Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1FK08U)

• DOT Name: Krueppel-like factor 1 (KLF1)
• Synonyms: Erythroid krueppel-like transcription factor; EKLF
• Gene Name: KLF1
• Related Disease:
  Congenital dyserythropoietic anemia type 4
  Hemolytic anemia
  Advanced cancer
  Alpha thalassemia
  Autoimmune disease
  Beta-thalassemia major
  Cervical cancer
  Cervical carcinoma
  Chronic myelomonocytic leukaemia
  Congenital dyserythropoietic anemia
  Hematologic disease
  Hemoglobin H disease
  Hereditary spherocytosis
  Hydrops fetalis
  Hypochromic microcytic anemia
  leukaemia
  Leukemia
  Thalassemia
  Beta thalassemia
  Diamond-Blackfan anemia
  Hemoglobin E disease
  Partial trisomy of the long arm of chromosome 5
  Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
  Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
  Acute myelogenous leukaemia
  Hemoglobinopathy
  Anemia
  Erythrocyte disorder
  Granular corneal dystrophy type II
  Sickle-cell anaemia
• UniProt ID: KLF1_HUMAN
• PDB ID: 2L2I; 2MBH; 2N23
• Pfam ID: PF16832 ; PF16833 ; PF00096
• Sequence:
  MATAETALPSISTLTALGPFPDTQDDFLKWWRSEEAQDMGPGPPDPTEPPLHVKSEDQPG
  EEEDDERGADATWDLDLLLTNFSGPEPGGAPQTCALAPSEASGAQYPPPPETLGAYAGGP
  GLVAGLLGSEDHSGWVRPALRARAPDAFVGPALAPAPAPEPKALALQPVYPGPGAGSSGG
  YFPRTGLSVPAASGAPYGLLSGYPAMYPAPQYQGHFQLFRGLQGPAPGPATSPSFLSCLG
  PGTVGTGLGGTAEDPGVIAETAPSKRGRRSWARKRQAAHTCAHPGCGKSYTKSSHLKAHL
  RTHTGEKPYACTWEGCGWRFARSDELTRHYRKHTGQRPFRCQLCPRAFSRSDHLALHMKR
  HL
• Function: Transcription regulator of erythrocyte development that probably serves as a general switch factor during erythropoiesis. Is a dual regulator of fetal-to-adult globin switching. Binds to the CACCC box in the beta-globin gene promoter and acts as a preferential activator of this gene. Furthermore, it binds to the BCL11A promoter and activates expression of BCL11A, which in turn represses the HBG1 and HBG2 genes. This dual activity ensures that, in most adults, fetal hemoglobin levels are low. Able to activate CD44 and AQP1 promoters. When sumoylated, acts as a transcriptional repressor by promoting interaction with CDH2/MI2beta and also represses megakaryocytic differentiation.
• Tissue Specificity: Expression restricted to adult bone marrow and fetal liver. Not expressed in myeloid nor lymphoid cell lines.

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital dyserythropoietic anemia type 4	DISGQXDE	Definitive	Autosomal dominant	[1]
Hemolytic anemia	DIS803XQ	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Beta-thalassemia major	DISW06BV	Strong	Genetic Variation	[6]
Cervical cancer	DISFSHPF	Strong	Biomarker	[7]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[7]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Posttranslational Modification	[8]
Congenital dyserythropoietic anemia	DIS6FAT6	Strong	Biomarker	[9]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[10]
Hemoglobin H disease	DISHFWO5	Strong	Genetic Variation	[11]
Hereditary spherocytosis	DISQYJP5	Strong	Genetic Variation	[12]
Hydrops fetalis	DISD9BBF	Strong	Genetic Variation	[13]
Hypochromic microcytic anemia	DIS0RMTQ	Strong	Genetic Variation	[14]
leukaemia	DISS7D1V	Strong	Altered Expression	[3]
Leukemia	DISNAKFL	Strong	Altered Expression	[3]
Thalassemia	DIS76XZB	Strong	Altered Expression	[15]
Beta thalassemia	DIS5RCQK	moderate	Altered Expression	[6]
Diamond-Blackfan anemia	DISI2SNW	moderate	Altered Expression	[16]
Hemoglobin E disease	DIS5OW63	moderate	Altered Expression	[17]
Partial trisomy of the long arm of chromosome 5	DISFHG81	moderate	Altered Expression	[16]
Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome	DISD21FA	Supportive	Autosomal dominant	[18]
Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome	DISK38J4	Supportive	Autosomal recessive	[18]
Acute myelogenous leukaemia	DISCSPTN	Disputed	Altered Expression	[19]
Hemoglobinopathy	DISCT4GX	Disputed	Genetic Variation	[20]
Anemia	DISTVL0C	Limited	Genetic Variation	[21]
Erythrocyte disorder	DISDMSC5	Limited	Biomarker	[20]
Granular corneal dystrophy type II	DISAEE20	Limited	Genetic Variation	[22]
Sickle-cell anaemia	DIS5YNZB	Limited	Genetic Variation	[13]

2 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 Krueppel-like factor 1 (KLF1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Krueppel-like factor 1 (KLF1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Krueppel-like factor 1 (KLF1).	[24]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Krueppel-like factor 1 (KLF1).	[25]
Pomalidomide	DMTGBAX	Approved	Pomalidomide decreases the expression of Krueppel-like factor 1 (KLF1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Krueppel-like factor 1 (KLF1).	[28]

References

• [1] A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia. Am J Hum Genet. 2010 Nov 12;87(5):721-7. doi: 10.1016/j.ajhg.2010.10.010. Epub 2010 Nov 4.
• [2] The mouse KLF1 Nan variant impairs nuclear condensation and erythroid maturation.PLoS One. 2019 Mar 28;14(3):e0208659. doi: 10.1371/journal.pone.0208659. eCollection 2019.
• [3] Survey and evaluation of mutations in the human KLF1 transcription unit.Sci Rep. 2018 Apr 26;8(1):6587. doi: 10.1038/s41598-018-24962-3.
• [4] Changes in HbA2 and HbF in alpha thalassemia carriers with KLF1 mutation.Blood Cells Mol Dis. 2017 May;64:30-32. doi: 10.1016/j.bcmd.2017.03.007. Epub 2017 Mar 18.
• [5] Egr2-independent, Klf1-mediated induction of PD-L1 in CD4(+) T cells.Sci Rep. 2018 May 4;8(1):7021. doi: 10.1038/s41598-018-25302-1.
• [6] A novel mutation in the erythroid transcription factor KLF1 is likely responsible for ameliorating -thalassemia major.Hum Mutat. 2019 Oct;40(10):1768-1780. doi: 10.1002/humu.23817. Epub 2019 Jun 24.
• [7] Downregulation of Krppellike factor 1 inhibits the metastasis and invasion of cervical cancer cells.Mol Med Rep. 2018 Oct;18(4):3932-3940. doi: 10.3892/mmr.2018.9401. Epub 2018 Aug 20.
• [8] 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.
• [9] A Krppel-like factor 1 (KLF1) Mutation Associated with Severe Congenital Dyserythropoietic Anemia Alters Its DNA-Binding Specificity.Mol Cell Biol. 2020 Feb 12;40(5):e00444-19. doi: 10.1128/MCB.00444-19. Print 2020 Feb 12.
• [10] Krppel-like factor 1: hematologic phenotypes associated with KLF1 gene mutations.Int J Lab Hematol. 2015 May;37 Suppl 1:78-84. doi: 10.1111/ijlh.12356.
• [11] Changes in hematological parameters in -thalassemia individuals co-inherited with erythroid Krppel-like factor mutations.Clin Genet. 2015 Jul;88(1):56-61. doi: 10.1111/cge.12443. Epub 2014 Jul 26.
• [12] Mutation in erythroid specific transcription factor KLF1 causes Hereditary Spherocytosis in the Nan hemolytic anemia mouse model.Genomics. 2010 Nov;96(5):303-7. doi: 10.1016/j.ygeno.2010.07.009. Epub 2010 Aug 5.
• [13] Gene expression in blood from an individual with -thalassemia: An RNA sequence analysis.Mol Genet Genomic Med. 2019 Jul;7(7):e00740. doi: 10.1002/mgg3.740. Epub 2019 May 27.
• [14] Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin.Eur J Hum Genet. 2015 Oct;23(10):1341-8. doi: 10.1038/ejhg.2014.291. Epub 2015 Jan 14.
• [15] Genetic variation of Krppel-like factor 1 (KLF1) and fetal hemoglobin (HbF) levels in (0)-thalassemia/HbE disease.Int J Hematol. 2018 Mar;107(3):297-310. doi: 10.1007/s12185-017-2357-3. Epub 2017 Oct 24.
• [16] Transcription factors Fli1 and EKLF in the differentiation of megakaryocytic and erythroid progenitor in 5q- syndrome and in Diamond-Blackfan anemia.Ann Hematol. 2013 Jan;92(1):11-8. doi: 10.1007/s00277-012-1568-1. Epub 2012 Sep 11.
• [17] Krppel-like factor 1 mutations and expression of hemoglobins F and A2 in homozygous hemoglobin E syndrome.Ann Hematol. 2015 Jul;94(7):1093-8. doi: 10.1007/s00277-015-2335-x. Epub 2015 Feb 20.
• [18] Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010 Sep;42(9):801-5. doi: 10.1038/ng.630. Epub 2010 Aug 1.
• [19] Clinical significance of Gata-1, Gata-2, EKLF, and c-MPL expression in acute myeloid leukemia.Am J Hematol. 2009 Feb;84(2):79-86. doi: 10.1002/ajh.21332.
• [20] Differential role of Kruppel like factor 1 (KLF1) gene in red blood cell disorders.Genomics. 2019 Dec;111(6):1771-1776. doi: 10.1016/j.ygeno.2018.11.032. Epub 2018 Dec 5.
• [21] Novel mutations in KLF1 encoding the In(Lu) phenotype reflect a diversity of clinical presentations.Transfusion. 2018 Jan;58(1):196-199. doi: 10.1111/trf.14378. Epub 2017 Oct 19.
• [22] Corrupted DNA-binding specificity and ectopic transcription underpin dominant neomorphic mutations in KLF/SP transcription factors.BMC Genomics. 2019 May 24;20(1):417. doi: 10.1186/s12864-019-5805-z.
• [23] 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.
• [24] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [25] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [26] Immunomodulatory derivative of thalidomide (IMiD CC-4047) induces a shift in lineage commitment by suppressing erythropoiesis and promoting myelopoiesis. Blood. 2005 May 15;105(10):3833-40. doi: 10.1182/blood-2004-03-0828. Epub 2004 Aug 3.
• [27] 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.
• [28] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.