Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT41UZU5)

• DOT Name: Protein ENL (MLLT1)
• Synonyms: YEATS domain-containing protein 1
• Gene Name: MLLT1
• Related Disease:
  Acute leukaemia
  Acute monocytic leukemia
  Blastic plasmacytoid dendritic cell neoplasm
  Fibrosarcoma
  Mixed phenotype acute leukemia
  Myelodysplastic syndrome
  Myeloid leukaemia
  Promyelocytic leukaemia
  Wilms tumor
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Childhood acute lymphoblastic leukemia
  leukaemia
  Leukemia
  Small lymphocytic lymphoma
  T-cell acute lymphoblastic leukaemia
• UniProt ID: ENL_HUMAN
• PDB ID: 5J9S; 6HPW; 6HPX; 6HPY; 6HPZ; 6HQ0; 6HT0; 6HT1; 6T1I; 6T1J; 6T1L; 6T1M; 6T1N; 6T1O; 7B0T; 7B10; 7E74; 7E7A; 7E7C; 7X88; 7X8B; 7X8F; 7X8G; 8PJI
• Pfam ID: PF17793 ; PF03366
• Sequence:
  MDNQCTVQVRLELGHRAQLRKKPTTEGFTHDWMVFVRGPEQCDIQHFVEKVVFWLHDSFP
  KPRRVCKEPPYKVEESGYAGFIMPIEVHFKNKEEPRKVCFTYDLFLNLEGNPPVNHLRCE
  KLTFNNPTTEFRYKLLRAGGVMVMPEGADTVSRPSPDYPMLPTIPLSAFSDPKKTKPSHG
  SKDANKESSKTSKPHKVTKEHRERPRKDSESKSSSKELEREQAKSSKDTSRKLGEGRLPK
  EEKAPPPKAAFKEPKMALKETKLESTSPKGGPPPPPPPPPRASSKRPATADSPKPSAKKQ
  KKSSSKGSRSAPGTSPRTSSSSSFSDKKPAKDKSSTRGEKVKAESEPREAKKALEVEESN
  SEDEASFKSESAQSSPSNSSSSSDSSSDSDFEPSQNHSQGPLRSMVEDLQSEESDEDDSS
  SGEEAAGKTNPGRDSRLSFSDSESDNSADSSLPSREPPPPQKPPPPNSKVSGRRSPESCS
  KPEKILKKGTYDKAYTDELVELHRRLMALRERNVLQQIVNLIEETGHFNVTNTTFDFDLF
  SLDETTVRKLQSCLEAVAT
• Function: Chromatin reader component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. Specifically recognizes and binds acetylated and crotonylated histones, with a preference for histones that are crotonylated. Has a slightly higher affinity for binding histone H3 crotonylated at 'Lys-27' (H3K27cr) than 'Lys-20' (H3K9cr20) ; Acts as a key chromatin reader in acute myeloid leukemia by recognizing and binding to acetylated histones via its YEATS domain, thereby regulating oncogenic gene transcription.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Genetic Variation	[2]
Blastic plasmacytoid dendritic cell neoplasm	DISLEJU7	Strong	Genetic Variation	[3]
Fibrosarcoma	DISWX7MU	Strong	Altered Expression	[4]
Mixed phenotype acute leukemia	DISNCHV9	Strong	Genetic Variation	[5]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[6]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[7]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[8]
Wilms tumor	DISB6T16	Strong	Biomarker	[9]
Acute lymphocytic leukaemia	DISPX75S	moderate	Biomarker	[10]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Biomarker	[10]
leukaemia	DISS7D1V	Limited	Biomarker	[11]
Leukemia	DISNAKFL	Limited	Biomarker	[11]
Small lymphocytic lymphoma	DIS30POX	Limited	Genetic Variation	[12]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Altered Expression	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein ENL (MLLT1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein ENL (MLLT1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein ENL (MLLT1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein ENL (MLLT1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Protein ENL (MLLT1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein ENL (MLLT1).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Protein ENL (MLLT1).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Protein ENL (MLLT1).	[21]

References

• [1] Structure-guided development of YEATS domain inhibitors by targeting -- stacking.Nat Chem Biol. 2018 Dec;14(12):1140-1149. doi: 10.1038/s41589-018-0144-y. Epub 2018 Oct 29.
• [2] A New Complex Karyotype Involving a KMT2A-r Variant Three-Way Translocation in a Rare Clinical Presentation of a Pediatric Patient with Acute Myeloid Leukemia.Cytogenet Genome Res. 2019;157(4):213-219. doi: 10.1159/000499640. Epub 2019 Apr 12.
• [3] KMT2A (MLL)-MLLT1 rearrangement in blastic plasmacytoid dendritic cell neoplasm.Cancer Genet. 2015 Sep;208(9):464-7. doi: 10.1016/j.cancergen.2015.04.011. Epub 2015 May 6.
• [4] Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR.J Clin Invest. 2012 Jan;122(1):241-52. doi: 10.1172/JCI58928. Epub 2011 Dec 1.
• [5] Mixed phenotype acute leukemia with t(11;19)(q23;p13.3)/ MLL-MLLT1(ENL), B/T-lymphoid type: A first case report.Am J Hematol. 2010 Jun;85(6):451-4. doi: 10.1002/ajh.21703.
• [6] Clinical outcome and monitoring of minimal residual disease in patients with acute lymphoblastic leukemia expressing the MLL/ENL fusion gene.Am J Hematol. 2011 Dec;86(12):993-7. doi: 10.1002/ajh.22161. Epub 2011 Sep 22.
• [7] The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX.Mol Cell Biol. 1998 Jan;18(1):122-9. doi: 10.1128/MCB.18.1.122.
• [8] Plzf drives MLL-fusion-mediated leukemogenesis specifically in long-term hematopoietic stem cells.Blood. 2013 Aug 15;122(7):1271-83. doi: 10.1182/blood-2012-09-456665. Epub 2013 Jul 9.
• [9] A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.Nat Genet. 2017 Oct;49(10):1487-1494. doi: 10.1038/ng.3940. Epub 2017 Aug 21.
• [10] Preclinical Efficacy and Safety of CD19CAR Cytokine-Induced Killer Cells Transfected with Sleeping Beauty Transposon for the Treatment of Acute Lymphoblastic Leukemia.Hum Gene Ther. 2018 May;29(5):602-613. doi: 10.1089/hum.2017.207. Epub 2018 Apr 16.
• [11] The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development.Blood Adv. 2019 Aug 13;3(15):2388-2399. doi: 10.1182/bloodadvances.2019000554.
• [12] CSPG4-Specific CAR T Cells for High-Risk Childhood B Cell Precursor Leukemia.Int J Mol Sci. 2019 Jun 5;20(11):2764. doi: 10.3390/ijms20112764.
• [13] Complex MLL rearrangement in a patient with T-cell acute lymphoblastic leukemia.Genes Chromosomes Cancer. 1995 Sep;14(1):76-84. doi: 10.1002/gcc.2870140114.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.