Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0EV3LX)

• DOT Name: Friend leukemia integration 1 transcription factor (FLI1)
• Synonyms: Proto-oncogene Fli-1; Transcription factor ERGB
• Gene Name: FLI1
• Related Disease:
  Medulloblastoma
  Acute erythroid leukemia
  Acute myelogenous leukaemia
  Bleeding disorder, platelet-type, 21
  Carcinoma
  Desmoplastic small round cell tumor
  leukaemia
  Leukemia
  Lymphoma
  Melanoma
  Nephritis
  Nephropathy
  Neuroblastoma
  Osteosarcoma
  Pancreatic tumour
  Primitive neuroectodermal tumor
  Prostate cancer
  Prostate carcinoma
  Sarcoma
  Small-cell lung cancer
  Systemic sclerosis
  Vitiligo
  Cutaneous leishmaniasis
  Essential thrombocythemia
  Mucocutaneous leishmaniasis
  Ewing sarcoma/peripheral primitive neuroectodermal tumor
  Autoimmune disease
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Lupus
  Malignant soft tissue neoplasm
  Metastatic malignant neoplasm
  Scleroderma
  Stomach cancer
  Systemic lupus erythematosus
  Vascular disease
• UniProt ID: FLI1_HUMAN
• PDB ID: 1FLI; 1X66; 2YTU; 5E8G; 5E8I; 5JVT; 6VG2; 6VG8; 6VGD
• Pfam ID: PF00178 ; PF02198
• Sequence:
  MDGTIKEALSVVSDDQSLFDSAYGAAAHLPKADMTASGSPDYGQPHKINPLPPQQEWINQ
  PVRVNVKREYDHMNGSRESPVDCSVSKCSKLVGGGESNPMNYNSYMDEKNGPPPPNMTTN
  ERRVIVPADPTLWTQEHVRQWLEWAIKEYSLMEIDTSFFQNMDGKELCKMNKEDFLRATT
  LYNTEVLLSHLSYLRESSLLAYNTTSHTDQSSRLSVKEDPSYDSVRRGAWGNNMNSGLNK
  SPPLGGAQTISKNTEQRPQPDPYQILGPTSSRLANPGSGQIQLWQFLLELLSDSANASCI
  TWEGTNGEFKMTDPDEVARRWGERKSKPNMNYDKLSRALRYYYDKNIMTKVHGKRYAYKF
  DFHGIAQALQPHPTESSMYKYPSDISYMPSYHAHQQKVNFVPPHPSSMPVTSSSFFGAAS
  QYWTSPTGGIYPNPNVPRHPNTHVPSHLGSYY
• Function: Sequence-specific transcriptional activator. Recognizes the DNA sequence 5'-C[CA]GGAAGT-3'.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway: Transcriptional regulation of granulopoiesis (R-HSA-9616222)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Medulloblastoma	DISZD2ZL	Definitive	Biomarker	[1]
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Bleeding disorder, platelet-type, 21	DIS68DB5	Strong	Autosomal dominant	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Desmoplastic small round cell tumor	DISLI2ME	Strong	Genetic Variation	[6]
leukaemia	DISS7D1V	Strong	Genetic Variation	[7]
Leukemia	DISNAKFL	Strong	Altered Expression	[8]
Lymphoma	DISN6V4S	Strong	Biomarker	[9]
Melanoma	DIS1RRCY	Strong	Altered Expression	[10]
Nephritis	DISQZQ70	Strong	Altered Expression	[11]
Nephropathy	DISXWP4P	Strong	Biomarker	[11]
Neuroblastoma	DISVZBI4	Strong	Genetic Variation	[12]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[13]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[14]
Primitive neuroectodermal tumor	DISFHXHA	Strong	Altered Expression	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Sarcoma	DISZDG3U	Strong	Biomarker	[17]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[18]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[19]
Vitiligo	DISR05SL	Strong	Genetic Variation	[20]
Cutaneous leishmaniasis	DISRK7TS	moderate	Altered Expression	[21]
Essential thrombocythemia	DISWWK11	moderate	Biomarker	[22]
Mucocutaneous leishmaniasis	DISQEME2	moderate	Altered Expression	[21]
Ewing sarcoma/peripheral primitive neuroectodermal tumor	DISD4VQC	Disputed	Biomarker	[23]
Autoimmune disease	DISORMTM	Limited	Biomarker	[24]
Brain neoplasm	DISY3EKS	Limited	Altered Expression	[25]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[26]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[26]
Gastric cancer	DISXGOUK	Limited	Biomarker	[27]
Lupus	DISOKJWA	Limited	Biomarker	[28]
Malignant soft tissue neoplasm	DISTC6NO	Limited	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[26]
Scleroderma	DISVQ342	Limited	Biomarker	[24]
Stomach cancer	DISKIJSX	Limited	Biomarker	[27]
Systemic lupus erythematosus	DISI1SZ7	Limited	Altered Expression	[28]
Vascular disease	DISVS67S	Limited	Biomarker	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Friend leukemia integration 1 transcription factor (FLI1) affects the response to substance of Vinblastine.	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Friend leukemia integration 1 transcription factor (FLI1).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Friend leukemia integration 1 transcription factor (FLI1).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Friend leukemia integration 1 transcription factor (FLI1).	[33]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Friend leukemia integration 1 transcription factor (FLI1).	[34]
Romidepsin	DMT5GNL	Approved	Romidepsin decreases the expression of Friend leukemia integration 1 transcription factor (FLI1).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Friend leukemia integration 1 transcription factor (FLI1).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Friend leukemia integration 1 transcription factor (FLI1).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Friend leukemia integration 1 transcription factor (FLI1).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Friend leukemia integration 1 transcription factor (FLI1).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Friend leukemia integration 1 transcription factor (FLI1).	[38]

References

• [1] Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma.Nat Genet. 2009 Apr;41(4):465-72. doi: 10.1038/ng.336. Epub 2009 Mar 8.
• [2] A novel synthesized 3', 5'-diprenylated chalcone mediates the proliferation of human leukemia cells by regulating apoptosis and autophagy pathways.Biomed Pharmacother. 2018 Oct;106:794-804. doi: 10.1016/j.biopha.2018.06.153. Epub 2018 Jul 11.
• [3] BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia.Mol Cell. 2015 Jun 18;58(6):1028-39. doi: 10.1016/j.molcel.2015.04.011. Epub 2015 May 14.
• [4] Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia. Immunity. 2000 Aug;13(2):167-77. doi: 10.1016/s1074-7613(00)00017-0.
• [5] IMP3 as a prognostic biomarker in patients with malignant peritoneal mesothelioma.Hum Pathol. 2018 Nov;81:138-147. doi: 10.1016/j.humpath.2018.07.003. Epub 2018 Jul 18.
• [6] Generation of conditional oncogenic chromosomal translocations using CRISPR-Cas9 genomic editing and homology-directed repair.J Pathol. 2017 May;242(1):102-112. doi: 10.1002/path.4883. Epub 2017 Mar 30.
• [7] The poor prognosis of the primary gastric epithelioid angiosarcoma: A case report.Medicine (Baltimore). 2018 Apr;97(15):e0287. doi: 10.1097/MD.0000000000010287.
• [8] Fli-1 promotes proliferation and upregulates NANOGP8 expression in T-lymphocyte leukemia cells.Biochimie. 2020 Jan;168:1-9. doi: 10.1016/j.biochi.2019.10.005. Epub 2019 Oct 15.
• [9] Novel flavagline-like compounds with potent Fli-1 inhibitory activity suppress diverse types of leukemia.FEBS J. 2018 Dec;285(24):4631-4645. doi: 10.1111/febs.14690. Epub 2018 Nov 20.
• [10] Identifying FL11 subtype by characterizing tumor immune microenvironment in prostate adenocarcinoma via Chou's 5-steps rule.Genomics. 2020 Mar;112(2):1500-1515. doi: 10.1016/j.ygeno.2019.08.021. Epub 2019 Aug 28.
• [11] FLI1 Levels Impact CXCR3 Expression and Renal Infiltration of T Cells and Renal Glycosphingolipid Metabolism in the MRL/lpr Lupus Mouse Strain.J Immunol. 2015 Dec 15;195(12):5551-60. doi: 10.4049/jimmunol.1500961. Epub 2015 Nov 4.
• [12] A rational approach to genetic testing for sarcoma.Diagn Mol Pathol. 2009 Mar;18(1):1-10. doi: 10.1097/PDM.0b013e318181fa05.
• [13] miR-145 promotes osteosarcoma growth by reducing expression of the transcription factor friend leukemia virus integration 1.Oncotarget. 2016 Jul 5;7(27):42241-42251. doi: 10.18632/oncotarget.9948.
• [14] BCL9L expression in pancreatic neoplasia with a focus on SPN: a possible explanation for the enigma of the benign neoplasia.BMC Cancer. 2016 Aug 18;16:648. doi: 10.1186/s12885-016-2707-1.
• [15] ZBTB16: A new biomarker for primitive neuroectodermal tumor element / Ewing sarcoma.Pathol Res Pract. 2019 Oct;215(10):152536. doi: 10.1016/j.prp.2019.152536. Epub 2019 Jul 13.
• [16] Locus-specific gene repositioning in prostate cancer.Mol Biol Cell. 2016 Jan 15;27(2):236-46. doi: 10.1091/mbc.E15-05-0280. Epub 2015 Nov 12.
• [17] FLI-1 distinguishes Ewing sarcoma from small cell osteosarcoma and mesenchymal chondrosarcoma.Appl Immunohistochem Mol Morphol. 2011 May;19(3):233-8. doi: 10.1097/PAI.0b013e3181fd6697.
• [18] FLI1 Exonic Circular RNAs as a Novel Oncogenic Driver to Promote Tumor Metastasis in Small Cell Lung Cancer.Clin Cancer Res. 2019 Feb 15;25(4):1302-1317. doi: 10.1158/1078-0432.CCR-18-1447. Epub 2018 Nov 14.
• [19] Increased expression of aquaporin-1 in dermal fibroblasts and dermal microvascular endothelial cells possibly contributes to skin fibrosis and edema in patients with systemic sclerosis.J Dermatol Sci. 2019 Jan;93(1):24-32. doi: 10.1016/j.jdermsci.2018.09.007. Epub 2018 Sep 21.
• [20] Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.Nat Genet. 2016 Nov;48(11):1418-1424. doi: 10.1038/ng.3680. Epub 2016 Oct 10.
• [21] Analysis of expression of FLI1 and MMP1 in American cutaneous leishmaniasis caused by Leishmania braziliensis infection.Infect Genet Evol. 2017 Apr;49:212-220. doi: 10.1016/j.meegid.2017.01.018. Epub 2017 Jan 21.
• [22] GATA-1: A potential novel biomarker for the differentiation of essential thrombocythemia and myelofibrosis.J Thromb Haemost. 2019 Jun;17(6):896-900. doi: 10.1111/jth.14433. Epub 2019 Apr 25.
• [23] Primitive Neuroectodermal Tumors of the Female Genital Tract: A Morphologic, Immunohistochemical, and Molecular Study of 19 Cases.Am J Surg Pathol. 2017 Jun;41(6):761-772. doi: 10.1097/PAS.0000000000000831.
• [24] Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma.J Exp Med. 2017 Apr 3;214(4):1129-1151. doi: 10.1084/jem.20160247. Epub 2017 Feb 23.
• [25] The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation.Int J Cancer. 2020 Jul 1;147(1):189-201. doi: 10.1002/ijc.32831. Epub 2020 Jan 7.
• [26] A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1.Genome Biol. 2018 Dec 11;19(1):218. doi: 10.1186/s13059-018-1594-y.
• [27] Analysis of the clinical significance of DNA methylation in gastric cancer based on a genome-wide high-resolution array.Clin Epigenetics. 2019 Nov 1;11(1):154. doi: 10.1186/s13148-019-0747-5.
• [28] Fli-1, a Functional Factor Performed in Autoimmune Lupus.Inflammation. 2016 Feb;39(1):493-498. doi: 10.1007/s10753-015-0257-3.
• [29] Cyclophosphamide Pulse Therapy Normalizes Vascular Abnormalities in a Mouse Model of Systemic Sclerosis Vasculopathy.J Invest Dermatol. 2019 May;139(5):1150-1160. doi: 10.1016/j.jid.2018.11.016. Epub 2018 Nov 30.
• [30] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [31] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [32] 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.
• [33] 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.
• [34] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [35] Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors. Int J Cancer. 2005 Sep 20;116(5):784-92. doi: 10.1002/ijc.21069.
• [36] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [37] 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.
• [38] 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.
• [39] 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.
• [40] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.