Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI6ZBP6)

• DOT Name: B-cell lymphoma/leukemia 11A (BCL11A)
• Synonyms: BCL-11A; B-cell CLL/lymphoma 11A; COUP-TF-interacting protein 1; Ecotropic viral integration site 9 protein homolog; EVI-9; Zinc finger protein 856
• Gene Name: BCL11A
• Related Disease:
  Dias-Logan syndrome
  Intellectual disability, autosomal dominant 40
• UniProt ID: BC11A_HUMAN
• PDB ID: 5VTB; 6KI6; 6U9Q; 8DTN; 8DTU
• Pfam ID: PF00096
• Sequence:
  MSRRKQGKPQHLSKREFSPEPLEAILTDDEPDHGPLGAPEGDHDLLTCGQCQMNFPLGDI
  LIFIEHKRKQCNGSLCLEKAVDKPPSPSPIEMKKASNPVEVGIQVTPEDDDCLSTSSRGI
  CPKQEHIADKLLHWRGLSSPRSAHGALIPTPGMSAEYAPQGICKDEPSSYTCTTCKQPFT
  SAWFLLQHAQNTHGLRIYLESEHGSPLTPRVGIPSGLGAECPSQPPLHGIHIADNNPFNL
  LRIPGSVSREASGLAEGRFPPTPPLFSPPPRHHLDPHRIERLGAEEMALATHHPSAFDRV
  LRLNPMAMEPPAMDFSRRLRELAGNTSSPPLSPGRPSPMQRLLQPFQPGSKPPFLATPPL
  PPLQSAPPPSQPPVKSKSCEFCGKTFKFQSNLVVHRRSHTGEKPYKCNLCDHACTQASKL
  KRHMKTHMHKSSPMTVKSDDGLSTASSPEPGTSDLVGSASSALKSVVAKFKSENDPNLIP
  ENGDEEEEEDDEEEEEEEEEEEEELTESERVDYGFGLSLEAARHHENSSRGAVVGVGDES
  RALPDVMQGMVLSSMQHFSEAFHQVLGEKHKRGHLAEAEGHRDTCDEDSVAGESDRIDDG
  TVNGRGCSPGESASGGLSKKLLLGSPSSLSPFSKRIKLEKEFDLPPAAMPNTENVYSQWL
  AGYAASRQLKDPFLSFGDSRQSPFASSSEHSSENGSLRFSTPPGELDGGISGRSGTGSGG
  STPHISGPGPGRPSSKEGRRSDTCEYCGKVFKNCSNLTVHRRSHTGERPYKCELCNYACA
  QSSKLTRHMKTHGQVGKDVYKCEICKMPFSVYSTLEKHMKKWHSDRVLNNDIKTE
• Function: Transcription factor. Associated with the BAF SWI/SNF chromatin remodeling complex. Binds to the 5'-TGACCA-3' sequence motif in regulatory regions of target genes, including a distal promoter of the HBG1 hemoglobin subunit gamma-1 gene. Involved in regulation of the developmental switch from gamma- to beta-globin, probably via direct repression of HBG1; hence indirectly repressing fetal hemoglobin (HbF) level. Involved in brain development. May play a role in hematopoiesis. Essential factor in lymphopoiesis required for B-cell formation in fetal liver. May function as a modulator of the transcriptional repression activity of NR2F2.
• Tissue Specificity: Expressed at high levels in brain, spleen thymus, bone marrow and testis. Expressed in CD34-positive myeloid precursor cells, B-cells, monocytes and megakaryocytes. Expression is tightly regulated during B-cell development.; [Isoform 1]: Expressed in fetal and adult brain, and in the plasmacytoid dendritic cell.
• Reactome Pathway:
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  ALK mutants bind TKIs (R-HSA-9700645)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dias-Logan syndrome	DISPG9AB	Definitive	Autosomal dominant	[1]
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[2]

21 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 B-cell lymphoma/leukemia 11A (BCL11A).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[8]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[11]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[8]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[4]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[9]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[3]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[19]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of B-cell lymphoma/leukemia 11A (BCL11A).	[20]

3 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 B-cell lymphoma/leukemia 11A (BCL11A).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of B-cell lymphoma/leukemia 11A (BCL11A).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of B-cell lymphoma/leukemia 11A (BCL11A).	[15]

References

• [1] 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.
• [2] Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. Epub 2014 Dec 24.
• [3] 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.
• [4] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [5] 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.
• [6] 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.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] 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.
• [11] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [12] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [15] 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.
• [16] 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.
• [17] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [19] 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.
• [20] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.