Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO4YKYI)

• DOT Name: Transcription factor Spi-B (SPIB)
• Gene Name: SPIB
• Related Disease:
  Autoimmune disease
  B-cell lymphoma
  Acute erythroid leukemia
  Adult lymphoma
  B-cell acute lymphoblastic leukaemia
  Classic Hodgkin lymphoma
  Hereditary leiomyomatosis and renal cell cancer
  leukaemia
  Leukemia
  Lymphoma
  Mantle cell lymphoma
  Mast cell leukaemia
  Neoplasm
  Pediatric lymphoma
  Primary biliary cholangitis
  Progressive multifocal leukoencephalopathy
  T-cell lymphoma
  Gingivitis
  Periodontitis
  Breast carcinoma
  Waldenstrom macroglobulinemia
• UniProt ID: SPIB_HUMAN
• Pfam ID: PF00178
• Sequence:
  MLALEAAQLDGPHFSCLYPDGVFYDLDSCKHSSYPDSEGAPDSLWDWTVAPPVPATPYEA
  FDPAAAAFSHPQAAQLCYEPPTYSPAGNLELAPSLEAPGPGLPAYPTENFASQTLVPPAY
  APYPSPVLSEEEDLPLDSPALEVSDSESDEALVAGPEGKGSEAGTRKKLRLYQFLLGLLT
  RGDMRECVWWVEPGAGVFQFSSKHKELLARRWGQQKGNRKRMTYQKLARALRNYAKTGEI
  RKVKRKLTYQFDSALLPAVRRA
• Function: Sequence specific transcriptional activator which binds to the PU-box, a purine-rich DNA sequence (5'-GAGGAA-3') that can act as a lymphoid-specific enhancer. Promotes development of plasmacytoid dendritic cells (pDCs), also known as type 2 DC precursors (pre-DC2) or natural interferon (IFN)-producing cells. These cells have the capacity to produce large amounts of interferon and block viral replication. May be required for B-cell receptor (BCR) signaling, which is necessary for normal B-cell development and antigenic stimulation.
• Tissue Specificity: Expressed in plasmacytoid dendritic cells (pDCs) and B-cells, not expressed in T-cells or granulocytes. May also be enriched in stem cell populations of the liver.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Definitive	Genetic Variation	[1]
B-cell lymphoma	DISIH1YQ	Definitive	Altered Expression	[2]
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[3]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[4]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Genetic Variation	[5]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[6]
Hereditary leiomyomatosis and renal cell cancer	DISN22G2	Strong	Altered Expression	[7]
leukaemia	DISS7D1V	Strong	Altered Expression	[5]
Leukemia	DISNAKFL	Strong	Altered Expression	[5]
Lymphoma	DISN6V4S	Strong	Altered Expression	[4]
Mantle cell lymphoma	DISFREOV	Strong	Altered Expression	[7]
Mast cell leukaemia	DIS7VQW9	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[4]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[9]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Altered Expression	[10]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[11]
Gingivitis	DISC8RMX	moderate	Altered Expression	[12]
Periodontitis	DISI9JOI	moderate	Altered Expression	[12]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[13]
Waldenstrom macroglobulinemia	DIS9O23I	Limited	Altered Expression	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Transcription factor Spi-B (SPIB) decreases the response to substance of Arsenic.	[22]

2 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 Spi-B (SPIB).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transcription factor Spi-B (SPIB).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transcription factor Spi-B (SPIB).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transcription factor Spi-B (SPIB).	[17]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Transcription factor Spi-B (SPIB).	[18]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Transcription factor Spi-B (SPIB).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Transcription factor Spi-B (SPIB).	[21]

References

• [1] Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes.Genes Immun. 2012 Jun;13(4):328-35. doi: 10.1038/gene.2011.89. Epub 2012 Jan 19.
• [2] 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.
• [3] Cell specific expression of human Bruton's agammaglobulinemia tyrosine kinase gene (Btk) is regulated by Sp1- and Spi-1/PU.1-family members.Oncogene. 1996 Nov 7;13(9):1955-64.
• [4] SPIB is a novel prognostic factor in diffuse large B-cell lymphoma that mediates apoptosis via the PI3K-AKT pathway.Cancer Sci. 2016 Sep;107(9):1270-80. doi: 10.1111/cas.13001. Epub 2016 Sep 6.
• [5] 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.
• [6] Aberrant expression of homeobox gene SIX1 in Hodgkin lymphoma.Oncotarget. 2015 Nov 24;6(37):40112-26. doi: 10.18632/oncotarget.5556.
• [7] Bortezomib prevents cytarabine resistance in MCL, which is characterized by down-regulation of dCK and up-regulation of SPIB resulting in high NF-B activity.BMC Cancer. 2018 Apr 25;18(1):466. doi: 10.1186/s12885-018-4346-1.
• [8] Spi-B-Mediated Silencing of Claudin-2 Promotes Early Dissemination of Lung Cancer Cells from Primary Tumors.Cancer Res. 2017 Sep 15;77(18):4809-4822. doi: 10.1158/0008-5472.CAN-17-0020. Epub 2017 Jul 28.
• [9] International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.Nat Commun. 2015 Sep 22;6:8019. doi: 10.1038/ncomms9019.
• [10] Lymphocyte gene expression and JC virus noncoding control region sequences are linked with the risk of progressive multifocal leukoencephalopathy.J Virol. 2014 May;88(9):5177-83. doi: 10.1128/JVI.03221-13. Epub 2014 Feb 19.
• [11] SPIB, a novel immunohistochemical marker for human blastic plasmacytoid dendritic cell neoplasms: characterization of its expression in major hematolymphoid neoplasms.Blood. 2013 Jan 24;121(4):643-7. doi: 10.1182/blood-2012-08-447599. Epub 2012 Nov 19.
• [12] Increased levels of the T-helper 22-associated cytokine (interleukin-22) and transcription factor (aryl hydrocarbon receptor) in patients with periodontitis are associated with osteoclast resorptive activity and severity of the disease.J Periodontal Res. 2017 Oct;52(5):893-902. doi: 10.1111/jre.12461. Epub 2017 Apr 10.
• [13] Comprehensive genome-wide transcription factor analysis reveals that a combination of high affinity and low affinity DNA binding is needed for human gene regulation.BMC Genomics. 2015;16 Suppl 7(Suppl 7):S12. doi: 10.1186/1471-2164-16-S7-S12. Epub 2015 Jun 11.
• [14] Transcriptional repression of plasma cell differentiation is orchestrated by aberrant over-expression of the ETS factor SPIB in Waldenstrm macroglobulinaemia.Br J Haematol. 2014 Sep;166(5):677-89. doi: 10.1111/bjh.12936. Epub 2014 May 7.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] 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.
• [19] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [20] 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.
• [21] Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell. 2013 Dec 9;24(6):777-90. doi: 10.1016/j.ccr.2013.11.003.
• [22] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.