Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG5RVHC)

• DOT Name: Protein AF1q (MLLT11)
• Gene Name: MLLT11
• Related Disease:
  Acute leukaemia
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Acute myelomonocytic leukemia M4
  Advanced cancer
  Bladder cancer
  Breast neoplasm
  Burkitt lymphoma
  Carcinoma of esophagus
  Childhood myelodysplastic syndrome
  Chromosomal disorder
  Colorectal carcinoma
  Epithelial ovarian cancer
  Esophageal cancer
  Metastatic malignant neoplasm
  Neoplasm
  Neoplasm of esophagus
  Ovarian cancer
  Ovarian neoplasm
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  leukaemia
  Leukemia
  Squamous cell carcinoma
  Breast cancer
  Breast carcinoma
  Myelodysplastic syndrome
• UniProt ID: AF1Q_HUMAN
• Pfam ID: PF15017
• Sequence:
  MRDPVSSQYSSFLFWRMPIPELDLSELEGLGLSDTATYKVKDSSVGKMIGQATAADQEKN
  PEGDGLLEYSTFNFWRAPIASIHSFELDLL
• Function: Cofactor for the transcription factor TCF7. Involved in regulation of lymphoid development by driving multipotent hematopoietic progenitor cells towards a T cell fate.
• Tissue Specificity: Expressed in myoepithelial cells of normal breast tissue (at protein level) . Highly expressed in thymus . Expressed in colon, small intestine, prostate and ovary. Not detected in peripheral blood lymphocytes and spleen .

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Genetic Variation	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[3]
Acute myelomonocytic leukemia M4	DISRRMV2	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[8]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[5]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Altered Expression	[9]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[3]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[5]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[3]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[13]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
leukaemia	DISS7D1V	moderate	Biomarker	[14]
Leukemia	DISNAKFL	moderate	Biomarker	[14]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[15]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[16]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[16]
Myelodysplastic syndrome	DISYHNUI	Limited	Altered Expression	[9]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Protein AF1q (MLLT11) affects the response to substance of Fluorouracil.	[40]
Etoposide	DMNH3PG	Approved	Protein AF1q (MLLT11) affects the response to substance of Etoposide.	[40]
Cyclophosphamide	DM4O2Z7	Approved	Protein AF1q (MLLT11) decreases the response to substance of Cyclophosphamide.	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Protein AF1q (MLLT11).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein AF1q (MLLT11).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein AF1q (MLLT11).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein AF1q (MLLT11).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein AF1q (MLLT11).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein AF1q (MLLT11).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein AF1q (MLLT11).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein AF1q (MLLT11).	[24]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Protein AF1q (MLLT11).	[25]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Protein AF1q (MLLT11).	[26]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Protein AF1q (MLLT11).	[27]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Protein AF1q (MLLT11).	[28]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Protein AF1q (MLLT11).	[29]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of Protein AF1q (MLLT11).	[30]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Protein AF1q (MLLT11).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein AF1q (MLLT11).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein AF1q (MLLT11).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein AF1q (MLLT11).	[35]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Protein AF1q (MLLT11).	[36]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Protein AF1q (MLLT11).	[37]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Protein AF1q (MLLT11).	[38]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Protein AF1q (MLLT11).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein AF1q (MLLT11).	[32]

References

• [1] MLL-AF1q fusion resulting from t(1;11) in acute leukemia.Leukemia. 1999 Feb;13(2):302-6. doi: 10.1038/sj.leu.2401299.
• [2] Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia.Blood. 2004 Nov 15;104(10):3058-63. doi: 10.1182/blood-2003-12-4347. Epub 2004 Jun 24.
• [3] Involvement of AF1q/MLLT11 in the progression of ovarian cancer.Oncotarget. 2017 Apr 4;8(14):23246-23264. doi: 10.18632/oncotarget.15574.
• [4] A novel gene, AF1q, fused to MLL in t(1;11) (q21;q23), is specifically expressed in leukemic and immature hematopoietic cells.Blood. 1995 Feb 1;85(3):650-6.
• [5] The Oncogene AF1Q is Associated with WNT and STAT Signaling and Offers a Novel Independent Prognostic Marker in Patients with Resectable Esophageal Cancer.Cells. 2019 Oct 30;8(11):1357. doi: 10.3390/cells8111357.
• [6] MicroRNA-411 Downregulation Enhances Tumor Growth by Upregulating MLLT11 Expression in Human Bladder Cancer.Mol Ther Nucleic Acids. 2018 Jun 1;11:312-322. doi: 10.1016/j.omtn.2018.03.003. Epub 2018 Mar 10.
• [7] Identification of the functional role of AF1Q in the progression of breast cancer.Breast Cancer Res Treat. 2008 Sep;111(1):65-78. doi: 10.1007/s10549-007-9761-y. Epub 2007 Oct 11.
• [8] The evaluation of Cannabidiol's effect on the immunotherapy of Burkitt lymphoma. Biochem Biophys Res Commun. 2019 Nov 26;520(1):225-230. doi: 10.1016/j.bbrc.2019.10.001. Epub 2019 Oct 3.
• [9] Elevated AF1q expression is a poor prognostic marker for adult acute myeloid leukemia patients with normal cytogenetics.Am J Hematol. 2009 May;84(5):308-9. doi: 10.1002/ajh.21396.
• [10] AF1q is a novel TCF7 co-factor which activates CD44 and promotes breast cancer metastasis.Oncotarget. 2015 Aug 21;6(24):20697-710. doi: 10.18632/oncotarget.4136.
• [11] AF1q Mediates Tumor Progression in Colorectal Cancer by Regulating AKT Signaling.Int J Mol Sci. 2017 May 5;18(5):987. doi: 10.3390/ijms18050987.
• [12] AF1q Expression Associates with CD44 and STAT3 and Impairs Overall Survival in Adenoid Cystic Carcinoma of the Head and Neck.Pathol Oncol Res. 2020 Apr;26(2):1287-1292. doi: 10.1007/s12253-019-00696-z. Epub 2019 Jul 4.
• [13] The Interaction of TXNIP and AFq1 Genes Increases the Susceptibility of Schizophrenia.Mol Neurobiol. 2017 Aug;54(6):4806-4812. doi: 10.1007/s12035-016-9954-7. Epub 2016 Aug 10.
• [14] Activation of Wnt signaling pathway by AF1q enriches stem-like population and enhance mammosphere formation of breast cells.Biochem Biophys Res Commun. 2017 Mar 18;484(4):884-889. doi: 10.1016/j.bbrc.2017.02.018. Epub 2017 Feb 8.
• [15] AF1q enhancement of gamma irradiation-induced apoptosis by up-regulation of BAD expression via NF-kappaB in human squamous carcinoma A431 cells.Oncol Rep. 2010 Aug;24(2):547-54.
• [16] Recombinant expression and purification of AF1q and its interaction with T-cell Factor 7.Protein Expr Purif. 2020 Jan;165:105499. doi: 10.1016/j.pep.2019.105499. Epub 2019 Sep 18.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [19] 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.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [23] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [24] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [25] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [26] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [27] 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.
• [28] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [29] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [30] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [31] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [32] 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.
• [33] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [34] 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.
• [35] Exposure to environmental bisphenol A inhibits HTR-8/SVneo cell migration and invasion. J Biomed Res. 2020 Jun 30;34(5):369-378. doi: 10.7555/JBR.34.20200013.
• [36] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [37] 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.
• [38] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [39] The marine toxin okadaic acid induces alterations in the expression level of cancer-related genes in human neuronal cells. Ecotoxicol Environ Saf. 2013 Jun;92:303-11. doi: 10.1016/j.ecoenv.2013.03.009. Epub 2013 Apr 3.
• [40] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [41] The evaluation of Cannabidiol's effect on the immunotherapy of Burkitt lymphoma. Biochem Biophys Res Commun. 2019 Nov 26;520(1):225-230. doi: 10.1016/j.bbrc.2019.10.001. Epub 2019 Oct 3.