Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOJ10S1)

• DOT Name: Protein CBFA2T3 (CBFA2T3)
• Synonyms: MTG8-related protein 2; Myeloid translocation gene on chromosome 16 protein; hMTG16; Zinc finger MYND domain-containing protein 4
• Gene Name: CBFA2T3
• Related Disease:
  Acute megakaryoblastic leukemia
  Advanced cancer
  leukaemia
  46,XY sex reversal 2
  Acute lymphocytic leukaemia
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Acute undifferentiated leukemia
  Adult lymphoma
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Charcot-Marie-Tooth disease type 3
  Childhood acute megakaryoblastic leukemia
  Chromosomal disorder
  Classic Hodgkin lymphoma
  Colitis
  Fibrolamellar liver cancer
  Inflammatory bowel disease
  Leukemia
  Lymphoma
  Pediatric lymphoma
  Ulcerative colitis
  Vitiligo
  Bone osteosarcoma
  Metastatic malignant neoplasm
  Osteosarcoma
  Breast neoplasm
  Colonic neoplasm
  Neoplasm
• UniProt ID: MTG16_HUMAN
• Pfam ID: PF08788 ; PF07531 ; PF01753
• Sequence:
  MPASRLRDRAASSASGSTCGSMSQTHPVLESGLLASAGCSAPRGPRKGGPAPVDRKAKAS
  AMPDSPAEVKTQPRSTPPSMPPPPPAASQGATRPPSFTPHTHREDGPATLPHGRFHGCLK
  WSMVCLLMNGSSHSPTAINGAPCTPNGFSNGPATSSTASLSTQHLPPACGARQLSKLKRF
  LTTLQQFGSDISPEIGERVRTLVLGLVNSTLTIEEFHSKLQEATNFPLRPFVIPFLKANL
  PLLQRELLHCARLAKQTPAQYLAQHEQLLLDASASSPIDSSELLLEVNENGKRRTPDRTK
  ENGSDRDPLHPEHLSKRPCTLNPAQRYSPSNGPPQPTPPPHYRLEDIAMAHHFRDAYRHP
  DPRELRERHRPLVVPGSRQEEVIDHKLTEREWAEEWKHLNNLLNCIMDMVEKTRRSLTVL
  RRCQEADREELNHWARRYSDAEDTKKGPAPAAARPRSSSAGPEGPQLDVPREFLPRTLTG
  YVPEDIWRKAEEAVNEVKRQAMSELQKAVSDAERKAHELITTERAKMERALAEAKRQASE
  DALTVINQQEDSSESCWNCGRKASETCSGCNAARYCGSFCQHRDWEKHHHVCGQSLQGPT
  AVVADPVPGPPEAAHSLGPSLPVGAASPSEAGSAGPSRPGSPSPPGPLDTVPR
• Function: Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes. Can repress the expression of MMP7 in a ZBTB33-dependent manner. Reduces the protein levels and stability of the transcriptinal regulator HIF1A; interacts with EGLN1 and promotes the HIF1A prolyl hydroxylation-dependent ubiquitination and proteasomal degradation pathway. Contributes to inhibition of glycolysis and stimulation of mitochondrial respiration by down-regulating the expression of glycolytic genes including PFKFB3, PFKFB4, PDK1, PFKP, LDHA and HK1 which are direct targets of HIF1A. Regulates the proliferation and the differentiation of erythroid progenitors by repressing the expression of TAL1 target genes. Plays a role in granulocyte differentiation ; Isoform 2 functions as an A-kinase-anchoring protein.
• Tissue Specificity: Widely expressed with higher expression in heart, pancreas, skeletal muscle, spleen, thymus and peripheral blood leukocytes. Expressed in hematopoietic cells (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute megakaryoblastic leukemia	DIS0JX3M	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[2]
leukaemia	DISS7D1V	Definitive	Biomarker	[3]
46,XY sex reversal 2	DIS0USUN	Strong	Biomarker	[4]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[5]
Acute monocytic leukemia	DIS28NEL	Strong	Genetic Variation	[6]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Acute undifferentiated leukemia	DISJ4SSG	Strong	Altered Expression	[6]
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[7]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Strong	Biomarker	[4]
Childhood acute megakaryoblastic leukemia	DIS5VZDR	Strong	Biomarker	[9]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[10]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Posttranslational Modification	[11]
Colitis	DISAF7DD	Strong	Biomarker	[4]
Fibrolamellar liver cancer	DISUDA2P	Strong	Biomarker	[2]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[12]
Leukemia	DISNAKFL	Strong	Biomarker	[3]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[7]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[7]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[12]
Vitiligo	DISR05SL	Strong	Genetic Variation	[13]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[14]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[14]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[14]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[15]
Colonic neoplasm	DISSZ04P	Limited	Biomarker	[4]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Protein CBFA2T3 (CBFA2T3).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein CBFA2T3 (CBFA2T3).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein CBFA2T3 (CBFA2T3).	[18]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Protein CBFA2T3 (CBFA2T3).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Protein CBFA2T3 (CBFA2T3).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein CBFA2T3 (CBFA2T3).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein CBFA2T3 (CBFA2T3).	[24]

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 CBFA2T3 (CBFA2T3).	[19]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Protein CBFA2T3 (CBFA2T3).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein CBFA2T3 (CBFA2T3).	[22]

References

• [1] Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-Positive AML Defines Novel Therapeutic Options: A COG and TARGET Pediatric AML Study.Clin Cancer Res. 2020 Feb 1;26(3):726-737. doi: 10.1158/1078-0432.CCR-19-1800. Epub 2019 Nov 12.
• [2] Emerging Roles of GLI-Similar Krppel-like Zinc Finger Transcription Factors in Leukemia and Other Cancers.Trends Cancer. 2019 Sep;5(9):547-557. doi: 10.1016/j.trecan.2019.07.005. Epub 2019 Aug 20.
• [3] The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice.Mol Cancer Res. 2019 Jul;17(7):1468-1479. doi: 10.1158/1541-7786.MCR-18-1327. Epub 2019 Apr 23.
• [4] Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma.Oncogene. 2019 Jun;38(25):5091-5106. doi: 10.1038/s41388-019-0777-7. Epub 2019 Mar 11.
• [5] Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways.Nucleic Acids Res. 2014 Jan;42(1):137-52. doi: 10.1093/nar/gkt855. Epub 2013 Sep 24.
• [6] Myeloid translocation gene CBFA2T3 directs a relapse gene program and determines patient-specific outcomes in AML.Blood Adv. 2019 May 14;3(9):1379-1393. doi: 10.1182/bloodadvances.2018028514.
• [7] The CBFA2T3/ACSF3 locus is recurrently involved in IGH chromosomal translocation t(14;16)(q32;q24) in pediatric B-cell lymphoma with germinal center phenotype.Genes Chromosomes Cancer. 2012 Apr;51(4):338-43. doi: 10.1002/gcc.21919.
• [8] Med19 promotes breast cancer cell proliferation by regulating CBFA2T3/HEB expression.Breast Cancer. 2017 May;24(3):433-441. doi: 10.1007/s12282-016-0722-3. Epub 2016 Aug 29.
• [9] ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia.Cancer Cell. 2017 Mar 13;31(3):452-465. doi: 10.1016/j.ccell.2017.02.006.
• [10] Myeloid neoplasms with t(16;21)(q24;q22)/RUNX1-RUNX1T3 mimics acute myeloid leukemia with RUNX1-RUNX1T1.Ann Hematol. 2018 Oct;97(10):1775-1783. doi: 10.1007/s00277-018-3389-3. Epub 2018 Jun 5.
• [11] Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma.Nat Med. 2010 May;16(5):571-9, 1p following 579. doi: 10.1038/nm.2129. Epub 2010 May 2.
• [12] MTG16 is a tumor suppressor in colitis-associated carcinoma.JCI Insight. 2017 Aug 17;2(16):e78210. doi: 10.1172/jci.insight.78210. eCollection 2017 Aug 17.
• [13] Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.Nat Genet. 2016 Nov;48(11):1418-1424. doi: 10.1038/ng.3680. Epub 2016 Oct 10.
• [14] miR-27a and miR-27a* contribute to metastatic properties of osteosarcoma cells.Oncotarget. 2015 Mar 10;6(7):4920-35. doi: 10.18632/oncotarget.3025.
• [15] ZNF652, a novel zinc finger protein, interacts with the putative breast tumor suppressor CBFA2T3 to repress transcription.Mol Cancer Res. 2006 Sep;4(9):655-65. doi: 10.1158/1541-7786.MCR-05-0249.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [19] 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.
• [20] 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.
• [21] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [22] 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.
• [23] 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.
• [24] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.