Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH1HRW5)

• DOT Name: Homeobox protein Hox-B4 (HOXB4)
• Synonyms: Homeobox protein Hox-2.6; Homeobox protein Hox-2F
• Gene Name: HOXB4
• Related Disease:
  Acute leukaemia
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Adult glioblastoma
  Aplastic anemia
  Breast cancer
  Breast carcinoma
  Campomelic dysplasia
  Endometriosis
  Glioblastoma multiforme
  Haematological malignancy
  Idiopathic thrombocytopenic purpura
  Immunodeficiency
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Medulloblastoma
  Neoplasm
  Neuroblastoma
  Renal carcinoma
  Renal cell carcinoma
  Skin disease
  Wilms tumor
  Metachromatic leukodystrophy
  Multiple sclerosis
  Mesothelioma
• UniProt ID: HXB4_HUMAN
• Pfam ID: PF00046
• Sequence:
  MAMSSFLINSNYVDPKFPPCEEYSQSDYLPSDHSPGYYAGGQRRESSFQPEAGFGRRAAC
  TVQRYAACRDPGPPPPPPPPPPPPPPPGLSPRAPAPPPAGALLPEPGQRCEAVSSSPPPP
  PCAQNPLHPSPSHSACKEPVVYPWMRKVHVSTVNPNYAGGEPKRSRTAYTRQQVLELEKE
  FHYNRYLTRRRRVEIAHALCLSERQIKIWFQNRRMKWKKDHKLPNTKIRSGGAAGSAGGP
  PGRPNGGPRAL
• Function: Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
• Reactome Pathway: Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Strong	Genetic Variation	[4]
Aplastic anemia	DISJRSC0	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Campomelic dysplasia	DISVTW53	Strong	Biomarker	[7]
Endometriosis	DISX1AG8	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[4]
Haematological malignancy	DISCDP7W	Strong	Altered Expression	[9]
Idiopathic thrombocytopenic purpura	DISFKGJU	Strong	Altered Expression	[5]
Immunodeficiency	DIS093I0	Strong	Altered Expression	[10]
leukaemia	DISS7D1V	Strong	Biomarker	[9]
Leukemia	DISNAKFL	Strong	Biomarker	[9]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[11]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[13]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[4]
Renal carcinoma	DISER9XT	Strong	Genetic Variation	[14]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[14]
Skin disease	DISDW8R6	Strong	Altered Expression	[15]
Wilms tumor	DISB6T16	Strong	Altered Expression	[13]
Metachromatic leukodystrophy	DIS3OMWS	moderate	Altered Expression	[16]
Multiple sclerosis	DISB2WZI	moderate	Altered Expression	[16]
Mesothelioma	DISKWK9M	Limited	Altered Expression	[17]

5 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 Hox-B4 (HOXB4).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeobox protein Hox-B4 (HOXB4).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Homeobox protein Hox-B4 (HOXB4).	[21]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Homeobox protein Hox-B4 (HOXB4).	[22]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Homeobox protein Hox-B4 (HOXB4).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Homeobox protein Hox-B4 (HOXB4).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homeobox protein Hox-B4 (HOXB4).	[24]

References

• [1] Controlled stem cell amplification by HOXB4 depends on its unique proline-rich region near the N terminus.Blood. 2017 Jan 19;129(3):319-323. doi: 10.1182/blood-2016-04-706978. Epub 2016 Nov 8.
• [2] Expression of selected human HOX-2 genes in B/T acute lymphoid leukemia and interleukin-2/interleukin-1 beta-stimulated natural killer lymphocytes.Blood. 1992 Jul 1;80(1):185-93.
• [3] Identification of differentially methylated markers among cytogenetic risk groups of acute myeloid leukemia.Epigenetics. 2015;10(6):526-35. doi: 10.1080/15592294.2015.1048060.
• [4] Modulation of HOX2 gene expression following differentiation of neuronal cell lines.Differentiation. 1992 Sep;51(1):39-47. doi: 10.1111/j.1432-0436.1992.tb00678.x.
• [5] Gene expression profiling identifies HOXB4 as a direct downstream target of GATA-2 in human CD34+ hematopoietic cells.PLoS One. 2012;7(9):e40959. doi: 10.1371/journal.pone.0040959. Epub 2012 Sep 24.
• [6] Homeobox B4 inhibits breast cancer cell migration by directly binding to StAR-related lipid transfer domain protein 13.Oncol Lett. 2017 Oct;14(4):4625-4632. doi: 10.3892/ol.2017.6825. Epub 2017 Aug 25.
• [7] Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1.Nat Genet. 1993 Jun;4(2):170-4. doi: 10.1038/ng0693-170.
• [8] HOXB4 Immunoreactivity in Endometrial Tissues From Women With or Without Endometriosis.Reprod Sci. 2018 Jun;25(6):950-957. doi: 10.1177/1933719117732164. Epub 2017 Oct 2.
• [9] Downregulation of Prdm16 mRNA is a specific antileukemic mechanism during HOXB4-mediated HSC expansion in vivo.Blood. 2014 Sep 11;124(11):1737-47. doi: 10.1182/blood-2013-10-534735. Epub 2014 Jul 31.
• [10] Lentiviral-mediated HoxB4 expression in human embryonic stem cells initiates early hematopoiesis in a dose-dependent manner but does not promote myeloid differentiation.Stem Cells. 2008 Oct;26(10):2455-66. doi: 10.1634/stemcells.2007-0876. Epub 2008 Jul 10.
• [11] Identification and validation of candidate epigenetic biomarkers in lung adenocarcinoma.Sci Rep. 2016 Oct 26;6:35807. doi: 10.1038/srep35807.
• [12] Functional analysis of HOXA10 and HOXB4 in human medulloblastoma cell lines.Int J Oncol. 2017 Dec;51(6):1929-1940. doi: 10.3892/ijo.2017.4151. Epub 2017 Oct 10.
• [13] Identification of the transcription factor HOXB4 as a novel target of miR-23a.Genes Chromosomes Cancer. 2013 Aug;52(8):709-15. doi: 10.1002/gcc.22066. Epub 2013 Apr 30.
• [14] HOX gene expression in normal and neoplastic human kidney.Int J Cancer. 1992 Jul 30;51(6):892-7. doi: 10.1002/ijc.2910510610.
• [15] HOXB4 homeodomain protein is expressed in developing epidermis and skin disorders and modulates keratinocyte proliferation.Dev Dyn. 2002 May;224(1):58-68. doi: 10.1002/dvdy.10085.
• [16] Successful treatment of metachromatic leukodystrophy using bone marrow transplantation of HoxB4 overexpressing cells.Mol Ther. 2010 Jul;18(7):1373-8. doi: 10.1038/mt.2010.74. Epub 2010 Apr 27.
• [17] HOX transcription factors are potential targets and markers in malignant mesothelioma.BMC Cancer. 2016 Feb 11;16:85. doi: 10.1186/s12885-016-2106-7.
• [18] 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.
• [19] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [20] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [21] 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.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [24] 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.