Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVL4NSU)

• DOT Name: Hemoglobin subunit gamma-1 (HBG1)
• Synonyms: Gamma-1-globin; Hb F Agamma; Hemoglobin gamma-1 chain; Hemoglobin gamma-A chain
• Gene Name: HBG1
• Related Disease:
  Acute megakaryoblastic leukemia
  Hereditary gingival fibromatosis
  High blood pressure
  Malaria
  Metabolic disorder
  Alpha thalassemia
  B-cell neoplasm
  Beta-thalassemia intermedia
  Beta-thalassemia major
  Cardiac arrest
  Erythrocyte disorder
  Hematologic disease
  Immunodeficiency
  Leukemia
  Melorheostosis
  Myeloid leukaemia
  Parkinson disease
  Prostate cancer
  Prostate neoplasm
  Sweetener
  Synovial sarcoma
  Thalassemia
  Triple negative breast cancer
  Acute erythroid leukemia
  Anemia
  Hemoglobinopathy
  Delta-beta-thalassemia
  Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
  Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
  Chronic myelomonocytic leukaemia
  Congenital heart disease
  Myelodysplastic syndrome
• UniProt ID: HBG1_HUMAN
• PDB ID: 1I3D; 1I3E
• Pfam ID: PF00042
• Sequence:
  MGHFTEEDKATITSLWGKVNVEDAGGETLGRLLVVYPWTQRFFDSFGNLSSASAIMGNPK
  VKAHGKKVLTSLGDATKHLDDLKGTFAQLSELHCDKLHVDPENFKLLGNVLVTVLAIHFG
  KEFTPEVQASWQKMVTAVASALSSRYH
• Function: Gamma chains make up the fetal hemoglobin F, in combination with alpha chains.
• Tissue Specificity: Red blood cells.
• Reactome Pathway: Factors involved in megakaryocyte development and platelet production (R-HSA-983231)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute megakaryoblastic leukemia	DIS0JX3M	Definitive	Altered Expression	[1]
Hereditary gingival fibromatosis	DISN1ML3	Definitive	Genetic Variation	[2]
High blood pressure	DISY2OHH	Definitive	Biomarker	[3]
Malaria	DISQ9Y50	Definitive	Altered Expression	[3]
Metabolic disorder	DIS71G5H	Definitive	Altered Expression	[3]
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[4]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[5]
Beta-thalassemia intermedia	DISYQ0NL	Strong	Altered Expression	[6]
Beta-thalassemia major	DISW06BV	Strong	Biomarker	[7]
Cardiac arrest	DIS9DIA4	Strong	Altered Expression	[8]
Erythrocyte disorder	DISDMSC5	Strong	Biomarker	[9]
Hematologic disease	DIS9XD9A	Strong	Altered Expression	[10]
Immunodeficiency	DIS093I0	Strong	Biomarker	[11]
Leukemia	DISNAKFL	Strong	Altered Expression	[12]
Melorheostosis	DISIMCL3	Strong	Altered Expression	[13]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[14]
Parkinson disease	DISQVHKL	Strong	Biomarker	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[16]
Sweetener	DISDGALM	Strong	Biomarker	[17]
Synovial sarcoma	DISEZJS7	Strong	Biomarker	[17]
Thalassemia	DIS76XZB	Strong	Biomarker	[18]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[19]
Acute erythroid leukemia	DISZFC1O	moderate	Altered Expression	[20]
Anemia	DISTVL0C	moderate	Biomarker	[11]
Hemoglobinopathy	DISCT4GX	moderate	Altered Expression	[21]
Delta-beta-thalassemia	DIS6CWYR	Supportive	Autosomal recessive	[22]
Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome	DISD21FA	Supportive	Autosomal dominant	[23]
Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome	DISK38J4	Supportive	Autosomal recessive	[24]
Chronic myelomonocytic leukaemia	DISDN5P7	Limited	Altered Expression	[25]
Congenital heart disease	DISQBA23	Limited	Genetic Variation	[26]
Myelodysplastic syndrome	DISYHNUI	Limited	Biomarker	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hemoglobin subunit gamma-1 (HBG1).	[28]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Hemoglobin subunit gamma-1 (HBG1).	[29]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Hemoglobin subunit gamma-1 (HBG1).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Hemoglobin subunit gamma-1 (HBG1).	[31]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol increases the expression of Hemoglobin subunit gamma-1 (HBG1).	[32]

References

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• [2] A novel locus for maternally inherited human gingival fibromatosis at chromosome 11p15.Hum Genet. 2007 Mar;121(1):113-23. doi: 10.1007/s00439-006-0283-1. Epub 2006 Oct 31.
• [3] Evolutionary context for the association of -globin, serum uric acid, and hypertension in African Americans.BMC Med Genet. 2015 Nov 5;16:103. doi: 10.1186/s12881-015-0249-z.
• [4] Molecular, hematological and clinical aspects of thalassemia major and thalassemia intermedia associated with Hb E-beta-thalassemia in Northeast Thailand.Blood Cells Mol Dis. 2009 Jan-Feb;42(1):32-5. doi: 10.1016/j.bcmd.2008.09.002. Epub 2008 Oct 23.
• [5] Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice.Blood. 2013 Mar 28;121(13):2553-62. doi: 10.1182/blood-2012-06-434530. Epub 2013 Jan 29.
• [6] Increased gamma-globin gene expression in beta-thalassemia intermedia patients correlates with a mutation in 3'HS1.Am J Hematol. 2007 Nov;82(11):1005-9. doi: 10.1002/ajh.20979.
• [7] Reciprocal regulation of -globin expression by exo-miRNAs: Relevance to -globin silencing in -thalassemia major.Sci Rep. 2017 Mar 16;7(1):202. doi: 10.1038/s41598-017-00150-7.
• [8] Development of phenotypic screening assays for -globin induction using primary human bone marrow day 7 erythroid progenitor cells.J Biomol Screen. 2013 Dec;18(10):1212-22. doi: 10.1177/1087057113499776. Epub 2013 Oct 25.
• [9] Understanding globin regulation in beta-thalassemia: it's as simple as alpha, beta, gamma, delta.J Clin Invest. 2005 Jun;115(6):1470-3. doi: 10.1172/JCI25398.
• [10] Increase in gamma-globin mRNA content in human erythroid cells treated with angelicin analogs.Int J Hematol. 2009 Oct;90(3):318-327. doi: 10.1007/s12185-009-0422-2. Epub 2009 Sep 25.
• [11] Lentiviral Transfer of -Globin with Fusion Gene NUP98-HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine -Thalassemia.Mol Ther. 2017 Mar 1;25(3):593-605. doi: 10.1016/j.ymthe.2017.01.019. Epub 2017 Feb 9.
• [12] Rapamycin-mediated induction of gamma-globin mRNA accumulation in human erythroid cells.Br J Haematol. 2004 Aug;126(4):612-21. doi: 10.1111/j.1365-2141.2004.05083.x.
• [13] Comparison of expression of human globin genes transferred into mouse erythroleukemia cells and in transgenic mice.Blood. 1998 Nov 1;92(9):3416-21.
• [14] 5-Aminolevulinate synthase expression and hemoglobin synthesis in a human myelogenous leukemia cell line.J Biochem. 1997 Mar;121(3):487-95. doi: 10.1093/oxfordjournals.jbchem.a021613.
• [15] Identification of candidate genes for Parkinson's disease through blood transcriptome analysis in LRRK2-G2019S carriers, idiopathic cases, and controls.Neurobiol Aging. 2015 Feb;36(2):1105-9. doi: 10.1016/j.neurobiolaging.2014.10.039. Epub 2014 Nov 5.
• [16] Microarray comparison of prostate tumor gene expression in African-American and Caucasian American males: a pilot project study.Infect Agent Cancer. 2009 Feb 10;4 Suppl 1(Suppl 1):S3. doi: 10.1186/1750-9378-4-S1-S3.
• [17] Sequence variations in the 5' flanking and IVS-II regions of the G gamma- and A gamma-globin genes of beta S chromosomes with five different haplotypes.Blood. 1991 Jun 1;77(11):2488-96.
• [18] A Novel BaEVRless-Pseudotyped -Globin Lentiviral Vector Drives High and Stable Fetal Hemoglobin Expression and Improves Thalassemic Erythropoiesis In Vitro.Hum Gene Ther. 2019 May;30(5):601-617. doi: 10.1089/hum.2018.022. Epub 2019 Mar 15.
• [19] Probing the interaction between the histone methyltransferase/deacetylase subunit RBBP4/7 and the transcription factor BCL11A in epigenetic complexes.J Biol Chem. 2018 Feb 9;293(6):2125-2136. doi: 10.1074/jbc.M117.811463. Epub 2017 Dec 20.
• [20] CARM1-mediated methylation of protein arginine methyltransferase 5 represses human -globin gene expression in erythroleukemia cells.J Biol Chem. 2018 Nov 9;293(45):17454-17463. doi: 10.1074/jbc.RA118.004028. Epub 2018 Sep 26.
• [21] The effect of histone deacetylase inhibitors on AHSP expression.PLoS One. 2018 Feb 1;13(2):e0189267. doi: 10.1371/journal.pone.0189267. eCollection 2018.
• [22] Molecular characterization of delta beta-thalassemia and hereditary persistence of fetal hemoglobin in the Indian population. Hemoglobin. 2008;32(5):425-33. doi: 10.1080/03630260802341687.
• [23] A molecular study of a family with Greek hereditary persistence of fetal hemoglobin and beta-thalassemia. EMBO J. 1984 Nov;3(11):2641-5. doi: 10.1002/j.1460-2075.1984.tb02187.x.
• [24] Role of the duplicated CCAAT box region in gamma-globin gene regulation and hereditary persistence of fetal haemoglobin. EMBO J. 1996 Jan 2;15(1):143-9.
• [25] Epigenetic dysregulation of the erythropoietic transcription factor KLF1 and the -like globin locus in juvenile myelomonocytic leukemia.Epigenetics. 2017 Aug;12(8):715-723. doi: 10.1080/15592294.2017.1356959. Epub 2017 Jul 27.
• [26] A novel haemoglobin variant mimicking cyanotic congenital heart disease.BMJ Case Rep. 2016 Jan 28;2016:bcr2015213615. doi: 10.1136/bcr-2015-213615.
• [27] In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies.Ann Hematol. 2005 Dec;84 Suppl 1:32-8. doi: 10.1007/s00277-005-0004-1.
• [28] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [29] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [30] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [31] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [32] Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway. Blood. 2011 Jun 2;117(22):5987-97.