Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT584VOQ)

• DOT Name: Homeobox protein MIXL1 (MIXL1)
• Synonyms: Homeodomain protein MIX; hMix; MIX1 homeobox-like protein 1; Mix.1 homeobox-like protein
• Gene Name: MIXL1
• Related Disease:
  Adult lymphoma
  B-cell lymphoma
  Burkitt lymphoma
  Classic Hodgkin lymphoma
  Haematological malignancy
  Lymphoma
  Neoplasm
  Non-hodgkin lymphoma
  Pediatric lymphoma
  Acute myelogenous leukaemia
  Bipolar disorder
  Bronchopulmonary dysplasia
  Colon cancer
  Colon carcinoma
  Diabetic kidney disease
  Hepatitis C virus infection
  Major depressive disorder
  Nocturia
  Non-insulin dependent diabetes
  Restless legs syndrome
  Periodontitis
  Type-1/2 diabetes
• UniProt ID: MIXL1_HUMAN
• Pfam ID: PF00046
• Sequence:
  MATAESRALQFAEGAAFPAYRAPHAGGALLPPPSPAAALLPAPPAGPGPATFAGFLGRDP
  GPAPPPPASLGSPAPPKGAAAPSASQRRKRTSFSAEQLQLLELVFRRTRYPDIHLRERLA
  ALTLLPESRIQVWFQNRRAKSRRQSGKSFQPLARPEIILNHCAPGTETKCLKPQLPLEVD
  VNCLPEPNGVGGGISDSSSQGQNFETCSPLSEDIGSKLDSWEEHIFSAFGNF
• Function: Transcription factor that play a central role in proper axial mesendoderm morphogenesis and endoderm formation. Required for efficient differentiation of cells from the primitive streak stage to blood, by acting early in the recruitment and/or expansion of mesodermal progenitors to the hemangioblastic and hematopoietic lineages. Also involved in the morphogenesis of the heart and the gut during embryogenesis. Acts as a negative regulator of brachyury expression.
• Tissue Specificity: Restricted to progenitors and secondary lymph tissues. In normal hematopoiesis, it is restricted to immature B- and T-lymphoid cells. Present in differentiating embryonic stem cells (at protein level).
• Reactome Pathway:
  Formation of definitive endoderm (R-HSA-9823730)
  Germ layer formation at gastrulation (R-HSA-9754189)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Definitive	Altered Expression	[1]
B-cell lymphoma	DISIH1YQ	Definitive	Altered Expression	[1]
Burkitt lymphoma	DIS9D5XU	Definitive	Altered Expression	[1]
Classic Hodgkin lymphoma	DISV1LU6	Definitive	Altered Expression	[1]
Haematological malignancy	DISCDP7W	Definitive	Altered Expression	[1]
Lymphoma	DISN6V4S	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Non-hodgkin lymphoma	DISS2Y8A	Definitive	Altered Expression	[1]
Pediatric lymphoma	DIS51BK2	Definitive	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[3]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[7]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[8]
Nocturia	DISD1F1J	Strong	Genetic Variation	[9]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[6]
Restless legs syndrome	DISNWY00	Strong	Biomarker	[10]
Periodontitis	DISI9JOI	Limited	Biomarker	[11]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[12]

14 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 Homeobox protein MIXL1 (MIXL1).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homeobox protein MIXL1 (MIXL1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Homeobox protein MIXL1 (MIXL1).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Homeobox protein MIXL1 (MIXL1).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Homeobox protein MIXL1 (MIXL1).	[17]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Homeobox protein MIXL1 (MIXL1).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Homeobox protein MIXL1 (MIXL1).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Homeobox protein MIXL1 (MIXL1).	[17]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Homeobox protein MIXL1 (MIXL1).	[19]
Dolutegravir	DMCZGRE	Approved	Dolutegravir increases the expression of Homeobox protein MIXL1 (MIXL1).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Homeobox protein MIXL1 (MIXL1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Homeobox protein MIXL1 (MIXL1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Homeobox protein MIXL1 (MIXL1).	[24]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Homeobox protein MIXL1 (MIXL1).	[16]

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 Homeobox protein MIXL1 (MIXL1).	[21]

References

• [1] Differential expression of the human MIXL1 gene product in non-Hodgkin and Hodgkin lymphomas.Hum Pathol. 2007 Mar;38(3):500-7. doi: 10.1016/j.humpath.2006.09.020.
• [2] A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy.Oncotarget. 2014 Dec 30;5(24):12675-93. doi: 10.18632/oncotarget.2564.
• [3] Aggressiveness in depression: a neglected symptom possibly associated with bipolarity and mixed features.Acta Psychiatr Scand. 2017 Oct;136(4):362-372. doi: 10.1111/acps.12777. Epub 2017 Jul 25.
• [4] Molecular identification of bacteria in tracheal aspirate fluid from mechanically ventilated preterm infants.PLoS One. 2011;6(10):e25959. doi: 10.1371/journal.pone.0025959. Epub 2011 Oct 10.
• [5] Lycopene, sulforaphane, quercetin, and curcumin applied together show improved antiproliferative potential in colon cancer cells in vitro.J Food Biochem. 2019 Apr;43(4):e12802. doi: 10.1111/jfbc.12802. Epub 2019 Feb 11.
• [6] Design and validation of a scoring model for differential diagnosis of diabetic nephropathy and nondiabetic renal diseases in type 2 diabetic patients.J Diabetes. 2020 Mar;12(3):237-246. doi: 10.1111/1753-0407.12994. Epub 2019 Dec 2.
• [7] Clinicopathological features of hepatitis C virus disease after living donor liver transplantation: relationship with in situ hybridisation data.Pathology. 2011 Feb;43(2):156-60. doi: 10.1097/PAT.0b013e32834317ed.
• [8] Antidepressant-induced hypomania/mania in patients with major depression: Evidence from the BRIDGE-II-MIX study.J Affect Disord. 2017 Sep;219:187-192. doi: 10.1016/j.jad.2017.05.035. Epub 2017 May 24.
• [9] Modified U-Shaped ileal neobladder designed for facilitating neobladder-urethral anastomosis in extracorporeal reconstruction after robotic-assisted radical cystectomy.J Cancer Res Ther. 2019 Mar;15(Supplement):S51-S55. doi: 10.4103/jcrt.JCRT_538_17.
• [10] Liver disease severity is poorly related to the presence of restless leg syndrome in patients with cirrhosis.Neurol India. 2019 May-Jun;67(3):732-737. doi: 10.4103/0028-3886.263171.
• [11] Indications for Extraction before Implant Therapy: Focus on Endodontic Status.J Endod. 2019 May;45(5):532-537. doi: 10.1016/j.joen.2019.01.008. Epub 2019 Mar 8.
• [12] Evaluation of the Antioxidant and Antiglycation Effects of Lactarius deterrimus and Castanea sativa Extracts on Hepatorenal Injury in Streptozotocin-Induced Diabetic Rats.Front Pharmacol. 2017 Oct 31;8:793. doi: 10.3389/fphar.2017.00793. eCollection 2017.
• [13] 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.
• [14] 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.
• [15] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [20] Dolutegravir Impairs Stem Cell-Based 3D Morphogenesis Models in a Manner Dependent on Dose and Timing of Exposure: An Implication for Its Developmental Toxicity. Toxicol Sci. 2021 Nov 24;184(2):191-203. doi: 10.1093/toxsci/kfab112.
• [21] 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.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.