Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU7J84H)

• DOT Name: Runt-related transcription factor 1 (RUNX1)
• Synonyms: Acute myeloid leukemia 1 protein; Core-binding factor subunit alpha-2; CBF-alpha-2; Oncogene AML-1; Polyomavirus enhancer-binding protein 2 alpha B subunit; PEA2-alpha B; PEBP2-alpha B; SL3-3 enhancer factor 1 alpha B subunit; SL3/AKV core-binding factor alpha B subunit
• Gene Name: RUNX1
• Related Disease:
  Hereditary thrombocytopenia and hematologic cancer predisposition syndrome
  Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
  Acute myelogenous leukaemia
• UniProt ID: RUNX1_HUMAN
• PDB ID: 1CMO; 1CO1; 1E50; 1H9D; 1LJM
• Pfam ID: PF00853 ; PF08504
• Sequence:
  MRIPVDASTSRRFTPPSTALSPGKMSEALPLGAPDAGAALAGKLRSGDRSMVEVLADHPG
  ELVRTDSPNFLCSVLPTHWRCNKTLPIAFKVVALGDVPDGTLVTVMAGNDENYSAELRNA
  TAAMKNQVARFNDLRFVGRSGRGKSFTLTITVFTNPPQVATYHRAIKITVDGPREPRRHR
  QKLDDQTKPGSLSFSERLSELEQLRRTAMRVSPHHPAPTPNPRASLNHSTAFNPQPQSQM
  QDTRQIQPSPPWSYDQSYQYLGSIASPSVHPATPISPGRASGMTTLSAELSSRLSTAPDL
  TAFSDPRQFPALPSISDPRMHYPGAFTYSPTPVTSGIGIGMSAMGSATRYHTYLPPPYPG
  SSQAQGGPFQASSPSYHLYYGASAGSYQFSMVGGERSPPRILPPCTNASTGSALLNPSLP
  NQSDVVEAEGSHSNSPTNMAPSARLEEAVWRPY
• Function: Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters (Probable). Essential for the development of normal hematopoiesis. Acts synergistically with ELF4 to transactivate the IL-3 promoter and with ELF2 to transactivate the BLK promoter. Inhibits KAT6B-dependent transcriptional activation. Involved in lineage commitment of immature T cell precursors. CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation. CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing. Controls the anergy and suppressive function of regulatory T-cells (Treg) by associating with FOXP3. Activates the expression of IL2 and IFNG and down-regulates the expression of TNFRSF18, IL2RA and CTLA4, in conventional T-cells. Positively regulates the expression of RORC in T-helper 17 cells; Isoform AML-1G shows higher binding activities for target genes and binds TCR-beta-E2 and RAG-1 target site with threefold higher affinity than other isoforms. It is less effective in the context of neutrophil terminal differentiation; Isoform AML-1L interferes with the transactivation activity of RUNX1.
• Tissue Specificity: Expressed in all tissues examined except brain and heart. Highest levels in thymus, bone marrow and peripheral blood.
• KEGG Pathway:
  Tight junction (hsa04530)
  Th17 cell differentiation (hsa04659)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
• Reactome Pathway:
  Organic cation transport (R-HSA-549127)
  RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) (R-HSA-8877330)
  RUNX1 regulates estrogen receptor mediated transcription (R-HSA-8931987)
  Regulation of RUNX1 Expression and Activity (R-HSA-8934593)
  RUNX1 regulates expression of components of tight junctions (R-HSA-8935964)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  RUNX1 regulates transcription of genes involved in differentiation of keratinocytes (R-HSA-8939242)
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  RUNX1 regulates transcription of genes involved in BCR signaling (R-HSA-8939245)
  RUNX1 regulates transcription of genes involved in differentiation of myeloid cells (R-HSA-8939246)
  RUNX1 regulates transcription of genes involved in interleukin signaling (R-HSA-8939247)
  RUNX1 regulates transcription of genes involved in WNT signaling (R-HSA-8939256)
  RUNX2 regulates genes involved in differentiation of myeloid cells (R-HSA-8941333)
  RUNX3 regulates p14-ARF (R-HSA-8951936)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Transcriptional regulation of granulopoiesis (R-HSA-9616222)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	DIS1HP20	Definitive	Autosomal dominant	[1]
Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	DIS7XO1W	Definitive	Autosomal dominant	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Runt-related transcription factor 1 (RUNX1) increases the response to substance of Doxorubicin.	[28]

6 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Runt-related transcription factor 1 (RUNX1).	[4]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Runt-related transcription factor 1 (RUNX1).	[12]
Cotinine	DMCEZ1B	Approved	Cotinine affects the methylation of Runt-related transcription factor 1 (RUNX1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Runt-related transcription factor 1 (RUNX1).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Runt-related transcription factor 1 (RUNX1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Runt-related transcription factor 1 (RUNX1).	[12]

24 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 Runt-related transcription factor 1 (RUNX1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Runt-related transcription factor 1 (RUNX1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Runt-related transcription factor 1 (RUNX1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Runt-related transcription factor 1 (RUNX1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Runt-related transcription factor 1 (RUNX1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Runt-related transcription factor 1 (RUNX1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Runt-related transcription factor 1 (RUNX1).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Runt-related transcription factor 1 (RUNX1).	[13]
Etoposide	DMNH3PG	Approved	Etoposide increases the mutagenesis of Runt-related transcription factor 1 (RUNX1).	[14]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Runt-related transcription factor 1 (RUNX1).	[15]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Runt-related transcription factor 1 (RUNX1).	[14]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Runt-related transcription factor 1 (RUNX1).	[16]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the mutagenesis of Runt-related transcription factor 1 (RUNX1).	[14]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Runt-related transcription factor 1 (RUNX1).	[8]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Runt-related transcription factor 1 (RUNX1).	[8]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of Runt-related transcription factor 1 (RUNX1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Runt-related transcription factor 1 (RUNX1).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Runt-related transcription factor 1 (RUNX1).	[20]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Runt-related transcription factor 1 (RUNX1).	[5]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of Runt-related transcription factor 1 (RUNX1).	[21]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of Runt-related transcription factor 1 (RUNX1).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Runt-related transcription factor 1 (RUNX1).	[24]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Runt-related transcription factor 1 (RUNX1).	[26]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Runt-related transcription factor 1 (RUNX1).	[27]

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] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] 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.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] 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.
• [13] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [14] "Exposure to the insecticides permethrin and malathion induces leukemia and lymphoma-associated gene aberrations in vitro". Toxicol In Vitro. 2017 Oct;44:17-26. doi: 10.1016/j.tiv.2017.06.013. Epub 2017 Jun 15.
• [15] 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.
• [16] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [17] t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy. Cancer. 2006 Apr 15;106(8):1730-8. doi: 10.1002/cncr.21797.
• [18] 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environ Health Perspect. 2012 Oct;120(10):1425-31. doi: 10.1289/ehp.1205412. Epub 2012 Jul 31.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [21] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [22] HDN-1 induces cell differentiation toward apoptosis in promyelocytic leukemia cells depending on its selective effect on client proteins of Hsp90. Toxicol Appl Pharmacol. 2021 Apr 15;417:115459. doi: 10.1016/j.taap.2021.115459. Epub 2021 Feb 17.
• [23] 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.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [26] Probiotic Bacillus subtilis CW14 reduces disruption of the epithelial barrier and toxicity of ochratoxin A to Caco-2?cells. Food Chem Toxicol. 2019 Apr;126:25-33. doi: 10.1016/j.fct.2019.02.009. Epub 2019 Feb 11.
• [27] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [28] Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia. Blood. 2004 Oct 15;104(8):2452-7. doi: 10.1182/blood-2003-12-4426. Epub 2004 Jun 24.