Abnormally high expression of POLD1, MCM2, and PLK4 promotes relapse of acute lymphoblastic leukemia

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.

Regulatory network analysis reveals the oncogenesis roles of feed-forward loops and therapeutic target in T-cell acute lymphoblastic leukemia

“…Beta carotene can increase the expression of BAX and CAPN2 and lead to the apoptosis of AML cell lines [41]. Furthermore, abnormally high expression of MCM2 was reported in recurrence of ALL [42], we found MCM2 was upregulated in the T-ALL samples and showed negative correlation with 39 drugs, which implied MCM2 may serve as a potential therapeutic target. Thus, our regulatory network may serve as a resource to explore the development of T-ALL and provide potential targets for drug treatment.…”

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

“…The results of two latter studies seem to be in line with our findings, suggesting that a high level of POLD1 may associate with lower progression and/or better prognosis in the thyroid, colorectal and renal tumors. However, the results of other studies reveal the potential oncogenic role of POLD1 in several human malignancies, reporting that POLD1 mRNA or protein overexpression correlates with the progression and/or worse prognosis in acute in vivo 36: 1188-1194 (2022) 1191 lymphoblastic leukemia (14), endometrial carcinoma (22), triple negative breast cancer (16) and lung adenocarcinoma (15).…”

“…Germline and sporadic POLD1 mutations and gene polymorphisms were shown to contribute to the malignant phenotype of several human tumors including colorectal cancer (CRC), endometrial cancer, glioblastoma and lung cancers (12,13). In addition to genetic alterations, disordered expression of POLD1 at the mRNA and/or protein levels could also associate with the progression of breast tumors, lung tumors and acute lymphoblastic leukemia (14)(15)(16). However, the significance of POLD1 immunoexpression as a prognostic marker in ccRCC and associations between POLD1 immunoreactivity in cancer cells and clinicopathological parameters of the patients have not been analyzed so far.…”

Centrosome Defects in Hematological Malignancies: Molecular Mechanisms and Therapeutic Insights

“…56 Moreover, studies by Zhang's group have identified Plk4 as one of the co-upregulated genes for relapsed acute lymphoblastic leukemia (ALL), indicating its role as a biomarker for this disease. 57 In addition, as mentioned above, mild Plk4 overexpression can drive overall but low-level CA in mammals, inducing a significant increase in spontaneous lymphoma formation. 35 So far, researchers have identified various transcription and post-translational factors that modulate Plk4 expression, activity, or stability.…”