Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT17GS18)

• DOT Name: Transcription regulator protein BACH2 (BACH2)
• Synonyms: BTB and CNC homolog 2
• Gene Name: BACH2
• Related Disease:
  Non-insulin dependent diabetes
  Acute myelogenous leukaemia
  Autoimmune disease, susceptibility to, 6
  Autoimmune thyroid disease
  B-cell neoplasm
  Hashimoto thyroiditis
  Hypothyroidism
  Immunodeficiency 60
  leukaemia
  Leukemia
  Mantle cell lymphoma
  Multiple sclerosis
  Nasal polyp
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Rheumatoid arthritis
  STAT3-related early-onset multisystem autoimmune disease
  Ulcerative colitis
  Waldenstrom macroglobulinemia
  Allergic rhinitis
  Coeliac disease
  Immune system disorder
  Lymphoma
  Neuroblastoma
  Vitiligo
  Ankylosing spondylitis
  Asthma
  B-cell lymphoma
  Basal cell carcinoma
  Basal cell neoplasm
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Central nervous system non-hodgkin lymphoma
  Crohn disease
  Graves disease
  Inflammatory bowel disease
  Lymphoma, non-Hodgkin, familial
  Non-hodgkin lymphoma
  Psoriasis
  Sclerosing cholangitis
  Squamous cell carcinoma
  Type-1 diabetes
• UniProt ID: BACH2_HUMAN
• PDB ID: 3OHU; 3OHV
• Pfam ID: PF00651 ; PF03131
• Sequence:
  MSVDEKPDSPMYVYESTVHCTNILLGLNDQRKKDILCDVTLIVERKEFRAHRAVLAACSE
  YFWQALVGQTKNDLVVSLPEEVTARGFGPLLQFAYTAKLLLSRENIREVIRCAEFLRMHN
  LEDSCFSFLQTQLLNSEDGLFVCRKDAACQRPHEDCENSAGEEEDEEEETMDSETAKMAC
  PRDQMLPEPISFEAAAIPVAEKEEALLPEPDVPTDTKESSEKDALTQYPRYKKYQLACTK
  NVYNASSHSTSGFASTFREDNSSNSLKPGLARGQIKSEPPSEENEEESITLCLSGDEPDA
  KDRAGDVEMDRKQPSPAPTPTAPAGAACLERSRSVASPSCLRSLFSITKSVELSGLPSTS
  QQHFARSPACPFDKGITQGDLKTDYTPFTGNYGQPHVGQKEVSNFTMGSPLRGPGLEALC
  KQEGELDRRSVIFSSSACDQVSTSVHSYSGVSSLDKDLSEPVPKGLWVGAGQSLPSSQAY
  SHGGLMADHLPGRMRPNTSCPVPIKVCPRSPPLETRTRTSSSCSSYSYAEDGSGGSPCSL
  PLCEFSSSPCSQGARFLATEHQEPGLMGDGMYNQVRPQIKCEQSYGTNSSDESGSFSEAD
  SESCPVQDRGQEVKLPFPVDQITDLPRNDFQMMIKMHKLTSEQLEFIHDVRRRSKNRIAA
  QRCRKRKLDCIQNLECEIRKLVCEKEKLLSERNQLKACMGELLDNFSCLSQEVCRDIQSP
  EQIQALHRYCPVLRPMDLPTASSINPAPLGAEQNIAASQCAVGENVPCCLEPGAAPPGPP
  WAPSNTSENCTSGRRLEGTDPGTFSERGPPLEPRSQTVTVDFCQEMTDKCTTDEQPRKDY
  T
• Function: Transcriptional regulator that acts as a repressor or activator. Binds to Maf recognition elements (MARE). Plays an important role in coordinating transcription activation and repression by MAFK. Induces apoptosis in response to oxidative stress through repression of the antiapoptotic factor HMOX1. Positively regulates the nuclear import of actin. Is a key regulator of adaptive immunity, crucial for the maintenance of regulatory T-cell function and B-cell maturation.
• Tissue Specificity: B-cell specific.

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[3]
Autoimmune thyroid disease	DISIHC6A	Strong	Genetic Variation	[4]
B-cell neoplasm	DISVY326	Strong	Biomarker	[5]
Hashimoto thyroiditis	DIS77CDF	Strong	Genetic Variation	[4]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[3]
Immunodeficiency 60	DIS5EAGO	Strong	Autosomal dominant	[6]
leukaemia	DISS7D1V	Strong	Genetic Variation	[7]
Leukemia	DISNAKFL	Strong	Genetic Variation	[7]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[8]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[9]
Nasal polyp	DISLP3XE	Strong	Genetic Variation	[10]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[11]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[12]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[13]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[3]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[14]
Waldenstrom macroglobulinemia	DIS9O23I	Strong	Biomarker	[15]
Allergic rhinitis	DIS3U9HN	moderate	Genetic Variation	[16]
Coeliac disease	DISIY60C	moderate	Biomarker	[14]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[17]
Lymphoma	DISN6V4S	moderate	Altered Expression	[18]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[19]
Vitiligo	DISR05SL	moderate	Genetic Variation	[20]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[21]
Asthma	DISW9QNS	Limited	Genetic Variation	[22]
B-cell lymphoma	DISIH1YQ	Limited	Biomarker	[5]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[23]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[23]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Limited	Altered Expression	[24]
Central nervous system non-hodgkin lymphoma	DISHGM86	Limited	Genetic Variation	[25]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[26]
Graves disease	DISU4KOQ	Limited	Genetic Variation	[27]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[28]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Limited	Genetic Variation	[29]
Non-hodgkin lymphoma	DISS2Y8A	Limited	Genetic Variation	[29]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[21]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[21]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[23]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[30]

3 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 regulator protein BACH2 (BACH2).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transcription regulator protein BACH2 (BACH2).	[37]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transcription regulator protein BACH2 (BACH2).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transcription regulator protein BACH2 (BACH2).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription regulator protein BACH2 (BACH2).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcription regulator protein BACH2 (BACH2).	[34]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Transcription regulator protein BACH2 (BACH2).	[35]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription regulator protein BACH2 (BACH2).	[36]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcription regulator protein BACH2 (BACH2).	[39]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Transcription regulator protein BACH2 (BACH2).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Transcription regulator protein BACH2 (BACH2).	[41]

References

• [1] Prioritizing candidate disease genes by network-based boosting of genome-wide association data.Genome Res. 2011 Jul;21(7):1109-21. doi: 10.1101/gr.118992.110. Epub 2011 May 2.
• [2] Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice.Nat Genet. 2011 May;43(5):470-5. doi: 10.1038/ng.796. Epub 2011 Mar 27.
• [3] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [4] Seven newly identified loci for autoimmune thyroid disease.Hum Mol Genet. 2012 Dec 1;21(23):5202-8. doi: 10.1093/hmg/dds357. Epub 2012 Aug 24.
• [5] Frequent downregulation of BTB and CNC homology 2 expression in Epstein-Barr virus-positive diffuse large B-cell lymphoma.Cancer Sci. 2017 May;108(5):1071-1079. doi: 10.1111/cas.13213. Epub 2017 Apr 24.
• [6] BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat Immunol. 2017 Jul;18(7):813-823. doi: 10.1038/ni.3753. Epub 2017 May 22.
• [7] Identification of IGHC-BACH2 fusion transcripts resulting from cryptic chromosomal rearrangements of 14q32 with 6q15 in aggressive B-cell lymphoma/leukemia.Genes Chromosomes Cancer. 2011 Apr;50(4):207-16. doi: 10.1002/gcc.20845. Epub 2011 Jan 13.
• [8] Bifurcated BACH2 control coordinates mantle cell lymphoma survival and dispersal during hypoxia.Blood. 2017 Aug 10;130(6):763-776. doi: 10.1182/blood-2017-02-767293. Epub 2017 Jun 7.
• [9] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [10] A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis.Nat Genet. 2019 Feb;51(2):267-276. doi: 10.1038/s41588-018-0314-6. Epub 2019 Jan 14.
• [11] Differentially androgen-modulated genes in ovarian epithelial cells from BRCA mutation carriers and control patients predict ovarian cancer survival and disease progression.Oncogene. 2007 Jan 11;26(2):198-214. doi: 10.1038/sj.onc.1209773. Epub 2006 Jul 10.
• [12] Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel.J Exp Clin Cancer Res. 2017 Dec 8;36(1):178. doi: 10.1186/s13046-017-0649-3.
• [13] Genetic variants associated with rheumatoid arthritis patients and serotypes in European populations.Clin Exp Rheumatol. 2016 Mar-Apr;34(2):236-41. Epub 2016 Mar 3.
• [14] Expression patterns common and unique to ulcerative colitis and celiac disease.Ann Hum Genet. 2019 Mar;83(2):86-94. doi: 10.1111/ahg.12293. Epub 2018 Nov 6.
• [15] BACH2 promotes indolent clinical presentation in Waldenstrm macroglobulinemia.Oncotarget. 2016 Jun 7;8(34):57451-57459. doi: 10.18632/oncotarget.9917. eCollection 2017 Aug 22.
• [16] Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.Nat Genet. 2018 Aug;50(8):1072-1080. doi: 10.1038/s41588-018-0157-1. Epub 2018 Jul 16.
• [17] Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
• [18] The NF-B subunit c-Rel regulates Bach2 tumour suppressor expression in B-cell lymphoma.Oncogene. 2016 Jun 30;35(26):3476-84. doi: 10.1038/onc.2015.399. Epub 2015 Nov 2.
• [19] Bach2 is involved in neuronal differentiation of N1E-115 neuroblastoma cells.Exp Cell Res. 2006 Jul 15;312(12):2264-78. doi: 10.1016/j.yexcr.2006.03.018. Epub 2006 Apr 24.
• [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 five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [22] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [23] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [24] Transcriptional suppression of BACH2 by the Bcr-Abl oncoprotein is mediated by PAX5.Leukemia. 2013 Feb;27(2):409-15. doi: 10.1038/leu.2012.220. Epub 2012 Aug 3.
• [25] A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25.3 and 3p22.1: a LOC Network study.Neuro Oncol. 2019 Aug 5;21(8):1039-1048. doi: 10.1093/neuonc/noz088.
• [26] A BACH2 Gene Variant Is Associated with Postoperative Recurrence of Crohn's Disease.J Am Coll Surg. 2018 May;226(5):902-908. doi: 10.1016/j.jamcollsurg.2018.01.052. Epub 2018 Feb 13.
• [27] Identification of BACH2 as a susceptibility gene for Graves' disease in the Chinese Han population based on a three-stage genome-wide association study.Hum Genet. 2014 May;133(5):661-71. doi: 10.1007/s00439-013-1404-2. Epub 2013 Dec 12.
• [28] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [29] High levels of BACH2 associated with lower levels of BCL2 transcript abundance in t(14;18)(q21;q34) translocation positive non-Hodgkin's lymphoma.Leuk Res. 2009 May;33(5):731-4. doi: 10.1016/j.leukres.2008.09.007. Epub 2008 Oct 16.
• [30] Hypomethylation within gene promoter regions and type 1 diabetes in discordant monozygotic twins.J Autoimmun. 2016 Apr;68:23-9. doi: 10.1016/j.jaut.2015.12.003. Epub 2016 Jan 9.
• [31] 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.
• [32] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [33] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [34] 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.
• [35] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [36] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [37] 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.
• [38] 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.
• [39] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [40] DON shares a similar mode of action as the ribotoxic stress inducer anisomycin while TBTO shares ER stress patterns with the ER stress inducer thapsigargin based on comparative gene expression profiling in Jurkat T cells. Toxicol Lett. 2014 Jan 30;224(3):395-406. doi: 10.1016/j.toxlet.2013.11.005. Epub 2013 Nov 15.
• [41] 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.