Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT2C78E)

• DOT Name: AF4/FMR2 family member 1 (AFF1)
• Synonyms: ALL1-fused gene from chromosome 4 protein; Protein AF-4; Protein FEL; Proto-oncogene AF4
• Gene Name: AFF1
• Related Disease:
  Acute leukaemia
  B-cell neoplasm
  Rheumatoid arthritis
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Alzheimer disease
  Amyloidosis
  Cataract
  leukaemia
  Leukemia
  Lupus
  Neoplasm
  Promyelocytic leukaemia
  Systemic lupus erythematosus
  Advanced cancer
  Childhood acute lymphoblastic leukemia
  Lewy body dementia
  Parkinson disease
• UniProt ID: AFF1_HUMAN
• PDB ID: 2LM0
• Pfam ID: PF05110 ; PF18875 ; PF18876
• Sequence:
  MAAQSSLYNDDRNLLRIREKERRNQEAHQEKEAFPEKIPLFGEPYKTAKGDELSSRIQNM
  LGNYEEVKEFLSTKSHTHRLDASENRLGKPKYPLIPDKGSSIPSSSFHTSVHHQSIHTPA
  SGPLSVGNISHNPKMAQPRTEPMPSLHAKSCGPPDSQHLTQDRLGQEGFGSSHHKKGDRR
  ADGDHCASVTDSAPERELSPLISLPSPVPPLSPIHSNQQTLPRTQGSSKVHGSSNNSKGY
  CPAKSPKDLAVKVHDKETPQDSLVAPAQPPSQTFPPPSLPSKSVAMQQKPTAYVRPMDGQ
  DQAPSESPELKPLPEDYRQQTFEKTDLKVPAKAKLTKLKMPSQSVEQTYSNEVHCVEEIL
  KEMTHSWPPPLTAIHTPSTAEPSKFPFPTKDSQHVSSVTQNQKQYDTSSKTHSNSQQGTS
  SMLEDDLQLSDSEDSDSEQTPEKPPSSSAPPSAPQSLPEPVASAHSSSAESESTSDSDSS
  SDSESESSSSDSEENEPLETPAPEPEPPTTNKWQLDNWLTKVSQPAAPPEGPRSTEPPRR
  HPESKGSSDSATSQEHSESKDPPPKSSSKAPRAPPEAPHPGKRSCQKSPAQQEPPQRQTV
  GTKQPKKPVKASARAGSRTSLQGEREPGLLPYGSRDQTSKDKPKVKTKGRPRAAASNEPK
  PAVPPSSEKKKHKSSLPAPSKALSGPEPAKDNVEDRTPEHFALVPLTESQGPPHSGSGSR
  TSGCRQAVVVQEDSRKDRLPLPLRDTKLLSPLRDTPPPQSLMVKITLDLLSRIPQPPGKG
  SRQRKAEDKQPPAGKKHSSEKRSSDSSSKLAKKRKGEAERDCDNKKIRLEKEIKSQSSSS
  SSSHKESSKTKPSRPSSQSSKKEMLPPPPVSSSSQKPAKPALKRSRREADTCGQDPPKSA
  SSTKSNHKDSSIPKQRRVEGKGSRSSSEHKGSSGDTANPFPVPSLPNGNSKPGKPQVKFD
  KQQADLHMREAKKMKQKAELMTDRVGKAFKYLEAVLSFIECGIATESESQSSKSAYSVYS
  ETVDLIKFIMSLKSFSDATAPTQEKIFAVLCMRCQSILNMAMFRCKKDIAIKYSRTLNKH
  FESSSKVAQAPSPCIASTGTPSPLSPMPSPASSVGSQSSAGSVGSSGVAATISTPVTIQN
  MTSSYVTITSHVLTAFDLWEQAEALTRKNKEFFARLSTNVCTLALNSSLVDLVHYTRQGF
  QQLQELTKTP
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Definitive	Genetic Variation	[1]
B-cell neoplasm	DISVY326	Definitive	Genetic Variation	[2]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[6]
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[7]
Cataract	DISUD7SL	Strong	Genetic Variation	[8]
leukaemia	DISS7D1V	Strong	Biomarker	[9]
Leukemia	DISNAKFL	Strong	Biomarker	[10]
Lupus	DISOKJWA	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[13]
Systemic lupus erythematosus	DISI1SZ7	Disputed	Genetic Variation	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[14]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Genetic Variation	[4]
Lewy body dementia	DISAE66J	Limited	Biomarker	[15]
Parkinson disease	DISQVHKL	Limited	Biomarker	[15]

10 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 1 (AFF1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of AF4/FMR2 family member 1 (AFF1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of AF4/FMR2 family member 1 (AFF1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of AF4/FMR2 family member 1 (AFF1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of AF4/FMR2 family member 1 (AFF1).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of AF4/FMR2 family member 1 (AFF1).	[22]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of AF4/FMR2 family member 1 (AFF1).	[23]
Malathion	DMXZ84M	Approved	Malathion increases the expression of AF4/FMR2 family member 1 (AFF1).	[24]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of AF4/FMR2 family member 1 (AFF1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of AF4/FMR2 family member 1 (AFF1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of AF4/FMR2 family member 1 (AFF1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of AF4/FMR2 family member 1 (AFF1).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of AF4/FMR2 family member 1 (AFF1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of AF4/FMR2 family member 1 (AFF1).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of AF4/FMR2 family member 1 (AFF1).	[28]

References

• [1] Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23).Genes Chromosomes Cancer. 2014 Mar;53(3):248-54. doi: 10.1002/gcc.22135. Epub 2013 Dec 5.
• [2] MLL-AF4 gene rearrangement in a child with Epstein-Barr virus-related posttransplant B-cell lymphoma.J Pediatr Hematol Oncol. 2003 Sep;25(9):740-2. doi: 10.1097/00043426-200309000-00013.
• [3] Association study of AFF1 rs340630 polymorphism with genetic susceptibility to rheumatoid arthritis in Chinese population.Braz J Med Biol Res. 2018;51(7):e7126. doi: 10.1590/1414-431x20187126. Epub 2018 May 17.
• [4] Simultaneous involvement of 11q23 translocation resulting in chimeric MLL-AFF1 and a second translocation [t (9;21) (p13; p11.2)] in an infant acute lymphoblastic leukemia patient at relapse: A case report.Medicine (Baltimore). 2018 May;97(21):e10874. doi: 10.1097/MD.0000000000010874.
• [5] Clinical and molecular epidemiology of neonatal leukemia in Brazil.Leuk Lymphoma. 2015 Apr;56(4):903-9. doi: 10.3109/10428194.2014.938327. Epub 2015 Jan 30.
• [6] Genome-wide association study of the rate of cognitive decline in Alzheimer's disease.Alzheimers Dement. 2014 Jan;10(1):45-52. doi: 10.1016/j.jalz.2013.01.008. Epub 2013 Mar 25.
• [7] In silico-guided identification of potential inhibitors against (2)m aggregation in dialysis-related amyloidosis.J Biomol Struct Dyn. 2020 Aug;38(13):3927-3941. doi: 10.1080/07391102.2019.1668852. Epub 2019 Sep 27.
• [8] The locus for an inherited cataract in sheep maps to ovine chromosome 6.Mol Vis. 2012;18:1384-94. Epub 2012 May 31.
• [9] AF4 encodes a ubiquitous protein that in both native and MLL-AF4 fusion types localizes to subnuclear compartments.Blood. 1998 Nov 15;92(10):3841-7.
• [10] Antigen receptor gene rearrangements reflect on the heterogeneity of adult Acute Lymphoblastic Leukaemia (ALL) with implications of cell-origin of ALL subgroups - a UKALLXII study.Br J Haematol. 2010 Feb;148(3):394-401. doi: 10.1111/j.1365-2141.2009.07966.x. Epub 2009 Nov 4.
• [11] A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese.PLoS Genet. 2012 Jan;8(1):e1002455. doi: 10.1371/journal.pgen.1002455. Epub 2012 Jan 26.
• [12] Preclinical PET imaging of HIP/PAP using 1'-(18)F-fluoroethyl--D-lactose.Oncotarget. 2017 Sep 6;8(43):75162-75173. doi: 10.18632/oncotarget.20654. eCollection 2017 Sep 26.
• [13] Real-Time PCR analysis of af4 and dek genes expression in acute promyelocytic leukemia t (15;17) patients.Exp Mol Med. 2004 Jun 30;36(3):279-82. doi: 10.1038/emm.2004.38.
• [14] 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.
• [15] Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials.Acta Neuropathol. 2014;127(6):861-79. doi: 10.1007/s00401-014-1256-4. Epub 2014 Feb 14.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [21] Inorganic arsenic as an endocrine disruptor: modulation of the glucocorticoid receptor pathway in placental cells via CpG methylation. Chem Res Toxicol. 2019 Mar 18;32(3):493-499.
• [22] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [23] 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.
• [24] "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.
• [25] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.