Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8KKCVJ)

• DOT Name: B-cell lymphoma/leukemia 11B (BCL11B)
• Synonyms: BCL-11B; B-cell CLL/lymphoma 11B; COUP-TF-interacting protein 2; Radiation-induced tumor suppressor gene 1 protein; hRit1
• Gene Name: BCL11B
• Related Disease:
  Acute myelogenous leukaemia
  Haematological malignancy
  Intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities
  Mycosis fungoides
  Primary cutaneous T-cell lymphoma
  Acute leukaemia
  Acute lymphocytic leukaemia
  Adult T-cell leukemia/lymphoma
  Allergic asthma
  Alopecia
  Atopic dermatitis
  Autoimmune disease
  B-cell neoplasm
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Cardiovascular disease
  Childhood acute lymphoblastic leukemia
  Colon cancer
  Corpus callosum, agenesis of
  Craniosynostosis
  Dermatitis
  Ewing sarcoma
  Glioma
  Head-neck squamous cell carcinoma
  Helminth infection
  Hematologic disease
  HIV infectious disease
  Huntington disease
  Immunodeficiency
  Immunodeficiency 49
  Inflammatory bowel disease
  Intellectual disability
  Leukemia
  Lung cancer
  Lung carcinoma
  Lymphoma
  Neurodevelopmental disorder
  Small lymphocytic lymphoma
  T-cell lymphoma
  Adult lymphoma
  Fetal growth restriction
  Neuroblastoma
  Pediatric lymphoma
  Severe combined immunodeficiency
  Amyotrophic lateral sclerosis
  Ankylosing spondylitis
  Bipolar disorder
  Schizophrenia
  T-cell leukaemia
• UniProt ID: BC11B_HUMAN
• Pfam ID: PF00096
• Sequence:
  MSRRKQGNPQHLSQRELITPEADHVEAAILEEDEGLEIEEPSGLGLMVGGPDPDLLTCGQ
  CQMNFPLGDILVFIEHKRKQCGGSLGACYDKALDKDSPPPSSRSELRKVSEPVEIGIQVT
  PDEDDHLLSPTKGICPKQENIAGPCRPAQLPAVAPIAASSHPHSSVITSPLRALGALPPC
  LPLPCCSARPVSGDGTQGEGQTEAPFGCQCQLSGKDEPSSYICTTCKQPFNSAWFLLQHA
  QNTHGFRIYLEPGPASSSLTPRLTIPPPLGPEAVAQSPLMNFLGDSNPFNLLRMTGPILR
  DHPGFGEGRLPGTPPLFSPPPRHHLDPHRLSAEEMGLVAQHPSAFDRVMRLNPMAIDSPA
  MDFSRRLRELAGNSSTPPPVSPGRGNPMHRLLNPFQPSPKSPFLSTPPLPPMPPGGTPPP
  QPPAKSKSCEFCGKTFKFQSNLIVHRRSHTGEKPYKCQLCDHACSQASKLKRHMKTHMHK
  AGSLAGRSDDGLSAASSPEPGTSELAGEGLKAADGDFRHHESDPSLGHEPEEEDEEEEEE
  EEELLLENESRPESSFSMDSELSRNRENGGGGVPGVPGAGGGAAKALADEKALVLGKVME
  NVGLGALPQYGELLADKQKRGAFLKRAAGGGDAGDDDDAGGCGDAGAGGAVNGRGGGFAP
  GTEPFPGLFPRKPAPLPSPGLNSAAKRIKVEKDLELPPAALIPSENVYSQWLVGYAASRH
  FMKDPFLGFTDARQSPFATSSEHSSENGSLRFSTPPGDLLDGGLSGRSGTASGGSTPHLG
  GPGPGRPSSKEGRRSDTCEYCGKVFKNCSNLTVHRRSHTGERPYKCELCNYACAQSSKLT
  RHMKTHGQIGKEVYRCDICQMPFSVYSTLEKHMKKWHGEHLLTNDVKIEQAERS
• Function: Key regulator of both differentiation and survival of T-lymphocytes during thymocyte development in mammals. Essential in controlling the responsiveness of hematopoietic stem cells to chemotactic signals by modulating the expression of the receptors CCR7 and CCR9, which direct the movement of progenitor cells from the bone marrow to the thymus. Is a regulator of IL2 promoter and enhances IL2 expression in activated CD4(+) T-lymphocytes. Tumor-suppressor that represses transcription through direct, TFCOUP2-independent binding to a GC-rich response element. May also function in the P53-signaling pathway.
• Tissue Specificity: Highly expressed in brain and in malignant T-cell lines derived from patients with adult T-cell leukemia/lymphoma.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Genetic Variation	[1]
Haematological malignancy	DISCDP7W	Definitive	Biomarker	[2]
Intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities	DISB0XLM	Definitive	Autosomal dominant	[3]
Mycosis fungoides	DIS62RB8	Definitive	Altered Expression	[4]
Primary cutaneous T-cell lymphoma	DIS35WVW	Definitive	Biomarker	[4]
Acute leukaemia	DISDQFDI	Strong	Genetic Variation	[5]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[6]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Altered Expression	[7]
Allergic asthma	DISHF0H3	Strong	Biomarker	[8]
Alopecia	DIS37HU4	Strong	Biomarker	[9]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[9]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[10]
B-cell neoplasm	DISVY326	Strong	Biomarker	[11]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Biomarker	[12]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[13]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[14]
Colon cancer	DISVC52G	Strong	Genetic Variation	[15]
Corpus callosum, agenesis of	DISO9P40	Strong	CausalMutation	[16]
Craniosynostosis	DIS6J405	Strong	Genetic Variation	[17]
Dermatitis	DISY5SZC	Strong	Biomarker	[9]
Ewing sarcoma	DISQYLV3	Strong	Altered Expression	[18]
Glioma	DIS5RPEH	Strong	Altered Expression	[19]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[20]
Helminth infection	DIS7CGKY	Strong	Biomarker	[8]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[21]
HIV infectious disease	DISO97HC	Strong	Biomarker	[22]
Huntington disease	DISQPLA4	Strong	Biomarker	[23]
Immunodeficiency	DIS093I0	Strong	Genetic Variation	[24]
Immunodeficiency 49	DIS9R0SM	Strong	Autosomal dominant	[24]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[25]
Intellectual disability	DISMBNXP	Strong	Biomarker	[24]
Leukemia	DISNAKFL	Strong	Biomarker	[26]
Lung cancer	DISCM4YA	Strong	Biomarker	[27]
Lung carcinoma	DISTR26C	Strong	Biomarker	[27]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[28]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[29]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[30]
Adult lymphoma	DISK8IZR	moderate	Biomarker	[2]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[31]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[32]
Pediatric lymphoma	DIS51BK2	moderate	Biomarker	[2]
Severe combined immunodeficiency	DIS6MF4Q	moderate	Biomarker	[16]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[33]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[34]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[35]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[36]
T-cell leukaemia	DISJ6YIF	Limited	Genetic Variation	[37]

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 B-cell lymphoma/leukemia 11B (BCL11B).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of B-cell lymphoma/leukemia 11B (BCL11B).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of B-cell lymphoma/leukemia 11B (BCL11B).	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of B-cell lymphoma/leukemia 11B (BCL11B).	[39]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of B-cell lymphoma/leukemia 11B (BCL11B).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of B-cell lymphoma/leukemia 11B (BCL11B).	[43]

References

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• [2] Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells.Oncogene. 2007 May 31;26(26):3797-810. doi: 10.1038/sj.onc.1210152. Epub 2006 Dec 18.
• [3] Mutant BCL11B in a Patient With a Neurodevelopmental Disorder and T-Cell Abnormalities. Front Pediatr. 2020 Oct 19;8:544894. doi: 10.3389/fped.2020.544894. eCollection 2020.
• [4] BCL11B-Mediated Epigenetic Repression Is a Crucial Target for Histone Deacetylase Inhibitors in Cutaneous T-Cell Lymphoma.J Invest Dermatol. 2017 Jul;137(7):1523-1532. doi: 10.1016/j.jid.2017.02.980. Epub 2017 Mar 10.
• [5] Identification of novel fusion genes with 28S ribosomal DNA in hematologic malignancies.Int J Oncol. 2014 Apr;44(4):1193-8. doi: 10.3892/ijo.2014.2291. Epub 2014 Feb 5.
• [6] Downregulated miR-17, miR-29c, miR-92a and miR-214 may be related to BCL11B overexpression in Tcell acute lymphoblastic leukemia.Asia Pac J Clin Oncol. 2018 Oct;14(5):e259-e265. doi: 10.1111/ajco.12979. Epub 2018 May 11.
• [7] Reduced level of the BCL11B protein is associated with adult T-cell leukemia/lymphoma.PLoS One. 2013;8(1):e55147. doi: 10.1371/journal.pone.0055147. Epub 2013 Jan 30.
• [8] Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma.Nat Commun. 2018 Apr 26;9(1):1679. doi: 10.1038/s41467-018-04111-0.
• [9] Selective ablation of Ctip2/Bcl11b in epidermal keratinocytes triggers atopic dermatitis-like skin inflammatory responses in adult mice.PLoS One. 2012;7(12):e51262. doi: 10.1371/journal.pone.0051262. Epub 2012 Dec 20.
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• [11] Bcl11b, a novel GATA3-interacting protein, suppresses Th1 while limiting Th2 cell differentiation.J Exp Med. 2018 May 7;215(5):1449-1462. doi: 10.1084/jem.20171127. Epub 2018 Mar 7.
• [12] Haploinsufficiency and acquired loss of Bcl11b and H2AX induces blast crisis of chronic myelogenous leukemia in a transgenic mouse model.Cancer Sci. 2009 Jul;100(7):1219-26. doi: 10.1111/j.1349-7006.2009.01172.x. Epub 2009 Apr 21.
• [13] Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium.Circ Cardiovasc Genet. 2012 Feb 1;5(1):81-90. doi: 10.1161/CIRCGENETICS.111.959817. Epub 2011 Nov 8.
• [14] The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2).Cancer Res. 2003 Sep 1;63(17):5329-34.
• [15] Bcl11b SWI/SNF-complex subunit modulates intestinal adenoma and regeneration after -irradiation through Wnt/-catenin pathway.Carcinogenesis. 2015 Jun;36(6):622-31. doi: 10.1093/carcin/bgv044. Epub 2015 Mar 31.
• [16] Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B. N Engl J Med. 2016 Dec 1;375(22):2165-2176. doi: 10.1056/NEJMoa1509164.
• [17] A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis.Hum Mol Genet. 2019 Aug 1;28(15):2501-2513. doi: 10.1093/hmg/ddz072.
• [18] Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets.Oncotarget. 2017 Aug 4;9(2):1587-1601. doi: 10.18632/oncotarget.20098. eCollection 2018 Jan 5.
• [19] Depletion of B cell CLL/Lymphoma 11B Gene Expression Represses Glioma Cell Growth.Mol Neurobiol. 2016 Aug;53(6):3528-3539. doi: 10.1007/s12035-015-9231-1. Epub 2015 Jun 23.
• [20] CTIP2 expression in human head and neck squamous cell carcinoma is linked to poorly differentiated tumor status.PLoS One. 2009;4(4):e5367. doi: 10.1371/journal.pone.0005367. Epub 2009 Apr 28.
• [21] Increased expression of bcl11b leads to chemoresistance accompanied by G1 accumulation.PLoS One. 2010 Sep 2;5(9):e12532. doi: 10.1371/journal.pone.0012532.
• [22] HIV brain latency as measured by CSF BcL11b relates to disrupted brain cellular energy in virally suppressed HIV infection.AIDS. 2019 Mar 1;33(3):433-441. doi: 10.1097/QAD.0000000000002076.
• [23] CTIP2-Regulated Reduction in PKA-Dependent DARPP32 Phosphorylation in Human Medium Spiny Neurons: Implications for Huntington Disease.Stem Cell Reports. 2019 Sep 10;13(3):448-457. doi: 10.1016/j.stemcr.2019.07.015. Epub 2019 Aug 22.
• [24] BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells. Brain. 2018 Aug 1;141(8):2299-2311. doi: 10.1093/brain/awy173.
• [25] Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease.J Exp Med. 2011 Sep 26;208(10):2069-81. doi: 10.1084/jem.20102683. Epub 2011 Aug 29.
• [26] A novel t(6;14)(q25-q27;q32) in acute myelocytic leukemia involves the BCL11B gene.Cancer Genet Cytogenet. 2004 Feb;149(1):72-6. doi: 10.1016/s0165-4608(03)00302-9.
• [27] Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells.Cell Physiol Biochem. 2018;49(4):1615-1632. doi: 10.1159/000493497. Epub 2018 Sep 17.
• [28] A De Novo heterozygous frameshift mutation identified in BCL11B causes neurodevelopmental disorder by whole exome sequencing.Mol Genet Genomic Med. 2019 Sep;7(9):e897. doi: 10.1002/mgg3.897. Epub 2019 Jul 25.
• [29] Bcl11b-A Critical Neurodevelopmental Transcription Factor-Roles in Health and Disease.Front Cell Neurosci. 2017 Mar 29;11:89. doi: 10.3389/fncel.2017.00089. eCollection 2017.
• [30] Comprehensive cytogenetic study of primary cutaneous gamma-delta T-cell lymphoma by means of spectral karyotyping and genome-wide single nucleotide polymorphism array.Cancer Genet. 2012 Sep;205(9):459-64. doi: 10.1016/j.cancergen.2012.05.006. Epub 2012 Jul 21.
• [31] Activation of glucose transport by a natural mutation in the human insulin receptor.Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):60-4. doi: 10.1073/pnas.90.1.60.
• [32] CTIP2 associates with the NuRD complex on the promoter of p57KIP2, a newly identified CTIP2 target gene.J Biol Chem. 2006 Oct 27;281(43):32272-83. doi: 10.1074/jbc.M602776200. Epub 2006 Sep 1.
• [33] Bcl11b: A New Piece to the Complex Puzzle of Amyotrophic Lateral Sclerosis Neuropathogenesis?.Neurotox Res. 2016 Feb;29(2):201-7. doi: 10.1007/s12640-015-9573-5. Epub 2015 Nov 12.
• [34] Promoter hypermethylation of BCL11B gene correlates with downregulation of gene transcription in ankylosing spondylitis patients.Genes Immun. 2017 Sep;18(3):170-175. doi: 10.1038/gene.2017.17. Epub 2017 Aug 10.
• [35] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [36] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [37] HELIOS-BCL11B fusion gene involvement in a t(2;14)(q34;q32) in an adult T-cell leukemia patient.Cancer Genet. 2012 Jul-Aug;205(7-8):356-64. doi: 10.1016/j.cancergen.2012.04.006.
• [38] 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.
• [39] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [40] 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.
• [41] 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.
• [42] 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.
• [43] 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.