Abnormally High Expression of POLD1, MCM2, and PLK4 Promotes Relapse of Acute Lymphoblastic Leukemia

Overview

Journal Medicine (Baltimore)

Specialty General Medicine

Date 2018 May 17

PMID 29768346

Citations 7

Authors

Sheng Li

Chengzhong Wang

Weikai Wang

Weidong Liu

Guiqin Zhang

Affiliations

Soon will be listed here.

Abstract

This study aimed to explore the underlying mechanism of relapsed acute lymphoblastic leukemia (ALL).Datasets of GSE28460 and GSE18497 were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between diagnostic and relapsed ALL samples were identified using Limma package in R, and a Venn diagram was drawn. Next, functional enrichment analyses of co-regulated DEGs were performed. Based on the String database, protein-protein interaction network and module analyses were also conducted. Moreover, transcription factors and miRNAs targeting co-regulated DEGs were predicted using the WebGestalt online tool.A total of 71 co-regulated DEGs were identified, including 56 co-upregulated genes and 15 co-downregulated genes. Functional enrichment analyses showed that upregulated DEGs were significantly enriched in the cell cycle, and DNA replication, and repair related pathways. POLD1, MCM2, and PLK4 were hub proteins in both protein-protein interaction network and module, and might be potential targets of E2F. Additionally, POLD1 and MCM2 were found to be regulated by miR-520H via E2F1.High expression of POLD1, MCM2, and PLK4 might play positive roles in the recurrence of ALL, and could serve as potential therapeutic targets for the treatment of relapsed ALL.

Citing Articles

The prognostic and neuroendocrine implications of SLC25A29-mediated biomass signature in prostate cancer.

Wu C, Hu S, Dong S, Tzou K, Li C Geroscience. 2025; .

PMID: 39890746 DOI: 10.1007/s11357-025-01538-4.

Prospects of POLD1 in Human Cancers: A Review.

Gola M, Stefaniak P, Godlewski J, Jereczek-Fossa B, Starzynska A Cancers (Basel). 2023; 15(6).

PMID: 36980791 PMC: 10047664. DOI: 10.3390/cancers15061905.

Centrosome Defects in Hematological Malignancies: Molecular Mechanisms and Therapeutic Insights.

Hu M, Wang Y, Zhou J Blood Sci. 2022; 4(3):143-151.

PMID: 36518599 PMC: 9742116. DOI: 10.1097/BS9.0000000000000127.

DNA Polymerase Delta 1 Catalytic Subunit (POLD1) as a Prognostic Factor in Clear Cell Renal Cell Carcinoma Patients.

Godlewski J, Stefaniak P, Kiezun J, Krazinski B In Vivo. 2022; 36(3):1188-1194.

PMID: 35478106 PMC: 9087055. DOI: 10.21873/invivo.12818.

Integrative Analysis of Gene Expression Through One-Class Logistic Regression Machine Learning Identifies Stemness Features in Multiple Myeloma.

Ban C, Yang F, Wei M, Liu Q, Wang J, Chen L Front Genet. 2021; 12:666561.

PMID: 34484287 PMC: 8415636. DOI: 10.3389/fgene.2021.666561.

References

Liao R, Sun J, Zhang L, Lou G, Chen M, Zhou D . MicroRNAs play a role in the development of human hematopoietic stem cells. J Cell Biochem. 2008; 104(3):805-17. DOI: 10.1002/jcb.21668. View

Yang J, Landier W, Yang W, Liu C, Hageman L, Cheng C . Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015; 33(11):1235-42. PMC: 4375304. DOI: 10.1200/JCO.2014.59.4671. View

Valle L, Hernandez-Illan E, Bellido F, Aiza G, Castillejo A, Castillejo M . New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet. 2014; 23(13):3506-12. DOI: 10.1093/hmg/ddu058. View

Ardjmand A, de Bock C, Shahrokhi S, Lincz L, Boyd A, Burns G . Fat1 cadherin provides a novel minimal residual disease marker in acute lymphoblastic leukemia. Hematology. 2013; 18(6):315-22. DOI: 10.1179/1607845413Y.0000000080. View

Chen H, Boutros P . VennDiagram: a package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinformatics. 2011; 12:35. PMC: 3041657. DOI: 10.1186/1471-2105-12-35. View

Kazazian K, Go C, Wu H, Brashavitskaya O, Xu R, Dennis J . Plk4 Promotes Cancer Invasion and Metastasis through Arp2/3 Complex Regulation of the Actin Cytoskeleton. Cancer Res. 2016; 77(2):434-447. DOI: 10.1158/0008-5472.CAN-16-2060. View

Robertson K, Ait-Si-Ali S, Yokochi T, Wade P, Jones P, Wolffe A . DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet. 2000; 25(3):338-42. DOI: 10.1038/77124. View

Tang Y, Li M, Wang J, Pan Y, Wu F . CytoNCA: a cytoscape plugin for centrality analysis and evaluation of protein interaction networks. Biosystems. 2014; 127:67-72. DOI: 10.1016/j.biosystems.2014.11.005. View

Nagel S, Venturini L, Przybylski G, Grabarczyk P, Schmidt C, Meyer C . Activation of miR-17-92 by NK-like homeodomain proteins suppresses apoptosis via reduction of E2F1 in T-cell acute lymphoblastic leukemia. Leuk Lymphoma. 2009; 50(1):101-8. DOI: 10.1080/10428190802626632. View

10.

Joshi-Tope G, Gillespie M, Vastrik I, DEustachio P, Schmidt E, de Bono B . Reactome: a knowledgebase of biological pathways. Nucleic Acids Res. 2004; 33(Database issue):D428-32. PMC: 540026. DOI: 10.1093/nar/gki072. View

11.

Goldsby R, Hays L, Chen X, Olmsted E, Slayton W, Spangrude G . High incidence of epithelial cancers in mice deficient for DNA polymerase delta proofreading. Proc Natl Acad Sci U S A. 2002; 99(24):15560-5. PMC: 137756. DOI: 10.1073/pnas.232340999. View

12.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

13.

Havelange V, Garzon R . MicroRNAs: emerging key regulators of hematopoiesis. Am J Hematol. 2010; 85(12):935-42. DOI: 10.1002/ajh.21863. View

14.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J . STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014; 43(Database issue):D447-52. PMC: 4383874. DOI: 10.1093/nar/gku1003. View

15.

Liu F, Yuan J, Huang J, Yang F, Wang T, Ma J . Long noncoding RNA FTX inhibits hepatocellular carcinoma proliferation and metastasis by binding MCM2 and miR-374a. Oncogene. 2016; 35(41):5422-5434. DOI: 10.1038/onc.2016.80. View

16.

Tallen G, Ratei R, Mann G, Kaspers G, Niggli F, Karachunsky A . Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. 2010; 28(14):2339-47. DOI: 10.1200/JCO.2009.25.1983. View

17.

Agirre X, Vilas-Zornoza A, Jimenez-Velasco A, Martin-Subero J, Cordeu L, Garate L . Epigenetic silencing of the tumor suppressor microRNA Hsa-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia. Cancer Res. 2009; 69(10):4443-53. DOI: 10.1158/0008-5472.CAN-08-4025. View

18.

Gautier L, Cope L, Bolstad B, Irizarry R . affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004; 20(3):307-15. DOI: 10.1093/bioinformatics/btg405. View

19.

Uckun F, Qazi S, Ma H, Yin L, Cheng J . A rationally designed nanoparticle for RNA interference therapy in B-lineage lymphoid malignancies. EBioMedicine. 2015; 1(2-3):141-155. PMC: 4292938. DOI: 10.1016/j.ebiom.2014.10.013. View

20.

Ohta M, Ashikawa T, Nozaki Y, Kozuka-Hata H, Goto H, Inagaki M . Direct interaction of Plk4 with STIL ensures formation of a single procentriole per parental centriole. Nat Commun. 2014; 5:5267. PMC: 4220463. DOI: 10.1038/ncomms6267. View