Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCZMG61)

• DOT Name: Transcription factor ETV6 (ETV6)
• Synonyms: ETS translocation variant 6; ETS-related protein Tel1; Tel
• Gene Name: ETV6
• Related Disease:
  T-cell leukaemia
  Thrombocytopenia 5
  Acute leukaemia
  Acute myelogenous leukaemia
  Ataxia-telangiectasia
  B-cell acute lymphoblastic leukaemia
  Breast carcinoma
  Carcinoma
  Chronic fatigue syndrome
  Chronic myelomonocytic leukemia
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Drug dependence
  Fibrosarcoma
  Haematological malignancy
  Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
  Juvenile idiopathic arthritis
  Lymphoid leukemia
  Myelodysplastic syndrome
  Myeloproliferative neoplasm
  Small lymphocytic lymphoma
  Substance abuse
  Substance dependence
  T-cell acute lymphoblastic leukaemia
  Thrombocytopenia
  Thyroid gland papillary carcinoma
  Acinar cell carcinoma
  Burkitt lymphoma
  Chronic myelomonocytic leukaemia
  Myeloid leukaemia
  Hereditary thrombocytopenia and hematologic cancer predisposition syndrome
  Breast cancer
  Breast neoplasm
  Childhood myelodysplastic syndrome
  Chromosomal disorder
• UniProt ID: ETV6_HUMAN
• PDB ID: 1JI7; 1LKY; 2DAO; 2QAR; 2QB0; 2QB1; 5L0P; 7JU2; 7N1O; 7N2B; 7T8J; 7TDY; 7TW7; 7TW8; 7TW9; 7U4W; 7U4Z; 8BWU; 8E1F; 8FRJ; 8FRK; 8FT6; 8FT8; 8FZ3; 8FZU; 8FZV; 8THA
• Pfam ID: PF00178 ; PF02198
• Sequence:
  MSETPAQCSIKQERISYTPPESPVPSYASSTPLHVPVPRALRMEEDSIRLPAHLRLQPIY
  WSRDDVAQWLKWAENEFSLRPIDSNTFEMNGKALLLLTKEDFRYRSPHSGDVLYELLQHI
  LKQRKPRILFSPFFHPGNSIHTQPEVILHQNHEEDNCVQRTPRPSVDNVHHNPPTIELLH
  RSRSPITTNHRPSPDPEQRPLRSPLDNMIRRLSPAERAQGPRPHQENNHQESYPLSVSPM
  ENNHCPASSESHPKPSSPRQESTRVIQLMPSPIMHPLILNPRHSVDFKQSRLSEDGLHRE
  GKPINLSHREDLAYMNHIMVSVSPPEEHAMPIGRIADCRLLWDYVYQLLSDSRYENFIRW
  EDKESKIFRIVDPNGLARLWGNHKNRTNMTYEKMSRALRHYYKLNIIRKEPGQRLLFRFM
  KTPDEIMSGRTDRLEHLESQELDEQIYQEDEC
• Function: Transcriptional repressor; binds to the DNA sequence 5'-CCGGAAGT-3'. Plays a role in hematopoiesis and malignant transformation.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Signaling by FLT3 fusion proteins (R-HSA-9703465)
  Signaling by membrane-tethered fusions of PDGFRA or PDGFRB (R-HSA-9673768)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
T-cell leukaemia	DISJ6YIF	Definitive	Genetic Variation	[1]
Thrombocytopenia 5	DISLM3IY	Definitive	Autosomal dominant	[2]
Acute leukaemia	DISDQFDI	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Autosomal dominant	[4]
Ataxia-telangiectasia	DISP3EVR	Strong	Genetic Variation	[5]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Genetic Variation	[6]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[7]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[8]
Chronic fatigue syndrome	DIS34WJ5	Strong	Genetic Variation	[9]
Chronic myelomonocytic leukemia	DISIL8UR	Strong	Genetic Variation	[10]
Colon cancer	DISVC52G	Strong	Genetic Variation	[11]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[11]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[11]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[11]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[11]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[11]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[11]
Drug dependence	DIS9IXRC	Strong	Biomarker	[12]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[13]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[14]
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	DIS7XO1W	Strong	GermlineCausalMutation	[15]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[16]
Lymphoid leukemia	DIS65TYQ	Strong	Genetic Variation	[17]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[18]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Biomarker	[19]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[20]
Substance abuse	DIS327VW	Strong	Biomarker	[12]
Substance dependence	DISDRAAR	Strong	Biomarker	[12]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Genetic Variation	[21]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[22]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Genetic Variation	[23]
Acinar cell carcinoma	DIS37Y0J	moderate	Biomarker	[24]
Burkitt lymphoma	DIS9D5XU	moderate	FusionGene	[25]
Chronic myelomonocytic leukaemia	DISDN5P7	moderate	Genetic Variation	[10]
Myeloid leukaemia	DISMN944	moderate	Biomarker	[26]
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	DIS1HP20	Supportive	Autosomal dominant	[15]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[27]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[28]
Childhood myelodysplastic syndrome	DISMN80I	Limited	Biomarker	[29]
Chromosomal disorder	DISM5BB5	Limited	Genetic Variation	[29]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Transcription factor ETV6 (ETV6) increases the response to substance of Doxorubicin.	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription factor ETV6 (ETV6).	[30]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcription factor ETV6 (ETV6).	[31]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcription factor ETV6 (ETV6).	[32]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcription factor ETV6 (ETV6).	[33]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transcription factor ETV6 (ETV6).	[34]
Etoposide	DMNH3PG	Approved	Etoposide increases the mutagenesis of Transcription factor ETV6 (ETV6).	[35]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Transcription factor ETV6 (ETV6).	[36]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Transcription factor ETV6 (ETV6).	[35]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the mutagenesis of Transcription factor ETV6 (ETV6).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Transcription factor ETV6 (ETV6).	[37]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcription factor ETV6 (ETV6).	[38]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transcription factor ETV6 (ETV6).	[41]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Transcription factor ETV6 (ETV6).	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transcription factor ETV6 (ETV6).	[39]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transcription factor ETV6 (ETV6).	[40]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transcription factor ETV6 (ETV6).	[40]

References

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• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Structural basis of allosteric regulation of Tel1/ATM kinase.Cell Res. 2019 Aug;29(8):655-665. doi: 10.1038/s41422-019-0176-1. Epub 2019 May 16.
• [6] ETV6-RUNX1 interacts with a region in SPIB intron 1 to regulate gene expression in pre-B-cell acute lymphoblastic leukemia.Exp Hematol. 2019 May;73:50-63.e2. doi: 10.1016/j.exphem.2019.03.004. Epub 2019 Apr 12.
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• [8] Immunohistochemistry with a pan-TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma.Histopathology. 2019 Jul;75(1):54-62. doi: 10.1111/his.13845. Epub 2019 May 16.
• [9] Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors.Am J Surg Pathol. 2000 Jul;24(7):937-46. doi: 10.1097/00000478-200007000-00005.
• [10] Chronic myelomonocytic leukemia with ETV6-ABL1 rearrangement and SMC1A mutation.Cancer Genet. 2019 Oct;238:31-36. doi: 10.1016/j.cancergen.2019.07.004. Epub 2019 Jul 13.
• [11] Common genetic variation in ETV6 is associated with colorectal cancer susceptibility.Nat Commun. 2016 May 5;7:11478. doi: 10.1038/ncomms11478.
• [12] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [13] Recurrent BCOR internal tandem duplication and BCOR or BCL6 expression distinguish primitive myxoid mesenchymal tumor of infancy from congenital infantile fibrosarcoma.Mod Pathol. 2017 Jun;30(6):884-891. doi: 10.1038/modpathol.2017.12. Epub 2017 Mar 3.
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• [16] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [17] Minimal residual disease monitoring in childhood B lymphoblastic leukemia with t(12;21)(p13;q22); ETV6-RUNX1: concordant results using quantitation of fusion transcript and flow cytometry.Int J Lab Hematol. 2017 Apr;39(2):121-128. doi: 10.1111/ijlh.12593. Epub 2016 Dec 22.
• [18] Hereditary myeloid malignancies.Best Pract Res Clin Haematol. 2019 Jun;32(2):163-176. doi: 10.1016/j.beha.2019.05.001. Epub 2019 May 3.
• [19] Myeloproliferative neoplasm with ABL1/ETV6 rearrangement mimics chronic myeloid leukemia and responds to tyrosine kinase inhibitors.Cancer Genet. 2018 Dec;228-229:41-46. doi: 10.1016/j.cancergen.2018.08.002. Epub 2018 Aug 27.
• [20] Molecular role of the PAX5-ETV6 oncoprotein in promoting B-cell acute lymphoblastic leukemia.EMBO J. 2017 Mar 15;36(6):718-735. doi: 10.15252/embj.201695495. Epub 2017 Feb 20.
• [21] Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia.Lancet Oncol. 2019 Mar;20(3):e142-e154. doi: 10.1016/S1470-2045(19)30031-2.
• [22] Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia.Int J Lab Hematol. 2019 May;41 Suppl 1:131-141. doi: 10.1111/ijlh.12999.
• [23] Sporadic pediatric papillary thyroid carcinoma harboring the ETV6/NTRK3 fusion oncogene in a 7-year-old Japanese girl: a case report and review of literature.J Pediatr Endocrinol Metab. 2018 Mar 28;31(4):461-467. doi: 10.1515/jpem-2017-0292.
• [24] The screening and electron microscopy observation of mammary analogue secretory carcinoma in Chinese.J Craniomaxillofac Surg. 2018 Jun;46(6):893-897. doi: 10.1016/j.jcms.2017.10.007. Epub 2017 Oct 19.
• [25] Simultaneous occurrence of ETV6-RUNX1 and BCR-ABL1 (e1a2) transcripts in a child with B-cell acute lymphoblastic leukemia.Cancer Genet. 2013 Mar;206(3):97-101. doi: 10.1016/j.cancergen.2013.01.004. Epub 2013 Mar 13.
• [26] Microdeletion del(22)(q12.2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature.BMC Med Genet. 2012 Mar 22;13:19. doi: 10.1186/1471-2350-13-19.
• [27] Is acinic cell carcinoma a variant of secretory carcinoma? A FISH study using ETV6'split apart' probes.Histopathology. 2008 Jun;52(7):840-6. doi: 10.1111/j.1365-2559.2008.03046.x. Epub 2008 May 6.
• [28] Chromatin-informed inference of transcriptional programs in gynecologic and basal breast cancers.Nat Commun. 2019 Sep 25;10(1):4369. doi: 10.1038/s41467-019-12291-6.
• [29] Myeloid neoplasms with t(12;22)(p13;q12)/MN1-EVT6: a systematic review of 12 cases.Ann Hematol. 2018 Mar;97(3):417-424. doi: 10.1007/s00277-017-3208-2. Epub 2017 Dec 22.
• [30] 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.
• [31] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [32] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [33] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [34] 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.
• [35] "Exposure to the insecticides permethrin and malathion induces leukemia and lymphoma-associated gene aberrations in vitro". Toxicol In Vitro. 2017 Oct;44:17-26. doi: 10.1016/j.tiv.2017.06.013. Epub 2017 Jun 15.
• [36] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [37] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [38] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [39] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [40] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
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• [42] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [43] Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia. Blood. 2004 Oct 15;104(8):2452-7. doi: 10.1182/blood-2003-12-4426. Epub 2004 Jun 24.