: Expressed abundantly in testis.

Molecular Interaction Atlas (MIA) of This DOT

26 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]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Genetic Variation	[7]
Intracranial meningioma	DISD09EF	Strong	Biomarker	[8]
Melanoma	DIS1RRCY	Strong	Biomarker	[9]
Mixed phenotype acute leukemia	DISNCHV9	Strong	Biomarker	[10]
Monocytic leukemia	DIS8M755	Strong	Biomarker	[11]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[6]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[10]
Lymphoma	DISN6V4S	moderate	Genetic Variation	[12]
Meningioma	DISPT4TG	moderate	Genetic Variation	[7]
Neoplasm	DISZKGEW	moderate	Biomarker	[13]
Myeloid leukaemia	DISMN944	Disputed	Biomarker	[14]
Acute monocytic leukemia	DIS28NEL	Limited	Genetic Variation	[15]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Genetic Variation	[16]
Chromosomal disorder	DISM5BB5	Limited	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[13]
Ovarian cancer	DISZJHAP	Limited	Genetic Variation	[18]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[19]
Ovarian serous adenocarcinoma	DISSU72Z	Limited	Genetic Variation	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein AF-10 (MLLT10).	[20]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein AF-10 (MLLT10).	[24]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein AF-10 (MLLT10).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein AF-10 (MLLT10).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein AF-10 (MLLT10).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein AF-10 (MLLT10).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein AF-10 (MLLT10).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein AF-10 (MLLT10).	[26]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein AF-10 (MLLT10).	[27]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Protein AF-10 (MLLT10).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein AF-10 (MLLT10).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein AF-10 (MLLT10).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein AF-10 (MLLT10).	[32]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein AF-10 (MLLT10).	[33]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Protein AF-10 (MLLT10).	[34]

References

• [1] Acute leukemias harboring KMT2A/MLLT10 fusion: a 10-year experience from a single genomics laboratory.Genes Chromosomes Cancer. 2019 Aug;58(8):567-577. doi: 10.1002/gcc.22741. Epub 2019 Mar 19.
• [2] Successful Treatment of a Very Late Isolated Relapse in an Adolescent With a PICALM-MLLT10 Positive T-lineage Acute Lymphoblastic Leukemia.J Pediatr Hematol Oncol. 2018 Apr;40(3):e191-e194. doi: 10.1097/MPH.0000000000000996.
• [3] MLL-MLLT10 fusion gene in pediatric acute megakaryoblastic leukemia.Leuk Res. 2005 Oct;29(10):1223-6. doi: 10.1016/j.leukres.2005.03.008. Epub 2005 Apr 11.
• [4] Novel Lysine-Based Thioureas as Mechanism-Based Inhibitors of Sirtuin 2 (SIRT2) with Anticancer Activity in a Colorectal Cancer Murine Model. J Med Chem. 2019 Apr 25; 62(8):4131-4141.
• [5] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [6] Integrated molecular analysis of clear-cell renal cell carcinoma.Nat Genet. 2013 Aug;45(8):860-7. doi: 10.1038/ng.2699. Epub 2013 Jun 24.
• [7] Brain tumor risk according to germ-line variation in the MLLT10 locus.Eur J Hum Genet. 2015 Jan;23(1):132-4. doi: 10.1038/ejhg.2014.70. Epub 2014 Apr 23.
• [8] Common variation at 10p12.31 near MLLT10 influences meningioma risk.Nat Genet. 2011 Jul 31;43(9):825-7. doi: 10.1038/ng.879.
• [9] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [10] CCAAT/enhancer-binding protein alpha (CEBPA) gene haploinsufficiency does not alter hematopoiesis or induce leukemia in Lck-CALM/AF10 transgenic mice.Braz J Med Biol Res. 2019;52(6):e8424. doi: 10.1590/1414-431X20198424. Epub 2019 May 27.
• [11] Cooperation of MLL/AF10(OM-LZ) with PTPN11 activating mutation induced monocytic leukemia with a shorter latency in a mouse bone marrow transplantation model.Int J Cancer. 2017 Mar 1;140(5):1159-1172. doi: 10.1002/ijc.30515. Epub 2016 Nov 25.
• [12] CALM/AF10-positive leukemias show upregulation of genes involved in chromatin assembly and DNA repair processes and of genes adjacent to the breakpoint at 10p12.Leukemia. 2012 May;26(5):1012-9. doi: 10.1038/leu.2011.307. Epub 2011 Nov 8.
• [13] MLLT10 promotes tumor migration, invasion, and metastasis in human colorectal cancer.Scand J Gastroenterol. 2018 Aug;53(8):964-971. doi: 10.1080/00365521.2018.1481521. Epub 2018 Aug 13.
• [14] CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRgammadelta lineage.Blood. 2003 Aug 1;102(3):1000-6. doi: 10.1182/blood-2002-09-2913. Epub 2003 Apr 3.
• [15] PICALM-MLLT10 acute myeloid leukemia: a French cohort of 18 patients.Leuk Res. 2012 Nov;36(11):1365-9. doi: 10.1016/j.leukres.2012.07.008. Epub 2012 Aug 5.
• [16] Acute leukemia with PICALM-MLLT10 fusion gene: diagnostic and treatment struggle.Cancer Genet Cytogenet. 2010 Oct 15;202(2):129-32. doi: 10.1016/j.cancergencyto.2010.07.126.
• [17] Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias.Blood. 2009 Jul 16;114(3):651-8. doi: 10.1182/blood-2009-03-209395. Epub 2009 May 14.
• [18] GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.Nat Genet. 2013 Apr;45(4):362-70, 370e1-2. doi: 10.1038/ng.2564.
• [19] Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.Nat Genet. 2017 May;49(5):680-691. doi: 10.1038/ng.3826. Epub 2017 Mar 27.
• [20] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [21] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [22] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [23] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [24] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [25] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [26] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [27] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [28] 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.
• [29] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [30] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [31] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [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.
• [33] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [34] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.