{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T10:57:33Z","timestamp":1784199453008,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Background: Acute myeloid leukemia (AML) is a malignancy characterized by the clonal expansion of hematopoietic stem and progenitor cells, often associated with mutations such as NPM1. DOT1L inhibitors have shown potential as new therapeutic opportunities for NPM1-mutant AML. The aim of this study was to investigate potential alternative targets of the small-molecule inhibitor EPZ004777, in addition to its primary target, DOT1L, using RNA sequencing data from the NCBI-GEO database (GSE85107). Methods: Differentially expressed genes (DEGs) were identified through bioinformatic analysis, followed by pathway enrichment analysis to uncover the relevant biological pathways. Additionally, molecular docking analysis was conducted to assess the binding affinity of EPZ004777 with the proteins CT45A3, HOXA4, SNX19, TPBG, and ZNF185, which were identified as significantly DEGs. The protein structures were obtained from AlphaFold and the Protein Data Bank. Results: EPZ004777 significantly altered gene expression. Oncofetal genes (CT45A3, TPBG) and genes associated with oncogenic pathways (HOXA4, ZNF185, SNX19) were downregulated, while the pro-apoptotic gene BEX3 was upregulated. Pathway enrichment analysis revealed the suppression of the Rap1 signaling pathway and cell adhesion molecules, which may reduce the invasiveness of AML cells. Additionally, upregulation of immune-related pathways suggests enhanced anti-tumor immune responses. Molecular docking analysis demonstrated that EPZ004777 has strong binding potential with SNX19, TPBG, and ZNF185 proteins. Conclusions: EPZ004777 has been identified as a potent modulator of SNX19, TPBG, and ZNF185 associated with apoptosis and tumor progression in AML.<\/jats:p>","DOI":"10.3390\/cimb47030173","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T09:01:33Z","timestamp":1741078893000},"page":"173","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exploring the Therapeutic Potential of the DOT1L Inhibitor EPZ004777 Using Bioinformatics and Molecular Docking Approaches in Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2405-8552","authenticated-orcid":false,"given":"Mehmet","family":"Kivrak","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, Faculty of Medicine, Recep Tayyip Erdogan University, 53020 Rize, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7246-2592","authenticated-orcid":false,"given":"Ihsan","family":"Nalkiran","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, 53020 Rize, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1115-2005","authenticated-orcid":false,"given":"Hatice","family":"Sevim Nalkiran","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, 53020 Rize, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e441","DOI":"10.1038\/bcj.2016.50","article-title":"Acute myeloid leukemia: A comprehensive review and 2016 update","volume":"6","year":"2016","journal-title":"Blood Cancer J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1182\/blood.2022016867","article-title":"Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN","volume":"140","author":"Wei","year":"2022","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1056\/NEJMoa041974","article-title":"Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype","volume":"352","author":"Falini","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/0092-8674(89)90241-9","article-title":"Major nucleolar proteins shuttle between nucleus and cytoplasm","volume":"56","author":"Borer","year":"1989","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nrc1885","article-title":"Nucleophosmin and cancer","volume":"6","author":"Grisendi","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/leu.2017.30","article-title":"Biological and clinical consequences of NPM1 mutations in AML","volume":"31","author":"Heath","year":"2017","journal-title":"Leukemia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.ccell.2018.08.005","article-title":"Mutant NPM1 Maintains the Leukemic State through HOX Expression","volume":"34","author":"Brunetti","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1182\/blood-2005-02-0560","article-title":"Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc + AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance","volume":"106","author":"Alcalay","year":"2005","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nrc2253","article-title":"MLL translocations, histone modifications and leukaemia stem-cell development","volume":"7","author":"Krivtsov","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3455","DOI":"10.1182\/blood-2014-11-611459","article-title":"Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells","volume":"125","author":"Martelli","year":"2015","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1002\/cncr.30515","article-title":"Imidazoquinoxaline derivative EAPB0503: A promising drug targeting mutant nucleophosmin 1 in acute myeloid leukemia","volume":"123","author":"Nabbouh","year":"2017","journal-title":"Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3096","DOI":"10.1182\/blood-2010-09-309674","article-title":"Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1","volume":"118","author":"Balusu","year":"2011","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1158\/2159-8290.CD-16-0237","article-title":"Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia","volume":"6","author":"Song","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ccr.2011.06.009","article-title":"Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor","volume":"20","author":"Daigle","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Everitt, B.S., and Howell, D.C. (2005). Principal Component Analysis. Encyclopedia of Statistics in Behavioral Science, Wiley.","DOI":"10.1002\/0470013192"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"D1373","DOI":"10.1093\/nar\/gkac956","article-title":"PubChem 2023 update","volume":"51","author":"Kim","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16","DOI":"10.6004\/jnccn.2021.0002","article-title":"NCCN guidelines insights: Acute myeloid leukemia, version 2.2021: Featured updates to the NCCN guidelines","volume":"19","author":"Pollyea","year":"2021","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.1038\/onc.2010.646","article-title":"Nucleophosmin and its complex network: A possible therapeutic target in hematological diseases","volume":"30","author":"Colombo","year":"2011","journal-title":"Oncogene"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/2040620719899818","article-title":"Nucleophosmin1 (NPM1) abnormality in hematologic malignancies, and therapeutic targeting of mutant NPM1 in acute myeloid leukemia","volume":"11","author":"Chen","year":"2020","journal-title":"Ther. Adv. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7821","DOI":"10.1038\/ncomms8821","article-title":"DOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression","volume":"6","author":"Cho","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1186\/s13148-019-0778-y","article-title":"Silencing or inhibition of H3K79 methyltransferase DOT1L induces cell cycle arrest by epigenetically modulating c-Myc expression in colorectal cancer","volume":"11","author":"Yang","year":"2019","journal-title":"Clin. Epigenet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.1038\/s41467-020-18013-7","article-title":"Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer","volume":"11","author":"Vatapalli","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_28","first-page":"386","article-title":"Nerve growth factor-dependent regulation of NADE-induced apoptosis","volume":"66","author":"Mukai","year":"2003","journal-title":"Vitam. Horm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1080\/15592294.2015.1062206","article-title":"DNA hypomethylation-mediated activation of Cancer\/Testis Antigen 45 (CT45) genes is associated with disease progression and reduced survival in epithelial ovarian cancer","volume":"10","author":"Zhang","year":"2015","journal-title":"Epigenetics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1021\/acs.jproteome.2c00841","article-title":"Quantitative Proteomics for the Development and Manufacturing of Human-Induced Pluripotent Stem Cell-Derived Neural Stem Cells Using Data-Independent Acquisition Mass Spectrometry","volume":"22","author":"Urasawa","year":"2023","journal-title":"J. Proteome Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1038\/leu.2015.6","article-title":"Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells","volume":"29","author":"Spencer","year":"2015","journal-title":"Leukemia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"709","DOI":"10.3892\/mco.2014.298","article-title":"Zinc finger protein 185 is a liver metastasis-associated factor in colon cancer patients","volume":"2","author":"Furukawa","year":"2014","journal-title":"Mol. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Olsson, A.H., Volkov, P., Bacos, K., Dayeh, T., Hall, E., Nilsson, E.A., Ladenvall, C., R\u00f6nn, T., and Ling, C. (2014). Genome-wide associations between genetic and epigenetic variation influence mRNA expression and insulin secretion in human pancreatic islets. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004735"},{"key":"ref_34","first-page":"226","article-title":"Brain-Expressed X-linked (BEX) proteins in human cancers","volume":"1856","author":"Kazi","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_35","first-page":"99","article-title":"5T4 oncotrophoblast glycoprotein: Janus molecule in life and a novel potential target against tumors","volume":"4","author":"Zhao","year":"2007","journal-title":"Cell. Mol. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1158\/2326-6066.CIR-13-0035","article-title":"Escalating regulation of 5T4-specific IFN-\u03b3+ CD4+ T cells distinguishes colorectal cancer patients from healthy controls and provides a target for in vivo therapy","volume":"1","author":"Scurr","year":"2013","journal-title":"Cancer Immunol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/bjc.1988.53","article-title":"A 72 kD trophoblast glycoprotein defined by a monoclonal antibody","volume":"57","author":"Hole","year":"1988","journal-title":"Br. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/bjc.1990.20","article-title":"Immunohistological distribution of 5T4 antigen in normal and malignant tissues","volume":"61","author":"Southall","year":"1990","journal-title":"Br. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/bjc.1994.173","article-title":"Prognostic significance of 5T4 oncofetal antigen expression in colorectal carcinoma","volume":"69","author":"Starzynska","year":"1994","journal-title":"Br. J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1046\/j.1525-1438.1995.05040269.x","article-title":"5T4 oncofetal antigen expression in ovarian carcinoma","volume":"5","author":"Wrigley","year":"1995","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_41","first-page":"1033","article-title":"Oncofetal antigen 5T4 expression as a prognostic factor in patients with gastric cancer","volume":"22","author":"Naganuma","year":"2002","journal-title":"Anticancer. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/nrm2427","article-title":"Endosomal sorting and signalling: An emerging role for sorting nexins","volume":"9","author":"Cullen","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1042\/BJ20111226","article-title":"Insights into the PX (phox-homology) domain and SNX (sorting nexin) protein families: Structures, functions and roles in disease","volume":"441","author":"Teasdale","year":"2012","journal-title":"Biochem. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.1210\/jc.2004-1337","article-title":"Two-Step Differential Expression Analysis Reveals a New Set of Genes Involved in Thyroid Oncocytic Tumors","volume":"90","author":"Jacques","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/gcc.20288","article-title":"Amplified, lost, and fused genes in 11q23-25 amplicon in acute myeloid leukemia, an array-CGH study","volume":"45","author":"Elonen","year":"2006","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/sj.onc.1209769","article-title":"ZNF185, an actin-cytoskeleton-associated growth inhibitory LIM protein in prostate cancer","volume":"26","author":"Zhang","year":"2007","journal-title":"Oncogene"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3181596","DOI":"10.1155\/2020\/3181596","article-title":"HEATR1 Deficiency Promotes Chemoresistance via Upregulating ZNF185 and Downregulating SMAD4 in Pancreatic Cancer","volume":"2020","author":"Fang","year":"2020","journal-title":"J. Oncol."},{"key":"ref_48","first-page":"3877","article-title":"Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression","volume":"63","author":"Vanaja","year":"2003","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1001\/archotol.129.7.754","article-title":"Identification of 9 genes differentially expressed in head and neck squamous cell carcinoma","volume":"129","author":"Gonzalez","year":"2003","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1093\/hmg\/ddi091","article-title":"Transcriptional targets of the chromatin-remodelling factor SMARCA4\/BRG1 in lung cancer cells","volume":"14","author":"Medina","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1080\/15384101.2022.2096715","article-title":"High expression of HOXA4 in patients with glioma indicates unfavorable clinical outcomes","volume":"21","author":"Yu","year":"2022","journal-title":"Cell Cycle"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1002\/jcp.25981","article-title":"Overexpression of HOXA4 and HOXA9 genes promotes self-renewal and contributes to colon cancer stem cell overpopulation","volume":"233","author":"Bhatlekar","year":"2018","journal-title":"J. Cell. Physiol."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/3\/173\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:47:03Z","timestamp":1760028423000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/3\/173"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,4]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["cimb47030173"],"URL":"https:\/\/doi.org\/10.3390\/cimb47030173","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,4]]}}}