Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXP9FH1)

• DOT Name: Motor neuron and pancreas homeobox protein 1 (MNX1)
• Synonyms: Homeobox protein HB9
• Gene Name: MNX1
• Related Disease:
  Currarino triad
  Acute megakaryoblastic leukemia
  Acute myelogenous leukaemia
  Adult glioblastoma
  Adult teratoma
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Childhood acute megakaryoblastic leukemia
  Classic Hodgkin lymphoma
  Colorectal carcinoma
  Endocrine disease
  Fetal growth restriction
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Holoprosencephaly
  leukaemia
  Leukemia
  Myeloid leukaemia
  Myotonic dystrophy type 1
  Neonatal diabetes mellitus
  Non-insulin dependent diabetes
  Permanent neonatal diabetes mellitus
  Preaxial polydactyly of fingers
  Teratoma
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Hirschsprung disease
  Isolated congenital microcephaly
  Mantle cell lymphoma
  Small lymphocytic lymphoma
  Intellectual disability
  Neoplasm
  Acute myelomonocytic leukemia M4
  Advanced cancer
  Amyotrophic lateral sclerosis
  Breast neoplasm
  Insulinoma
  Neuroblastoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: MNX1_HUMAN
• Pfam ID: PF00046
• Sequence:
  MEKSKNFRIDALLAVDPPRAASAQSAPLALVTSLAAAASGTGGGGGGGGASGGTSGSCSP
  ASSEPPAAPADRLRAESPSPPRLLAAHCALLPKPGFLGAGGGGGGTGGGHGGPHHHAHPG
  AAAAAAAAAAAAAAGGLALGLHPGGAQGGAGLPAQAALYGHPVYGYSAAAAAAALAGQHP
  ALSYSYPQVQGAHPAHPADPIKLGAGTFQLDQWLRASTAGMILPKMPDFNSQAQSNLLGK
  CRRPRTAFTSQQLLELEHQFKLNKYLSRPKRFEVATSLMLTETQVKIWFQNRRMKWKRSK
  KAKEQAAQEAEKQKGGGGGAGKGGAEEPGAEELLGPPAPGDKGSGRRLRDLRDSDPEEDE
  DEDDEDHFPYSNGASVHAASSDCSSEDDSPPPRPSHQPAPQ
• Function: Transcription factor. Recognizes and binds to the regulatory elements of target genes, such as visual system homeobox CHX10, negatively modulating transcription. Plays a role in establishing motor neuron identity, in concert with LIM domain transcription factor LMO4. Involved in negatively modulating transcription of interneuron genes in motor neurons, acting, at least in part, by blocking regulatory sequence interactions of the ISL1-LHX3 complex. Involved in pancreas development and function; may play a role in pancreatic cell fate specification.
• Tissue Specificity: Expressed in lymphoid and pancreatic tissues.
• KEGG Pathway: Maturity onset diabetes of the young (hsa04950)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Currarino triad	DISKH37P	Definitive	Autosomal dominant	[1]
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Adult teratoma	DISBY81U	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[8]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[8]
Childhood acute megakaryoblastic leukemia	DIS5VZDR	Strong	Altered Expression	[2]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Endocrine disease	DISRGY2N	Strong	Genetic Variation	[11]
Fetal growth restriction	DIS5WEJ5	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[13]
Holoprosencephaly	DISR35EC	Strong	Altered Expression	[14]
leukaemia	DISS7D1V	Strong	Biomarker	[15]
Leukemia	DISNAKFL	Strong	Genetic Variation	[16]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[17]
Myotonic dystrophy type 1	DISJC0OX	Strong	Altered Expression	[18]
Neonatal diabetes mellitus	DISFHF9K	Strong	Autosomal recessive	[19]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[20]
Permanent neonatal diabetes mellitus	DIS5AEXS	Strong	Autosomal recessive	[19]
Preaxial polydactyly of fingers	DISXO6C9	Strong	Genetic Variation	[21]
Teratoma	DIS6ICY4	Strong	Biomarker	[5]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[18]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[6]
Hirschsprung disease	DISUUSM1	moderate	Genetic Variation	[22]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[23]
Mantle cell lymphoma	DISFREOV	moderate	Biomarker	[24]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[24]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[25]
Neoplasm	DISZKGEW	Disputed	Biomarker	[26]
Acute myelomonocytic leukemia M4	DISRRMV2	Limited	Altered Expression	[27]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[28]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[29]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[7]
Insulinoma	DISIU1JS	Limited	Biomarker	[11]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[30]
Prostate cancer	DISF190Y	Limited	Altered Expression	[28]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[28]

3 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 Motor neuron and pancreas homeobox protein 1 (MNX1).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Motor neuron and pancreas homeobox protein 1 (MNX1).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Motor neuron and pancreas homeobox protein 1 (MNX1).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Motor neuron and pancreas homeobox protein 1 (MNX1).	[32]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Motor neuron and pancreas homeobox protein 1 (MNX1).	[33]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Motor neuron and pancreas homeobox protein 1 (MNX1).	[34]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Motor neuron and pancreas homeobox protein 1 (MNX1).	[35]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Motor neuron and pancreas homeobox protein 1 (MNX1).	[36]

References

• [1] Involvement of the HLXB9 homeobox gene in Currarino syndrome. Am J Hum Genet. 2000 Jan;66(1):312-9. doi: 10.1086/302723.
• [2] MNX1-ETV6 fusion gene in an acute megakaryoblastic leukemia and expression of the MNX1 gene in leukemia and normal B cell lines.Cancer Genet Cytogenet. 2008 Oct 15;186(2):115-9. doi: 10.1016/j.cancergencyto.2008.06.009.
• [3] Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is associated with infancy and trisomy 19: Data from Nordic Society for Pediatric Hematology and Oncology (NOPHO-AML) and review of the literature.Genes Chromosomes Cancer. 2018 Jul;57(7):359-365. doi: 10.1002/gcc.22538. Epub 2018 Apr 30.
• [4] Upregulated expression of MNX1-AS1 long noncoding RNA predicts poor prognosis in gastric cancer.Bosn J Basic Med Sci. 2019 May 20;19(2):164-171. doi: 10.17305/bjbms.2019.3713.
• [5] Prenatal diagnosis of sacrococcygeal teratoma with constitutional partial monosomy 7q/trisomy 2p.Prenat Diagn. 2003 Dec 15;23(12):981-4. doi: 10.1002/pd.742.
• [6] Motor neuron and pancreas homeobox1/HLXB9 promotes sustained proliferation in bladder cancer by upregulating CCNE1/2.J Exp Clin Cancer Res. 2018 Jul 16;37(1):154. doi: 10.1186/s13046-018-0829-9.
• [7] MNX1-AS1 is a functional oncogene that induces EMT and activates the AKT/mTOR pathway and MNX1 in breast cancer.Cancer Manag Res. 2019 Jan 17;11:803-812. doi: 10.2147/CMAR.S188007. eCollection 2019.
• [8] Motor Neuron and Pancreas Homeobox 1 (MNX1) Is Involved in Promoting Squamous Cervical Cancer Proliferation via Regulating Cyclin E.Med Sci Monit. 2019 Aug 22;25:6304-6312. doi: 10.12659/MSM.914233.
• [9] HLXB9 activates IL6 in Hodgkin lymphoma cell lines and is regulated by PI3K signalling involving E2F3.Leukemia. 2005 May;19(5):841-6. doi: 10.1038/sj.leu.2403716.
• [10] MNX1 promotes cell proliferation and activates Wnt/-catenin signaling in colorectal cancer.Cell Biol Int. 2019 Apr;43(4):402-408. doi: 10.1002/cbin.11096. Epub 2019 Feb 19.
• [11] Functional Defects From Endocrine Disease-Associated Mutations in HLXB9 and Its Interacting Partner, NONO.Endocrinology. 2018 Feb 1;159(2):1199-1212. doi: 10.1210/en.2017-03155.
• [12] Transcription factor gene MNX1 is a novel cause of permanent neonatal diabetes in a consanguineous family.Diabetes Metab. 2013 May;39(3):276-80. doi: 10.1016/j.diabet.2013.02.007. Epub 2013 Apr 4.
• [13] The homeobox gene HLXB9 is upregulated in a morphological subset of poorly differentiated hepatocellular carcinoma.Virchows Arch. 2011 Jun;458(6):697-708. doi: 10.1007/s00428-011-1070-5. Epub 2011 Apr 12.
• [14] Minimal clinical expression of the holoprosencephaly spectrum and of Currarino syndrome due to different cytogenetic rearrangements deleting the Sonic Hedgehog gene and the HLXB9 gene at 7q36.3.Am J Med Genet A. 2004 Jul 1;128A(1):85-92. doi: 10.1002/ajmg.a.30031.
• [15] The dual role of HLXB9 in leukemia.Pediatr Blood Cancer. 2011 Mar;56(3):349-52. doi: 10.1002/pbc.22679.
• [16] Nuclear Repositioning of the Non-Translocated HLXB9 Allele in the Leukaemia Cell Line GDM-1 Harbouring a t(6;7)(q23;q36).Cytogenet Genome Res. 2017;153(1):10-17. doi: 10.1159/000480745. Epub 2017 Sep 29.
• [17] High incidence of t(7;12)(q36;p13) in infant AML but not in infant ALL, with a dismal outcome and ectopic expression of HLXB9.Genes Chromosomes Cancer. 2006 Aug;45(8):731-9. doi: 10.1002/gcc.20335.
• [18] The synthetic pyrethroid deltamethrin impairs zebrafish (Danio rerio) swim bladder development.Sci Total Environ. 2020 Jan 20;701:134870. doi: 10.1016/j.scitotenv.2019.134870. Epub 2019 Oct 31.
• [19] 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.
• [20] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [21] A physical and transcriptional map of the preaxial polydactyly locus on chromosome 7q36.Genomics. 1999 May 1;57(3):342-51. doi: 10.1006/geno.1999.5796.
• [22] Adult index patient with Currarino syndrome due to a novel HLXB9 mutation, c.336dupG (p.P113fsX224), presenting with Hirschsprung's disease, cephalgia, and lumbodynia.Birth Defects Res A Clin Mol Teratol. 2007 Mar;79(3):249-51. doi: 10.1002/bdra.20340.
• [23] Microcephaly, sensorineural deafness and Currarino triad with duplication-deletion of distal 7q.Eur J Pediatr. 2010 Apr;169(4):475-81. doi: 10.1007/s00431-009-1061-6. Epub 2009 Oct 17.
• [24] Mantle cell lymphoma displays a homogenous methylation profile: a comparative analysis with chronic lymphocytic leukemia.Am J Hematol. 2012 Apr;87(4):361-7. doi: 10.1002/ajh.23115. Epub 2012 Feb 28.
• [25] Phenotype analysis impacts testing strategy in patients with Currarino syndrome.Clin Genet. 2016 Jan;89(1):109-14. doi: 10.1111/cge.12572. Epub 2015 Mar 15.
• [26] Expression, Clinical Significance, and Functional Prediction of MNX1 in Breast Cancer.Mol Ther Nucleic Acids. 2018 Dec 7;13:399-406. doi: 10.1016/j.omtn.2018.09.014. Epub 2018 Sep 27.
• [27] Activation of HLXB9 by juxtaposition with MYB via formation of t(6;7)(q23;q36) in an AML-M4 cell line (GDM-1).Genes Chromosomes Cancer. 2005 Feb;42(2):170-8. doi: 10.1002/gcc.20113.
• [28] RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression. Cancer Res. 2017 Aug 15;77(16):4247-4257.
• [29] Generation and characterization of transgenic mice expressing mitochondrial targeted red fluorescent protein selectively in neurons: modeling mitochondriopathy in excitotoxicity and amyotrophic lateral sclerosis.Mol Neurodegener. 2011 Nov 2;6:75. doi: 10.1186/1750-1326-6-75.
• [30] HLXB9 gene expression, and nuclear location during in vitro neuronal differentiation in the SK-N-BE neuroblastoma cell line.PLoS One. 2014 Aug 19;9(8):e105481. doi: 10.1371/journal.pone.0105481. eCollection 2014.
• [31] 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.
• [32] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [33] 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.
• [34] 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.
• [35] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [36] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [37] 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.
• [38] 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.