Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCW1FKL)

DOT Name DNA-binding protein Ikaros (IKZF1)
Synonyms Ikaros family zinc finger protein 1; Lymphoid transcription factor LyF-1
Gene Name IKZF1
Related Disease
Acute leukaemia ( )
Neoplasm ( )
Pancytopenia due to IKZF1 mutations ( )
Stevens-Johnson syndrome ( )
Acute monocytic leukemia ( )
AIDS-related lymphoma ( )
B-cell acute lymphoblastic leukaemia ( )
Common variable immunodeficiency ( )
Digestive system neuroendocrine tumor, grade 1/2 ( )
Fanconi's anemia ( )
Glomerulonephritis ( )
Haematological malignancy ( )
Inborn error of immunity ( )
Lung cancer ( )
Lung carcinoma ( )
Lymphoproliferative syndrome ( )
Multiple sclerosis ( )
Nasopharyngeal carcinoma ( )
Plasma cell myeloma ( )
Schwartz-Jampel syndrome ( )
Systemic lupus erythematosus ( )
T-cell acute lymphoblastic leukaemia ( )
Toxic epidermal necrolysis ( )
Acute lymphocytic leukaemia ( )
Autoimmune disease ( )
Burkitt lymphoma ( )
Chronic obstructive pulmonary disease ( )
Graft-versus-host disease ( )
Lupus nephritis ( )
Lymphoid leukemia ( )
Lymphoma ( )
Ulcerative colitis ( )
Myelodysplastic syndrome ( )
Myeloproliferative neoplasm ( )
Acute myelogenous leukaemia ( )
B-cell lymphoma ( )
Bone osteosarcoma ( )
Colorectal carcinoma ( )
leukaemia ( )
Leukemia ( )
Osteosarcoma ( )
UniProt ID
IKZF1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
6H0F; 8D7Z; 8D80
Pfam ID
PF00096
Sequence
MDADEGQDMSQVSGKESPPVSDTPDEGDEPMPIPEDLSTTSGGQQSSKSDRVVASNVKVE
TQSDEENGRACEMNGEECAEDLRMLDASGEKMNGSHRDQGSSALSGVGGIRLPNGKLKCD
ICGIICIGPNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHSGEKPFKCHLCNY
ACRRRDALTGHLRTHSVGKPHKCGYCGRSYKQRSSLEEHKERCHNYLESMGLPGTLYPVI
KEETNHSEMAEDLCKIGSERSLVLDRLASNVAKRKSSMPQKFLGDKGLSDTPYDSSASYE
KENEMMKSHVMDQAINNAINYLGAESLRPLVQTPPGGSEVVPVISPMYQLHKPLAEGTPR
SNHSAQDSAVENLLLLSKAKLVPSEREASPSNSCQDSTDTESNNEEQRSGLIYLTNHIAP
HARNGLSLKEEHRAYDLLRAASENSQDALRVVSTSGEQMKVYKCEHCRVLFLDHVMYTIH
MGCHGFRDPFECNMCGYHSQDRYEFSSHITRGEHRFHMS
Function
Transcription regulator of hematopoietic cell differentiation. Binds gamma-satellite DNA. Plays a role in the development of lymphocytes, B- and T-cells. Binds and activates the enhancer (delta-A element) of the CD3-delta gene. Repressor of the TDT (fikzfterminal deoxynucleotidyltransferase) gene during thymocyte differentiation. Regulates transcription through association with both HDAC-dependent and HDAC-independent complexes. Targets the 2 chromatin-remodeling complexes, NuRD and BAF (SWI/SNF), in a single complex (PYR complex), to the beta-globin locus in adult erythrocytes. Increases normal apoptosis in adult erythroid cells. Confers early temporal competence to retinal progenitor cells (RPCs). Function is isoform-specific and is modulated by dominant-negative inactive isoforms.
Tissue Specificity Abundantly expressed in thymus, spleen and peripheral blood Leukocytes and lymph nodes. Lower expression in bone marrow and small intestine.

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Acute leukaemia DISDQFDI Definitive Biomarker [1]
Neoplasm DISZKGEW Definitive Altered Expression [2]
Pancytopenia due to IKZF1 mutations DISW0L5G Definitive Autosomal dominant [3]
Stevens-Johnson syndrome DISZG4YX Definitive SusceptibilityMutation [4]
Acute monocytic leukemia DIS28NEL Strong Biomarker [5]
AIDS-related lymphoma DISSLRAU Strong Biomarker [6]
B-cell acute lymphoblastic leukaemia DISKLOKC Strong Biomarker [7]
Common variable immunodeficiency DISHE7JQ Strong Altered Expression [8]
Digestive system neuroendocrine tumor, grade 1/2 DISDR98B Strong Biomarker [9]
Fanconi's anemia DISGW6Q8 Strong Genetic Variation [10]
Glomerulonephritis DISPZIQ3 Strong Biomarker [11]
Haematological malignancy DISCDP7W Strong Biomarker [12]
Inborn error of immunity DISNGCMN Strong Genetic Variation [8]
Lung cancer DISCM4YA Strong Posttranslational Modification [13]
Lung carcinoma DISTR26C Strong Posttranslational Modification [13]
Lymphoproliferative syndrome DISMVL8O Strong Altered Expression [14]
Multiple sclerosis DISB2WZI Strong Biomarker [15]
Nasopharyngeal carcinoma DISAOTQ0 Strong Genetic Variation [16]
Plasma cell myeloma DIS0DFZ0 Strong Biomarker [17]
Schwartz-Jampel syndrome DIS3HCR8 Strong Genetic Variation [18]
Systemic lupus erythematosus DISI1SZ7 Strong Genetic Variation [19]
T-cell acute lymphoblastic leukaemia DIS17AI2 Strong Biomarker [20]
Toxic epidermal necrolysis DISIWPFR Strong Genetic Variation [18]
Acute lymphocytic leukaemia DISPX75S moderate Genetic Variation [21]
Autoimmune disease DISORMTM Moderate Autosomal dominant [3]
Burkitt lymphoma DIS9D5XU moderate Biomarker [22]
Chronic obstructive pulmonary disease DISQCIRF moderate Genetic Variation [23]
Graft-versus-host disease DIS0QADF moderate Altered Expression [24]
Lupus nephritis DISCVGPZ moderate Genetic Variation [19]
Lymphoid leukemia DIS65TYQ moderate Biomarker [25]
Lymphoma DISN6V4S moderate Altered Expression [26]
Ulcerative colitis DIS8K27O moderate Biomarker [27]
Myelodysplastic syndrome DISYHNUI Disputed Biomarker [28]
Myeloproliferative neoplasm DIS5KAPA Disputed Biomarker [29]
Acute myelogenous leukaemia DISCSPTN Limited Genetic Variation [1]
B-cell lymphoma DISIH1YQ Limited Genetic Variation [30]
Bone osteosarcoma DIST1004 Limited Biomarker [31]
Colorectal carcinoma DIS5PYL0 Limited Biomarker [32]
leukaemia DISS7D1V Limited Genetic Variation [33]
Leukemia DISNAKFL Limited Genetic Variation [33]
Osteosarcoma DISLQ7E2 Limited Biomarker [31]
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⏷ Show the Full List of 41 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
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 DNA-binding protein Ikaros (IKZF1). [34]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of DNA-binding protein Ikaros (IKZF1). [40]
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8 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Tretinoin DM49DUI Approved Tretinoin decreases the expression of DNA-binding protein Ikaros (IKZF1). [35]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of DNA-binding protein Ikaros (IKZF1). [36]
Calcitriol DM8ZVJ7 Approved Calcitriol decreases the expression of DNA-binding protein Ikaros (IKZF1). [37]
Bortezomib DMNO38U Approved Bortezomib decreases the expression of DNA-binding protein Ikaros (IKZF1). [38]
Vitamin C DMXJ7O8 Approved Vitamin C decreases the activity of DNA-binding protein Ikaros (IKZF1). [39]
Tamibarotene DM3G74J Phase 3 Tamibarotene affects the expression of DNA-binding protein Ikaros (IKZF1). [35]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of DNA-binding protein Ikaros (IKZF1). [41]
Deguelin DMXT7WG Investigative Deguelin decreases the expression of DNA-binding protein Ikaros (IKZF1). [42]
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⏷ Show the Full List of 8 Drug(s)

References

1 The functional polymorphisms of ARID5B and IKZF1 are associated with acute myeloid leukemia risk in a Han Chinese population.Gene. 2018 Mar 20;647:115-120. doi: 10.1016/j.gene.2017.12.059. Epub 2017 Dec 29.
2 Whole-genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm.Genes Chromosomes Cancer. 2020 May;59(5):295-308. doi: 10.1002/gcc.22831. Epub 2019 Dec 31.
3 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.
4 IKZF1, a new susceptibility gene for cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement.J Allergy Clin Immunol. 2015 Jun;135(6):1538-45.e17. doi: 10.1016/j.jaci.2014.12.1916. Epub 2015 Feb 8.
5 High frequency of Ikaros isoform 6 expression in acute myelomonocytic and monocytic leukemias: implications for up-regulation of the antiapoptotic protein Bcl-XL in leukemogenesis.Blood. 2002 Feb 15;99(4):1350-5. doi: 10.1182/blood.v99.4.1350.
6 CK1 and IRF4 are essential and independent effectors of immunomodulatory drugs in primary effusion lymphoma.Blood. 2018 Aug 9;132(6):577-586. doi: 10.1182/blood-2018-01-828418. Epub 2018 Jun 28.
7 Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis.Leukemia. 2018 Jan;32(1):38-48. doi: 10.1038/leu.2017.166. Epub 2017 May 30.
8 Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency.Front Immunol. 2019 Apr 16;10:568. doi: 10.3389/fimmu.2019.00568. eCollection 2019.
9 A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.Nat Genet. 2018 Jul;50(7):979-989. doi: 10.1038/s41588-018-0138-4. Epub 2018 Jun 18.
10 Congenital pancytopenia and absence of B lymphocytes in a neonate with a mutation in the Ikaros gene. Pediatr Blood Cancer. 2012 Apr;58(4):591-7. doi: 10.1002/pbc.23160. Epub 2011 May 5.
11 Association between polymorphisms of the IKZF3 gene and systemic lupus erythematosus in a Chinese Han population.PLoS One. 2014 Oct 1;9(10):e108661. doi: 10.1371/journal.pone.0108661. eCollection 2014.
12 Aberrant DNA methylation of key genes and Acute Lymphoblastic Leukemia.Biomed Pharmacother. 2018 Jan;97:1493-1500. doi: 10.1016/j.biopha.2017.11.033. Epub 2017 Nov 20.
13 Ectopic Ikaros expression positively correlates with lung cancer progression.Anat Rec (Hoboken). 2013 Jun;296(6):907-13. doi: 10.1002/ar.22700. Epub 2013 Apr 12.
14 A novel, non-canonical splice variant of the Ikaros gene is aberrantly expressed in B-cell lymphoproliferative disorders.PLoS One. 2013 Jul 9;8(7):e68080. doi: 10.1371/journal.pone.0068080. Print 2013.
15 Microarray gene expression profiling analysis combined with bioinformatics in multiple sclerosis.Mol Biol Rep. 2013 May;40(5):3731-7. doi: 10.1007/s11033-012-2449-3. Epub 2013 Mar 1.
16 A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
17 A phenylphthalimide derivative, TC11, induces apoptosis by degrading MCL1 in multiple myeloma cells.Biochem Biophys Res Commun. 2020 Jan 1;521(1):252-258. doi: 10.1016/j.bbrc.2019.10.119. Epub 2019 Oct 22.
18 Results of Detailed Investigations Into Stevens-Johnson Syndrome With Severe Ocular Complications.Invest Ophthalmol Vis Sci. 2018 Nov 1;59(14):DES183-DES191. doi: 10.1167/iovs.17-23537.
19 Association of the IKZF1 5' UTR variant rs1456896 with lupus nephritis in a northern Han Chinese population.Scand J Rheumatol. 2017 May;46(3):210-214. doi: 10.1080/03009742.2016.1194458. Epub 2016 Aug 16.
20 CRLF2 expression associates with ICN1 stabilization in T-cell acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2019 Jun;58(6):396-401.
21 The Genetic Variants of IKZF1 Gene Linked with the Growing Risk of Childhood Acute Lymphoblastic Leukaemia.Curr Mol Med. 2019;19(1):32-39. doi: 10.2174/1566524019666190219123900.
22 High frequency of IKZF1 genetic alterations in adult patients with B-cell acute lymphoblastic leukemia.Eur J Haematol. 2013 Sep;91(3):201-208. doi: 10.1111/ejh.12155. Epub 2013 Jul 7.
23 Relationship Among Chlamydia and Mycoplasma Pneumoniae Seropositivity, IKZF1 Genotype and Chronic Obstructive Pulmonary Disease in A General Japanese Population: The Nagahama Study.Medicine (Baltimore). 2016 Apr;95(15):e3371. doi: 10.1097/MD.0000000000003371.
24 Biomarkers for acute and chronic graft-versus-host disease in regulatory T cells.Transpl Immunol. 2012 Dec;27(4):179-83. doi: 10.1016/j.trim.2012.07.003. Epub 2012 Aug 4.
25 Intensifying Treatment of Childhood B-Lymphoblastic Leukemia With IKZF1 Deletion Reduces Relapse and Improves Overall Survival: Results of Malaysia-Singapore ALL 2010 Study.J Clin Oncol. 2018 Sep 10;36(26):2726-2735. doi: 10.1200/JCO.2018.78.3050. Epub 2018 Jul 25.
26 Aberrant Ikaros, Aiolos, and Helios expression in Hodgkin and non-Hodgkin lymphoma.Blood. 2008 Mar 15;111(6):3296-7. doi: 10.1182/blood-2007-12-125682.
27 Genome-wide association identifies multiple ulcerative colitis susceptibility loci.Nat Genet. 2010 Apr;42(4):332-7. doi: 10.1038/ng.549. Epub 2010 Mar 14.
28 A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes.Nat Med. 2016 Jul;22(7):727-34. doi: 10.1038/nm.4127. Epub 2016 Jun 13.
29 Myeloproliferative neoplasms: Current molecular biology and genetics.Crit Rev Oncol Hematol. 2016 Feb;98:375-89. doi: 10.1016/j.critrevonc.2015.11.004. Epub 2015 Nov 28.
30 Polymorphism in IKZF1 gene affects clinical outcome in diffuse large B-cell lymphoma.Int J Hematol. 2017 Dec;106(6):794-800. doi: 10.1007/s12185-017-2315-0. Epub 2017 Sep 6.
31 Analyzing the disease module associated with osteosarcoma via a network- and pathway-based approach.Exp Ther Med. 2018 Sep;16(3):2584-2592. doi: 10.3892/etm.2018.6506. Epub 2018 Jul 23.
32 Relationship between post-surgery detection of methylated circulating tumor DNA with risk of residual disease and recurrence-free survival.J Cancer Res Clin Oncol. 2018 Sep;144(9):1741-1750. doi: 10.1007/s00432-018-2701-x. Epub 2018 Jul 10.
33 Association of ARID5B and IKZF1 Variants with Leukemia from Northern India.Genet Test Mol Biomarkers. 2019 Mar;23(3):176-179. doi: 10.1089/gtmb.2018.0283. Epub 2019 Feb 27.
34 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.
35 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.
36 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.
37 Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
38 The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
39 Induction of alkaline phosphatase activity by L-ascorbic acid in human osteoblastic cells: a potential role for CK2 and Ikaros. Nutrition. 2007 Oct;23(10):745-53. doi: 10.1016/j.nut.2007.06.013. Epub 2007 Jul 30.
40 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.
41 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
42 Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.