Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC5BKHU)

• DOT Name: Myeloid leukemia factor 1 (MLF1)
• Synonyms: Myelodysplasia-myeloid leukemia factor 1
• Gene Name: MLF1
• Related Disease:
  Huntington disease
  Inclusion body myositis
  Neoplasm
  Oculopharyngeal muscular dystrophy
  Acute erythroid leukemia
  Acute leukaemia
  Acute myelogenous leukaemia
  Autism spectrum disorder
  Childhood myelodysplastic syndrome
  leukaemia
  Leukemia
  Promyelocytic leukaemia
  Stomach cancer
  Thyroid gland carcinoma
  Myelodysplastic syndrome
  Cardiomyopathy
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Neuroblastoma
• UniProt ID: MLF1_HUMAN
• PDB ID: 3UAL; 3UBW; 6Y8E
• Pfam ID: PF10248
• Sequence:
  MFRMLNSSFEDDPFFSESILAHRENMRQMIRSFSEPFGRDLLSISDGRGRAHNRRGHNDG
  EDSLTHTDVSSFQTMDQMVSNMRNYMQKLERNFGQLSVDPNGHSFCSSSVMTYSKIGDEP
  PKVFQASTQTRRAPGGIKETRKAMRDSDSGLEKMAIGHHIHDRAHVIKKSKNKKTGDEEV
  NQEFINMNESDAHAFDEEWQSEVLKYKPGRHNLGNTRMRSVGHENPGSRELKRREKPQQS
  PAIEHGRRSNVLGDKLHIKGSSVKSNKK
• Function: Involved in lineage commitment of primary hemopoietic progenitors by restricting erythroid formation and enhancing myeloid formation. Interferes with erythropoietin-induced erythroid terminal differentiation by preventing cells from exiting the cell cycle through suppression of CDKN1B/p27Kip1 levels. Suppresses COP1 activity via CSN3 which activates p53 and induces cell cycle arrest. Binds DNA and affects the expression of a number of genes so may function as a transcription factor in the nucleus.
• Tissue Specificity: Most abundant in testis, ovary, skeletal muscle, heart, kidney and colon. Low expression in spleen, thymus and peripheral blood leukocytes.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Huntington disease	DISQPLA4	Definitive	Biomarker	[1]
Inclusion body myositis	DISZXXG5	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Oculopharyngeal muscular dystrophy	DISF4G07	Definitive	Biomarker	[1]
Acute erythroid leukemia	DISZFC1O	Strong	Biomarker	[3]
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[4]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[5]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Genetic Variation	[6]
leukaemia	DISS7D1V	Strong	Biomarker	[4]
Leukemia	DISNAKFL	Strong	Biomarker	[4]
Promyelocytic leukaemia	DISYGG13	Strong	Genetic Variation	[7]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[9]
Myelodysplastic syndrome	DISYHNUI	moderate	Genetic Variation	[6]
Cardiomyopathy	DISUPZRG	Limited	Altered Expression	[10]
Gastric cancer	DISXGOUK	Limited	Biomarker	[8]
Gastric neoplasm	DISOKN4Y	Limited	Biomarker	[11]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Limited	Biomarker	[11]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[12]

14 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 Myeloid leukemia factor 1 (MLF1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Myeloid leukemia factor 1 (MLF1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Myeloid leukemia factor 1 (MLF1).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Myeloid leukemia factor 1 (MLF1).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Myeloid leukemia factor 1 (MLF1).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Myeloid leukemia factor 1 (MLF1).	[11]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Myeloid leukemia factor 1 (MLF1).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Myeloid leukemia factor 1 (MLF1).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Myeloid leukemia factor 1 (MLF1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Myeloid leukemia factor 1 (MLF1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Myeloid leukemia factor 1 (MLF1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Myeloid leukemia factor 1 (MLF1).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Myeloid leukemia factor 1 (MLF1).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Myeloid leukemia factor 1 (MLF1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Myeloid leukemia factor 1 (MLF1).	[20]

References

• [1] Non-pathogenic protein aggregates in skeletal muscle in MLF1 transgenic mice.J Neurol Sci. 2008 Jan 15;264(1-2):77-86. doi: 10.1016/j.jns.2007.07.027. Epub 2007 Sep 12.
• [2] Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBP to prevent Trib1-driven acute myeloid leukemia.Blood Adv. 2017 Sep 1;1(20):1682-1693. doi: 10.1182/bloodadvances.2017007054. eCollection 2017 Sep 12.
• [3] The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1.Oncogene. 1996 Jan 18;12(2):265-75.
• [4] NPM and NPM-MLF1 interact with chromatin remodeling complexes and influence their recruitment to specific genes.PLoS Genet. 2019 Nov 1;15(11):e1008463. doi: 10.1371/journal.pgen.1008463. eCollection 2019 Nov.
• [5] Candidate Genes for Inherited Autism Susceptibility in the Lebanese Population.Sci Rep. 2017 Mar 30;7:45336. doi: 10.1038/srep45336.
• [6] Detection of t(3;5) and NPM1/MLF1 rearrangement in an elderly patient with acute myeloid leukemia: clinical and laboratory study with review of the literature.Cancer Genet Cytogenet. 2010 Jun;199(2):101-9. doi: 10.1016/j.cancergencyto.2010.02.009.
• [7] Nucleophosmin: a versatile molecule associated with hematological malignancies.Cancer Sci. 2006 Oct;97(10):963-9. doi: 10.1111/j.1349-7006.2006.00270.x.
• [8] Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes.Gastroenterology. 2009 Jun;136(7):2149-58. doi: 10.1053/j.gastro.2009.02.085. Epub 2009 Apr 16.
• [9] Identification of novel diagnostic biomarkers for thyroid carcinoma.Oncotarget. 2017 Dec 4;8(67):111551-111566. doi: 10.18632/oncotarget.22873. eCollection 2017 Dec 19.
• [10] Myeloid leukemia factor-1 is a novel modulator of neonatal rat cardiomyocyte proliferation.Biochim Biophys Acta Mol Cell Res. 2017 Apr;1864(4):634-644. doi: 10.1016/j.bbamcr.2017.01.004. Epub 2017 Jan 10.
• [11] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [12] Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma.PLoS Genet. 2017 May 18;13(5):e1006787. doi: 10.1371/journal.pgen.1006787. eCollection 2017 May.
• [13] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] 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.
• [18] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [19] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [20] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.