Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTL5Y8R)

• DOT Name: AF4/FMR2 family member 4 (AFF4)
• Synonyms: ALL1-fused gene from chromosome 5q31 protein; Protein AF-5q31; Major CDK9 elongation factor-associated protein
• Gene Name: AFF4
• Related Disease:
  Bone development disease
  Childhood acute lymphoblastic leukemia
  Cognitive impairment
  Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome
  Cornelia de Lange syndrome
  Lung adenocarcinoma
  Osteochondrodysplasia
  Pulmonary disease
  Skeletal dysplasia
  Acute myelogenous leukaemia
  Head-neck squamous cell carcinoma
  leukaemia
  Leukemia
  Obesity
  Acute lymphocytic leukaemia
  Advanced cancer
  Bladder cancer
  Lymphoid leukemia
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: AFF4_HUMAN
• PDB ID: 4IMY; 4OGR; 4OR5; 5JW9; 5L1Z; 6CYT; 6K7P; 6KN5; 6R80
• Pfam ID: PF05110 ; PF18875 ; PF18876
• Sequence:
  MNREDRNVLRMKERERRNQEIQQGEDAFPPSSPLFAEPYKVTSKEDKLSSRIQSMLGNYD
  EMKDFIGDRSIPKLVAIPKPTVPPSADEKSNPNFFEQRHGGSHQSSKWTPVGPAPSTSQS
  QKRSSGLQSGHSSQRTSAGSSSGTNSSGQRHDRESYNNSGSSSRKKGQHGSEHSKSRSSS
  PGKPQAVSSLNSSHSRSHGNDHHSKEHQRSKSPRDPDANWDSPSRVPFSSGQHSTQSFPP
  SLMSKSNSMLQKPTAYVRPMDGQESMEPKLSSEHYSSQSHGNSMTELKPSSKAHLTKLKI
  PSQPLDASASGDVSCVDEILKEMTHSWPPPLTAIHTPCKTEPSKFPFPTKESQQSNFGTG
  EQKRYNPSKTSNGHQSKSMLKDDLKLSSSEDSDGEQDCDKTMPRSTPGSNSEPSHHNSEG
  ADNSRDDSSSHSGSESSSGSDSESESSSSDSEANEPSQSASPEPEPPPTNKWQLDNWLNK
  VNPHKVSPASSVDSNIPSSQGYKKEGREQGTGNSYTDTSGPKETSSATPGRDSKTIQKGS
  ESGRGRQKSPAQSDSTTQRRTVGKKQPKKAEKAAAEEPRGGLKIESETPVDLASSMPSSR
  HKAATKGSRKPNIKKESKSSPRPTAEKKKYKSTSKSSQKSREIIETDTSSSDSDESESLP
  PSSQTPKYPESNRTPVKPSSVEEEDSFFRQRMFSPMEEKELLSPLSEPDDRYPLIVKIDL
  NLLTRIPGKPYKETEPPKGEKKNVPEKHTREAQKQASEKVSNKGKRKHKNEDDNRASESK
  KPKTEDKNSAGHKPSSNRESSKQSAAKEKDLLPSPAGPVPSKDPKTEHGSRKRTISQSSS
  LKSSSNSNKETSGSSKNSSSTSKQKKTEGKTSSSSKEVKEKAPSSSSNCPPSAPTLDSSK
  PRRTKLVFDDRNYSADHYLQEAKKLKHNADALSDRFEKAVYYLDAVVSFIECGNALEKNA
  QESKSPFPMYSETVDLIKYTMKLKNYLAPDATAADKRLTVLCLRCESLLYLRLFKLKKEN
  ALKYSKTLTEHLKNSYNNSQAPSPGLGSKAVGMPSPVSPKLSPGNSGNYSSGASSASASG
  SSVTIPQKIHQMAASYVQVTSNFLYATEIWDQAEQLSKEQKEFFAELDKVMGPLIFNASI
  MTDLVRYTRQGLHWLRQDAKLIS
• Function: Key component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. In the SEC complex, AFF4 acts as a central scaffold that recruits other factors through direct interactions with ELL proteins (ELL, ELL2 or ELL3) and the P-TEFb complex. In case of infection by HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression.
• Tissue Specificity: Ubiquitously expressed. Strongly expressed in heart, placenta, skeletal muscle, pancreas and to a lower extent in brain.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway:
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone development disease	DISVKAZS	Strong	Biomarker	[1]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[2]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[1]
Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	DISE7NIL	Strong	Autosomal dominant	[3]
Cornelia de Lange syndrome	DISEQSXO	Strong	Genetic Variation	[1]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[4]
Osteochondrodysplasia	DIS9SPWW	Strong	Genetic Variation	[1]
Pulmonary disease	DIS6060I	Strong	Biomarker	[1]
Skeletal dysplasia	DIS5Z8U6	Strong	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[5]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[6]
leukaemia	DISS7D1V	moderate	Biomarker	[7]
Leukemia	DISNAKFL	moderate	Biomarker	[7]
Obesity	DIS47Y1K	moderate	Genetic Variation	[1]
Acute lymphocytic leukaemia	DISPX75S	Disputed	Altered Expression	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]
Bladder cancer	DISUHNM0	Limited	Biomarker	[9]
Lymphoid leukemia	DIS65TYQ	Limited	Altered Expression	[7]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[9]

6 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 AF4/FMR2 family member 4 (AFF4).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of AF4/FMR2 family member 4 (AFF4).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of AF4/FMR2 family member 4 (AFF4).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of AF4/FMR2 family member 4 (AFF4).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of AF4/FMR2 family member 4 (AFF4).	[27]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of AF4/FMR2 family member 4 (AFF4).	[25]

17 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 AF4/FMR2 family member 4 (AFF4).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of AF4/FMR2 family member 4 (AFF4).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of AF4/FMR2 family member 4 (AFF4).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of AF4/FMR2 family member 4 (AFF4).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of AF4/FMR2 family member 4 (AFF4).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of AF4/FMR2 family member 4 (AFF4).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of AF4/FMR2 family member 4 (AFF4).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of AF4/FMR2 family member 4 (AFF4).	[18]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of AF4/FMR2 family member 4 (AFF4).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of AF4/FMR2 family member 4 (AFF4).	[20]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of AF4/FMR2 family member 4 (AFF4).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of AF4/FMR2 family member 4 (AFF4).	[24]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of AF4/FMR2 family member 4 (AFF4).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of AF4/FMR2 family member 4 (AFF4).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of AF4/FMR2 family member 4 (AFF4).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of AF4/FMR2 family member 4 (AFF4).	[30]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of AF4/FMR2 family member 4 (AFF4).	[31]

References

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• [3] Clinical and molecular spectrum of CHOPS syndrome. Am J Med Genet A. 2019 Jul;179(7):1126-1138. doi: 10.1002/ajmg.a.61174. Epub 2019 May 6.
• [4] Long noncoding RNA ZFPM2-AS1 is involved in lung adenocarcinoma via miR-511-3p/AFF4 pathway.J Cell Biochem. 2020 Mar;121(3):2534-2542. doi: 10.1002/jcb.29476. Epub 2019 Nov 6.
• [5] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
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• [7] The super elongation complex family of RNA polymerase II elongation factors: gene target specificity and transcriptional output.Mol Cell Biol. 2012 Jul;32(13):2608-17. doi: 10.1128/MCB.00182-12. Epub 2012 Apr 30.
• [8] MCEF, the newest member of the AF4 family of transcription factors involved in leukemia, is a positive transcription elongation factor-b-associated protein.J Biomed Sci. 2002 May-Jun;9(3):234-45. doi: 10.1007/BF02256070.
• [9] The m(6)A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-B/MYC signaling network.Oncogene. 2019 May;38(19):3667-3680. doi: 10.1038/s41388-019-0683-z. Epub 2019 Jan 18.
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• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] Phosphoproteomics reveals resveratrol-dependent inhibition of Akt/mTORC1/S6K1 signaling. J Proteome Res. 2014 Dec 5;13(12):5734-42. doi: 10.1021/pr500714a. Epub 2014 Oct 29.
• [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] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [27] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [28] 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.
• [29] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [30] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [31] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.