Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVCA1D0)

• DOT Name: Transcription factor PU.1 (SPI1)
• Synonyms: 31 kDa-transforming protein
• Gene Name: SPI1
• Related Disease:
  Alzheimer disease
  B-cell neoplasm
  Classic Hodgkin lymphoma
  Acute erythroid leukemia
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Acute undifferentiated leukemia
  Agammaglobulinemia 10, autosomal dominant
  Alcohol use disorder
  Anxiety
  Arteriosclerosis
  Atherosclerosis
  B-cell lymphoma
  Enterocolitis
  Gastroenteritis
  Glioma
  leukaemia
  Leukemia
  Obesity
  Osteoporosis
  Promyelocytic leukaemia
  Salmonella infection
  Systemic lupus erythematosus
  T-cell acute lymphoblastic leukaemia
  Urinary tract infection
  Wilms tumor
  Myeloid leukaemia
  Waldenstrom macroglobulinemia
• UniProt ID: SPI1_HUMAN
• PDB ID: 8E3K; 8E3R; 8E4H; 8E5Y; 8EBH; 8EE9; 8EJ6; 8EJ8; 8EK3; 8EK8; 8EKJ; 8EKU; 8EKV; 8EKZ; 8EM9; 8EMD; 8ENG; 8EO1; 8EO4; 8EQG; 8EQK; 8EQL; 8T9U
• Pfam ID: PF00178
• Sequence:
  MLQACKMEGFPLVPPPSEDLVPYDTDLYQRQTHEYYPYLSSDGESHSDHYWDFHPHHVHS
  EFESFAENNFTELQSVQPPQLQQLYRHMELEQMHVLDTPMVPPHPSLGHQVSYLPRMCLQ
  YPSLSPAQPSSDEEEGERQSPPLEVSDGEADGLEPGPGLLPGETGSKKKIRLYQFLLDLL
  RSGDMKDSIWWVDKDKGTFQFSSKHKEALAHRWGIQKGNRKKMTYQKMARALRNYGKTGE
  VKKVKKKLTYQFSGEVLGRGGLAERRHPPH
• Function: Pioneer transcription factor, which controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing other transcription factors to enter otherwise inaccessible genomic sites. Once in open chromatin, can directly control gene expression by binding genetic regulatory elements and can also more broadly influence transcription by recruiting transcription factors, such as interferon regulatory factors (IRFs), to otherwise inaccessible genomic regions. Transcriptionally activates genes important for myeloid and lymphoid lineages, such as CSF1R. Transcriptional activation from certain promoters, possibly containing low affinity binding sites, is achieved cooperatively with other transcription factors. FCER1A transactivation is achieved in cooperation with GATA1. May be particularly important for the pro- to pre-B cell transition. Binds (via the ETS domain) onto the purine-rich DNA core sequence 5'-GAGGAA-3', also known as the PU-box. In vitro can bind RNA and interfere with pre-mRNA splicing.
• Tissue Specificity: In the bone marrow, concentrated in hematopoietic stem cell, lymphoid progenitor, myeloid lineage (granulocyte macrophage progenitors, classical dendritic cells, monocytes) and B-cell clusters. Among B-cells, predominantly expressed in pre-B1 cells . Expressed in germinal center B-cells .
• KEGG Pathway:
  Osteoclast differentiation (hsa04380)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Acute myeloid leukemia (hsa05221)
• Reactome Pathway:
  Transcriptional regulation of granulopoiesis (R-HSA-9616222)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Definitive	Biomarker	[1]
B-cell neoplasm	DISVY326	Definitive	Biomarker	[2]
Classic Hodgkin lymphoma	DISV1LU6	Definitive	Altered Expression	[3]
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[4]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[5]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[6]
Acute undifferentiated leukemia	DISJ4SSG	Strong	Biomarker	[7]
Agammaglobulinemia 10, autosomal dominant	DISCFY2M	Strong	Autosomal dominant	[8]
Alcohol use disorder	DISMB65Y	Strong	Therapeutic	[9]
Anxiety	DISIJDBA	Strong	Genetic Variation	[10]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[11]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[11]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[12]
Enterocolitis	DISYACTL	Strong	Biomarker	[13]
Gastroenteritis	DISXQCG5	Strong	Biomarker	[13]
Glioma	DIS5RPEH	Strong	Biomarker	[14]
leukaemia	DISS7D1V	Strong	Altered Expression	[15]
Leukemia	DISNAKFL	Strong	Altered Expression	[15]
Obesity	DIS47Y1K	Strong	Biomarker	[16]
Osteoporosis	DISF2JE0	Strong	Biomarker	[16]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[17]
Salmonella infection	DISTJ434	Strong	Biomarker	[18]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[19]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[20]
Urinary tract infection	DISMT6UV	Strong	Biomarker	[21]
Wilms tumor	DISB6T16	Strong	Biomarker	[22]
Myeloid leukaemia	DISMN944	Limited	Altered Expression	[23]
Waldenstrom macroglobulinemia	DIS9O23I	Limited	Altered Expression	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transcription factor PU.1 (SPI1).	[25]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the methylation of Transcription factor PU.1 (SPI1).	[28]
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Transcription factor PU.1 (SPI1).	[30]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the phosphorylation of Transcription factor PU.1 (SPI1).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription factor PU.1 (SPI1).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transcription factor PU.1 (SPI1).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transcription factor PU.1 (SPI1).	[27]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Transcription factor PU.1 (SPI1).	[29]
Pomalidomide	DMTGBAX	Approved	Pomalidomide increases the expression of Transcription factor PU.1 (SPI1).	[32]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the activity of Transcription factor PU.1 (SPI1).	[33]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transcription factor PU.1 (SPI1).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transcription factor PU.1 (SPI1).	[36]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Transcription factor PU.1 (SPI1).	[37]

References

• [1] Genetic risk for Alzheimer's disease is concentrated in specific macrophage and microglial transcriptional networks.Genome Med. 2018 Feb 26;10(1):14. doi: 10.1186/s13073-018-0523-8.
• [2] Leukocyte-specific phosphoprotein-1 and PU.1: two useful markers for distinguishing T-cell-rich B-cell lymphoma from lymphocyte-predominant Hodgkin's disease.Haematologica. 2004 Aug;89(8):957-64.
• [3] Alterations of loci encoding PU.1, BOB1, and OCT2 transcription regulators do not correlate with their suppressed expression in Hodgkin lymphoma.Cancer Genet Cytogenet. 2005 Apr 15;158(2):167-71. doi: 10.1016/j.cancergencyto.2004.09.005.
• [4] Senescence is a Spi1-induced anti-proliferative mechanism in primary hematopoietic cells.Haematologica. 2017 Nov;102(11):1850-1860. doi: 10.3324/haematol.2016.157636. Epub 2017 Sep 14.
• [5] CREBBP mutations in relapsed acute lymphoblastic leukaemia.Nature. 2011 Mar 10;471(7337):235-9. doi: 10.1038/nature09727.
• [6] The clinical and prognostic significance of FIS1, SPI1, PDCD7 and Ang2 expression levels in acute myeloid leukemia.Cancer Genet. 2019 Apr;233-234:84-95. doi: 10.1016/j.cancergen.2018.12.001. Epub 2018 Dec 7.
• [7] T-ALL leukemia stem cell 'stemness' is epigenetically controlled by the master regulator SPI1.Elife. 2018 Nov 9;7:e38314. doi: 10.7554/eLife.38314.
• [8] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [9] Zinc supplementation restores PU.1 and Nrf2 nuclear binding in alveolar macrophages and improves redox balance and bacterial clearance in the lungs of alcohol-fed rats.Alcohol Clin Exp Res. 2011 Aug;35(8):1519-28. doi: 10.1111/j.1530-0277.2011.01488.x. Epub 2011 Mar 29.
• [10] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [11] Identification of key transcription factors associated with cerebral ischemiareperfusion injury based on geneset enrichment analysis.Int J Mol Med. 2019 Jun;43(6):2429-2439. doi: 10.3892/ijmm.2019.4159. Epub 2019 Apr 9.
• [12] The ETS Inhibitors YK-4-279 and TK-216 Are Novel Antilymphoma Agents.Clin Cancer Res. 2019 Aug 15;25(16):5167-5176. doi: 10.1158/1078-0432.CCR-18-2718. Epub 2019 Jun 10.
• [13] Salmonella enterica serovar Senftenberg human clinical isolates lacking SPI-1.J Clin Microbiol. 2008 Apr;46(4):1330-6. doi: 10.1128/JCM.01255-07. Epub 2008 Feb 13.
• [14] Transcription factor PU.1 is involved in the progression of glioma.Oncol Lett. 2018 Mar;15(3):3753-3759. doi: 10.3892/ol.2018.7766. Epub 2018 Jan 10.
• [15] The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia.Oncotarget. 2017 Jun 6;8(23):37104-37114. doi: 10.18632/oncotarget.16183.
• [16] Transcription Factor Co-expression Networks of Adipose RNA-Seq Data Reveal Regulatory Mechanisms of Obesity.Curr Genomics. 2018 May;19(4):289-299. doi: 10.2174/1389202918666171005095059.
• [17] ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression.Blood. 2006 Apr 15;107(8):3330-8. doi: 10.1182/blood-2005-07-3068. Epub 2005 Dec 13.
• [18] S. Enteritidis and S. Typhimurium Harboring SPI-1 and SPI-2 Are the Predominant Serotypes Associated With Human Salmonellosis in Saudi Arabia.Front Cell Infect Microbiol. 2019 May 31;9:187. doi: 10.3389/fcimb.2019.00187. eCollection 2019.
• [19] Association of a functional polymorphism in the 3'-untranslated region of SPI1 with systemic lupus erythematosus.Arthritis Rheum. 2011 Mar;63(3):755-63. doi: 10.1002/art.30188.
• [20] Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia.Nat Genet. 2017 Aug;49(8):1274-1281. doi: 10.1038/ng.3900. Epub 2017 Jul 3.
• [21] The Escherichia coli Type III Secretion System 2 Has a Global Effect on Cell Surface.mBio. 2018 Jul 3;9(4):e01070-18. doi: 10.1128/mBio.01070-18.
• [22] The Trop-2 signalling network in cancer growth.Oncogene. 2013 Mar 21;32(12):1594-600. doi: 10.1038/onc.2012.151. Epub 2012 May 7.
• [23] Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia.Blood. 2011 Oct 27;118(17):4674-81. doi: 10.1182/blood-2011-04-351528. Epub 2011 Aug 30.
• [24] A Recurrent Activating Missense Mutation in Waldenstrm Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation.Cancer Discov. 2019 Jun;9(6):796-811. doi: 10.1158/2159-8290.CD-18-0873. Epub 2019 Apr 24.
• [25] 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.
• [26] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. Oncotarget. 2015 Aug 28;6(25):21493-506. doi: 10.18632/oncotarget.4085.
• [29] 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.
• [30] Down-regulation of PU.1 by methylation of distal regulatory elements and the promoter is required for myeloma cell growth. Cancer Res. 2007 Jun 1;67(11):5328-36. doi: 10.1158/0008-5472.CAN-06-4265.
• [31] PU.1 phosphorylation correlates with hydroquinone-induced alterations in myeloid differentiation and cytokine-dependent clonogenic response in human CD34(+) hematopoietic progenitor cells. Cell Biol Toxicol. 2006 Jul;22(4):229-41. doi: 10.1007/s10565-006-0128-7. Epub 2006 Apr 26.
• [32] 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.
• [33] Selective activation of NF-kappaB and E2F by low concentration of arsenite in U937 human monocytic leukemia cells. J Biochem Mol Toxicol. 2008 Mar-Apr;22(2):136-46. doi: 10.1002/jbt.20222.
• [34] 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.
• [35] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [36] Bisphenol A significantly enhances the neutrophilic differentiation of promyelocytic HL-60 cells. Int Immunopharmacol. 2003 Nov;3(12):1601-8. doi: 10.1016/S1567-5769(03)00182-6.
• [37] Toxicity of nickel ions and comprehensive analysis of nickel ion-associated gene expression profiles in THP-1 cells. Mol Med Rep. 2015 Sep;12(3):3273-3278. doi: 10.3892/mmr.2015.3878. Epub 2015 Jun 3.