Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9HB9H8)

• DOT Name: Zinc finger protein Gfi-1 (GFI1)
• Synonyms: Growth factor independent protein 1; Zinc finger protein 163
• Gene Name: GFI1
• Related Disease:
  Acute myelogenous leukaemia
  Adult lymphoma
  Advanced cancer
  Attention deficit hyperactivity disorder
  Autoimmune disease
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Digestive system neuroendocrine tumor, grade 1/2
  leukaemia
  Leukemia
  Lung cancer
  Lung carcinoma
  Lymphoma
  Matthew-Wood syndrome
  Medulloblastoma
  Multiple sclerosis
  Neutropenia, severe congenital, 2, autosomal dominant
  Obesity
  Osteoporosis
  Pediatric lymphoma
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Small-cell lung cancer
  Systemic lupus erythematosus
  Childhood myelodysplastic syndrome
  Severe congenital neutropenia
  Autosomal dominant severe congenital neutropenia
  Acute lymphocytic leukaemia
  Cardiomyopathy
  Childhood acute lymphoblastic leukemia
  Acute monocytic leukemia
  Autosomal dominant cerebellar ataxia type II
  Colorectal carcinoma
  Lymphoid leukemia
  Myelodysplastic syndrome
  Prostate neoplasm
  Spinocerebellar ataxia type 1
  Spinocerebellar ataxia type 2
  Spinocerebellar ataxia type 5
  Spinocerebellar ataxia type 6
• UniProt ID: GFI1_HUMAN
• Pfam ID: PF00096
• Sequence:
  MPRSFLVKSKKAHSYHQPRSPGPDYSLRLENVPAPSRADSTSNAGGAKAEPRDRLSPESQ
  LTEAPDRASASPDSCEGSVCERSSEFEDFWRPPSPSASPASEKSMCPSLDEAQPFPLPFK
  PYSWSGLAGSDLRHLVQSYRPCGALERGAGLGLFCEPAPEPGHPAALYGPKRAAGGAGAG
  APGSCSAGAGATAGPGLGLYGDFGSAAAGLYERPTAAAGLLYPERGHGLHADKGAGVKVE
  SELLCTRLLLGGGSYKCIKCSKVFSTPHGLEVHVRRSHSGTRPFACEMCGKTFGHAVSLE
  QHKAVHSQERSFDCKICGKSFKRSSTLSTHLLIHSDTRPYPCQYCGKRFHQKSDMKKHTF
  IHTGEKPHKCQVCGKAFSQSSNLITHSRKHTGFKPFGCDLCGKGFQRKVDLRRHRETQHG
  LK
• Function: Transcription repressor essential for hematopoiesis. Functions in a cell-context and development-specific manner. Binds to 5'-TAAATCAC[AT]GCA-3' in the promoter region of a large number of genes. Component of several complexes, including the EHMT2-GFI1-HDAC1, AJUBA-GFI1-HDAC1 and RCOR-GFI-KDM1A-HDAC complexes, that suppress, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Regulates neutrophil differentiation, promotes proliferation of lymphoid cells, and is required for granulocyte development. Inhibits SPI1 transcriptional activity at macrophage-specific genes, repressing macrophage differentiation of myeloid progenitor cells and promoting granulocyte commitment. Mediates, together with U2AF1L4, the alternative splicing of CD45 and controls T-cell receptor signaling. Regulates the endotoxin-mediated Toll-like receptor (TLR) inflammatory response by antagonizing RELA. Cooperates with CBFA2T2 to regulate ITGB1-dependent neurite growth. Controls cell-cycle progression by repressing CDKNIA/p21 transcription in response to TGFB1 via recruitment of GFI1 by ZBTB17 to the CDKNIA/p21 and CDKNIB promoters. Required for the maintenance of inner ear hair cells.
• Reactome Pathway: Transcriptional regulation of granulopoiesis (R-HSA-9616222)

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[7]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[7]
Digestive system neuroendocrine tumor, grade 1/2	DISDR98B	Strong	Biomarker	[8]
leukaemia	DISS7D1V	Strong	Biomarker	[9]
Leukemia	DISNAKFL	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[6]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[10]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[11]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[12]
Neutropenia, severe congenital, 2, autosomal dominant	DISIHLPK	Strong	Autosomal dominant	[13]
Obesity	DIS47Y1K	Strong	Altered Expression	[14]
Osteoporosis	DISF2JE0	Strong	Biomarker	[15]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[16]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[3]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[6]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[5]
Childhood myelodysplastic syndrome	DISMN80I	moderate	Genetic Variation	[1]
Severe congenital neutropenia	DISES99N	Moderate	Autosomal dominant	[17]
Autosomal dominant severe congenital neutropenia	DISZC7BV	Supportive	Autosomal dominant	[13]
Acute lymphocytic leukaemia	DISPX75S	Disputed	Biomarker	[18]
Cardiomyopathy	DISUPZRG	Disputed	Biomarker	[19]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Disputed	Biomarker	[18]
Acute monocytic leukemia	DIS28NEL	Limited	Biomarker	[20]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Limited	Biomarker	[21]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[3]
Lymphoid leukemia	DIS65TYQ	Limited	Altered Expression	[22]
Myelodysplastic syndrome	DISYHNUI	Limited	Genetic Variation	[1]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[23]
Spinocerebellar ataxia type 1	DISF7BO2	Limited	Biomarker	[21]
Spinocerebellar ataxia type 2	DISF7WDI	Limited	Biomarker	[21]
Spinocerebellar ataxia type 5	DISPYXJ0	Limited	Biomarker	[21]
Spinocerebellar ataxia type 6	DISH7224	Limited	Biomarker	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Zinc finger protein Gfi-1 (GFI1).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Zinc finger protein Gfi-1 (GFI1).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Zinc finger protein Gfi-1 (GFI1).	[26]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Zinc finger protein Gfi-1 (GFI1).	[27]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Zinc finger protein Gfi-1 (GFI1).	[29]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Zinc finger protein Gfi-1 (GFI1).	[30]
Pomalidomide	DMTGBAX	Approved	Pomalidomide increases the expression of Zinc finger protein Gfi-1 (GFI1).	[31]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Zinc finger protein Gfi-1 (GFI1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Zinc finger protein Gfi-1 (GFI1).	[33]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Zinc finger protein Gfi-1 (GFI1).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Zinc finger protein Gfi-1 (GFI1).	[28]
Cotinine	DMCEZ1B	Approved	Cotinine affects the methylation of Zinc finger protein Gfi-1 (GFI1).	[32]

References

• [1] LSD1-mediated repression of GFI1 super-enhancer plays an essential role in erythroleukemia.Leukemia. 2020 Mar;34(3):746-758. doi: 10.1038/s41375-019-0614-6. Epub 2019 Nov 1.
• [2] From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation.Blood. 2015 Dec 10;126(24):2561-9. doi: 10.1182/blood-2015-06-655043. Epub 2015 Oct 7.
• [3] Growth Factor-Independent 1 Is a Tumor Suppressor Gene in Colorectal Cancer.Mol Cancer Res. 2019 Mar;17(3):697-708. doi: 10.1158/1541-7786.MCR-18-0666. Epub 2019 Jan 3.
• [4] Locus-specific DNA methylation changes and phenotypic variability in children with attention-deficit hyperactivity disorder.Psychiatry Res. 2017 Oct;256:298-304. doi: 10.1016/j.psychres.2017.06.048. Epub 2017 Jun 20.
• [5] The transcriptional repressor Gfi1 prevents lupus autoimmunity by restraining TLR7 signaling.Eur J Immunol. 2016 Dec;46(12):2801-2811. doi: 10.1002/eji.201646573. Epub 2016 Oct 4.
• [6] Growth factor independence-1 is expressed in primary human neuroendocrine lung carcinomas and mediates the differentiation of murine pulmonary neuroendocrine cells.Cancer Res. 2004 Oct 1;64(19):6874-82. doi: 10.1158/0008-5472.CAN-04-0633.
• [7] Gfi-1 promotes proliferation of human cervical carcinoma via targeting of FBW7 ubiquitin ligase expression.Cancer Manag Res. 2018 Aug 23;10:2849-2857. doi: 10.2147/CMAR.S161130. eCollection 2018.
• [8] A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.Nat Genet. 2018 Jul;50(7):979-989. doi: 10.1038/s41588-018-0138-4. Epub 2018 Jun 18.
• [9] Reduced expression but not deficiency of GFI1 causes a fatal myeloproliferative disease in mice.Leukemia. 2019 Jan;33(1):110-121. doi: 10.1038/s41375-018-0166-1. Epub 2018 Jun 20.
• [10] Simvastatin attenuates macrophage-mediated gemcitabine resistance of pancreatic ductal adenocarcinoma by regulating the TGF-1/Gfi-1 axis.Cancer Lett. 2017 Jan 28;385:65-74. doi: 10.1016/j.canlet.2016.11.006. Epub 2016 Nov 11.
• [11] Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma.Nat Commun. 2019 Jan 18;10(1):332. doi: 10.1038/s41467-018-08269-5.
• [12] Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.Sci Adv. 2016 Jun 17;2(6):e1501678. doi: 10.1126/sciadv.1501678. eCollection 2016 Jun.
• [13] Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat Genet. 2003 Jul;34(3):308-12. doi: 10.1038/ng1170.
• [14] Obesity alters the long-term fitness of the hematopoietic stem cell compartment through modulation of Gfi1 expression.J Exp Med. 2018 Feb 5;215(2):627-644. doi: 10.1084/jem.20170690. Epub 2017 Dec 27.
• [15] Loss of murine Gfi1 causes neutropenia and induces osteoporosis depending on the pathogen load and systemic inflammation.PLoS One. 2018 Jun 7;13(6):e0198510. doi: 10.1371/journal.pone.0198510. eCollection 2018.
• [16] Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis.J Hematol Oncol. 2018 Oct 4;11(1):123. doi: 10.1186/s13045-018-0666-5.
• [17] Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nat Genet. 2002 Mar;30(3):295-300. doi: 10.1038/ng831. Epub 2002 Jan 28.
• [18] Growth factor independence 1 antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia.Cancer Cell. 2013 Feb 11;23(2):200-14. doi: 10.1016/j.ccr.2013.01.011.
• [19] GFI-1 Protects Against Lipopolysaccharide-Induced Inflammatory Responses and Apoptosis by Inhibition of the NF-B/TNF- Pathway in H9c2 Cells.Inflammation. 2020 Feb;43(1):74-84. doi: 10.1007/s10753-019-01095-x.
• [20] LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML.Leukemia. 2019 Jun;33(6):1411-1426. doi: 10.1038/s41375-018-0375-7. Epub 2019 Jan 24.
• [21] The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins.Cell. 2005 Aug 26;122(4):633-44. doi: 10.1016/j.cell.2005.06.012.
• [22] GFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1.Nat Commun. 2018 Apr 12;9(1):1418. doi: 10.1038/s41467-018-03817-5.
• [23] Role of oncoprotein growth factor independent-1 (GFI1) in repression of 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1): a comparative analysis in human prostate cancer and kidney cells. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):742-6.
• [24] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [25] Diminished proteasomal degradation results in accumulation of Gfi1 protein in monocytes. Blood. 2007 Jan 1;109(1):100-8. doi: 10.1182/blood-2006-02-003590. Epub 2006 Aug 3.
• [26] 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.
• [27] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [28] 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.
• [29] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [30] Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol. 2011 Aug 15;187(4):1778-87. doi: 10.4049/jimmunol.1003919. Epub 2011 Jul 18.
• [31] Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis. Blood. 2005 May 15;105(10):3833-40. doi: 10.1182/blood-2004-03-0828. Epub 2004 Aug 3.
• [32] 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environ Health Perspect. 2012 Oct;120(10):1425-31. doi: 10.1289/ehp.1205412. Epub 2012 Jul 31.
• [33] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [34] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.