Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8M52QY)

• DOT Name: Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1)
• Synonyms: H-l(3)mbt; H-l(3)mbt protein; L(3)mbt-like; L(3)mbt protein homolog; L3MBTL1
• Gene Name: L3MBTL1
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Brain neoplasm
  Colorectal carcinoma
  Haematological malignancy
  leukaemia
  Leukemia
  Myelodysplastic syndrome
  Myeloid leukaemia
  Myeloproliferative neoplasm
  Neoplasm
  Polycythemia vera
  Shwachman-Diamond syndrome
  Breast cancer
  Breast carcinoma
  Amyotrophic lateral sclerosis
  Brain cancer
  Frontotemporal dementia
  Pick disease
• UniProt ID: LMBL1_HUMAN
• PDB ID: 1OYX; 1OZ2; 1OZ3; 2PQW; 2RHI; 2RHU; 2RHX; 2RHY; 2RHZ; 2RI2; 2RI3; 2RI5; 2RJC; 2RJD; 2RJE; 2RJF; 3OQ5; 3P8H; 3UWN; 6BYB
• Pfam ID: PF02820 ; PF01530
• Sequence:
  MHLVAGDSPGSGPHLPATAFIIPASSATLGLPSSALDVSCFPREPIHVGAPEQVAGCEPV
  SATVLPQLSAGPASSSTSTVRLLEWTEAAAPPPGGGLRFRISEYKPLNMAGVEQPPSPEL
  RQEGVTEYEDGGAPAGDGEAGPQQAEDHPQNPPEDPNQDPPEDDSTCQCQACGPHQAAGP
  DLGSSNDGCPQLFQERSVIVENSSGSTSASELLKPMKKRKRREYQSPSEEESEPEAMEKQ
  EEGKDPEGQPTASTPESEEWSSSQPATGEKKECWSWESYLEEQKAITAPVSLFQDSQAVT
  HNKNGFKLGMKLEGIDPQHPSMYFILTVAEVCGYRLRLHFDGYSECHDFWVNANSPDIHP
  AGWFEKTGHKLQPPKGYKEEEFSWSQYLRSTRAQAAPKHLFVSQSHSPPPLGFQVGMKLE
  AVDRMNPSLVCVASVTDVVDSRFLVHFDNWDDTYDYWCDPSSPYIHPVGWCQKQGKPLTP
  PQDYPDPDNFCWEKYLEETGASAVPTWAFKVRPPHSFLVNMKLEAVDRRNPALIRVASVE
  DVEDHRIKIHFDGWSHGYDFWIDADHPDIHPAGWCSKTGHPLQPPLGPREPSSASPGGCP
  PLSYRSLPHTRTSKYSFHHRKCPTPGCDGSGHVTGKFTAHHCLSGCPLAERNQSRLKAEL
  SDSEASARKKNLSGFSPRKKPRHHGRIGRPPKYRKIPQEDFQTLTPDVVHQSLFMSALSA
  HPDRSLSVCWEQHCKLLPGVAGISASTVAKWTIDEVFGFVQTLTGCEDQARLFKDEARIV
  RVTHVSGKTLVWTVAQLGDLVCSDHLQEGKGILETGVHSLLCSLPTHLLAKLSFASDSQY
• Function: Polycomb group (PcG) protein that specifically recognizes and binds mono- and dimethyllysine residues on target proteins, therey acting as a 'reader' of a network of post-translational modifications. PcG proteins maintain the transcriptionally repressive state of genes: acts as a chromatin compaction factor by recognizing and binding mono- and dimethylated histone H1b/H1-4 at 'Lys-26' (H1bK26me1 and H1bK26me2) and histone H4 at 'Lys-20' (H4K20me1 and H4K20me2), leading to condense chromatin and repress transcription. Recognizes and binds p53/TP53 monomethylated at 'Lys-382', leading to repress p53/TP53-target genes. Also recognizes and binds RB1/RB monomethylated at 'Lys-860'. Participates in the ETV6-mediated repression. Probably plays a role in cell proliferation. Overexpression induces multinucleated cells, suggesting that it is required to accomplish normal mitosis.
• Tissue Specificity: Widely expressed. Expression is reduced in colorectal cancer cell line SW480 and promyelocytic leukemia cell line HL-60.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: Regulation of TP53 Activity through Methylation (R-HSA-6804760)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[2]
leukaemia	DISS7D1V	Strong	Genetic Variation	[5]
Leukemia	DISNAKFL	Strong	Genetic Variation	[5]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[6]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[6]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Polycythemia vera	DISB5FPO	Strong	Biomarker	[1]
Shwachman-Diamond syndrome	DISW57NW	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[10]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[10]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[11]
Brain cancer	DISBKFB7	Limited	Genetic Variation	[12]
Frontotemporal dementia	DISKYHXL	Limited	Biomarker	[11]
Pick disease	DISP6X50	Limited	Biomarker	[11]

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 Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[13]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1).	[23]

References

• [1] Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q- polycythemia vera.Blood. 2010 Oct 14;116(15):2812-21. doi: 10.1182/blood-2010-02-270611. Epub 2010 Jun 28.
• [2] L3MBTL1 polycomb protein, a candidate tumor suppressor in del(20q12) myeloid disorders, is essential for genome stability.Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22552-7. doi: 10.1073/pnas.1017092108. Epub 2010 Dec 13.
• [3] The histone code reader PHD finger protein 7 controls sex-linked disparities in gene expression and malignancy in Drosophila.Sci Adv. 2019 Aug 14;5(8):eaaw7965. doi: 10.1126/sciadv.aaw7965. eCollection 2019 Aug.
• [4] Competing endogenous RNA network crosstalk reveals novel molecular markers in colorectal cancer.J Cell Biochem. 2018 Aug;119(8):6869-6881. doi: 10.1002/jcb.26884. Epub 2018 May 8.
• [5] The human L(3)MBT polycomb group protein is a transcriptional repressor and interacts physically and functionally with TEL (ETV6).J Biol Chem. 2003 Apr 25;278(17):15412-20. doi: 10.1074/jbc.M300592200. Epub 2003 Feb 14.
• [6] Structural integrity and expression of the L3MBTL gene in normal and malignant hematopoietic cells.Genes Chromosomes Cancer. 2004 Nov;41(3):203-13. doi: 10.1002/gcc.20087.
• [7] Disordered epigenetic regulation in the pathophysiology of myeloproliferative neoplasms.Curr Hematol Malig Rep. 2012 Mar;7(1):34-42. doi: 10.1007/s11899-011-0105-y.
• [8] L(3)mbt and the LINT complex safeguard cellular identity in the Drosophila ovary.Development. 2018 Apr 4;145(7):dev160721. doi: 10.1242/dev.160721.
• [9] Atypical erythroblastosis in a patient with Diamond-Blackfan anemia who developed del(20q) myelodysplasia.Int J Hematol. 2018 Aug;108(2):228-231. doi: 10.1007/s12185-018-2424-4. Epub 2018 Feb 23.
• [10] Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1.Breast Cancer Res Treat. 2012 May;133(1):127-35. doi: 10.1007/s10549-011-1716-7. Epub 2011 Aug 12.
• [11] L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control.Nat Neurosci. 2019 Jun;22(6):875-886. doi: 10.1038/s41593-019-0384-5. Epub 2019 May 6.
• [12] Use of the CRISPR-Cas9 system for genome editing in cultured Drosophila ovarian somatic cells.Methods. 2017 Aug 15;126:186-192. doi: 10.1016/j.ymeth.2017.05.021. Epub 2017 May 25.
• [13] 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.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] 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.
• [16] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] 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.
• [20] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [21] 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.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.