Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO73DZ2)

• DOT Name: Thrombopoietin (THPO)
• Synonyms: C-mpl ligand; ML; Megakaryocyte colony-stimulating factor; Megakaryocyte growth and development factor; MGDF; Myeloproliferative leukemia virus oncogene ligand
• Gene Name: THPO
• Related Disease:
  Thrombocythemia 1
  Congenital amegakaryocytic thrombocytopenia
  Hereditary thrombocytosis with transverse limb defect
  Obsolete congenital amegakaryocytic thrombocytopenia
  Obsolete hereditary isolated aplastic anemia
  Thrombocythemia
• UniProt ID: TPO_HUMAN
• PDB ID: 1V7M; 1V7N; 8G04
• Pfam ID: PF00758
• Sequence:
  MELTELLLVVMLLLTARLTLSSPAPPACDLRVLSKLLRDSHVLHSRLSQCPEVHPLPTPV
  LLPAVDFSLGEWKTQMEETKAQDILGAVTLLLEGVMAARGQLGPTCLSSLLGQLSGQVRL
  LLGALQSLLGTQLPPQGRTTAHKDPNAIFLSFQHLLRGKVRFLMLVGGSTLCVRRAPPTT
  AVPSRTSLVLTLNELPNRTSGLLETNFTASARTTGSGLLKWQQGFRAKIPGLLNQTSRSL
  DQIPGYLNRIHELLNGTRGLFPGPSRRTLGAPDISSGTSDTGSLPPNLQPGYSPSPTHPP
  TGQYTLFPLPPTLPTPVVQLHPLLPDPSAPTPTPTSPLLNTSYTHSQNLSQEG
• Function: Lineage-specific cytokine affecting the proliferation and maturation of megakaryocytes from their committed progenitor cells. It acts at a late stage of megakaryocyte development. It may be the major physiological regulator of circulating platelets.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  JAK-STAT sig.ling pathway (hsa04630)
  Hematopoietic cell lineage (hsa04640)
• Reactome Pathway: Platelet Aggregation (Plug Formation) (R-HSA-76009)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thrombocythemia 1	DISVREYO	Strong	Autosomal dominant	[1]
Congenital amegakaryocytic thrombocytopenia	DISA8WAP	Moderate	Autosomal recessive	[2]
Hereditary thrombocytosis with transverse limb defect	DISFWEQH	Supportive	Autosomal dominant	[3]
Obsolete congenital amegakaryocytic thrombocytopenia	DISTJQ17	Supportive	Autosomal recessive	[4]
Obsolete hereditary isolated aplastic anemia	DIS2B0NW	Supportive	Autosomal dominant	[5]
Thrombocythemia	DISL38J3	Supportive	Autosomal dominant	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methylprednisolone	DM4BDON	Approved	Thrombopoietin (THPO) increases the Idiopathic thrombocytopenic purpura ADR of Methylprednisolone.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Thrombopoietin (THPO).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Thrombopoietin (THPO).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Thrombopoietin (THPO).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Thrombopoietin (THPO).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Thrombopoietin (THPO).	[11]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Thrombopoietin (THPO).	[12]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Thrombopoietin (THPO).	[13]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of Thrombopoietin (THPO).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Thrombopoietin (THPO).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Thrombopoietin (THPO).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Thrombopoietin (THPO).	[17]

References

• [1] 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.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Association of hereditary thrombocythemia and distal limb defects with a thrombopoietin gene mutation. Blood. 2009 Aug 20;114(8):1655-7. doi: 10.1182/blood-2009-04-217851. Epub 2009 Jun 24.
• [4] Thrombopoietin mutation in congenital amegakaryocytic thrombocytopenia treatable with?romiplostim. EMBO Mol Med. 2018 Jan;10(1):63-75. doi: 10.15252/emmm.201708168.
• [5] Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia. Blood. 2013 Nov 14;122(20):3440-9. doi: 10.1182/blood-2012-12-473538. Epub 2013 Oct 1.
• [6] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 1,25(OH)2-vitamin D3 inhibits proliferation and decreases production of monocyte chemoattractant protein-1, thrombopoietin, VEGF, and angiogenin by human annulus cells in vitro. Spine (Phila Pa 1976). 2008 Apr 1;33(7):755-65. doi: 10.1097/BRS.0b013e3181695d59.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma. Br J Cancer. 2010 Jun 29;103(1):52-60.
• [13] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [14] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.