Potential therapeutic targets and small molecular drugs for pediatric B-precursor acute lymphoblastic leukemia treatment based on microarray data

Abstract

The current study investigated the molecular mechanisms underlying pediatric acute lymphoblastic leukemia (ALL) and screened for small molecular drugs as supplementary drugs to aid current therapy. Gene expression data of Gene Expression Omnibus (GEO) DataSet GSE42221, which consists of 7 primary human B-precursor samples and 4 control B-cell progenitor lymphoblast samples from patients with pediatric ALL, were downloaded from the public GEO database. Linear Models for Microarray Analysis package for R statistical software was used to identify differentially expressed genes (DEGs). Subsequently, biclustering analysis of DEGs was performed using pheatmap package for R. Functional enrichment analysis of DEGs was conducted using the Database for Annotation, Visualization and Integrated Discovery tool. Additionally, Search Tool for the Retrieval of Interacting Genes software was used to screen protein-protein interactions (PPIs) of the DEGs, and Connectivity Map database was employed to obtain small-molecule drugs that were significantly associated with DEGs. In total, 116 genes were identified as DEGs in pediatric ALL, including 56 downregulated and 60 upregulated genes. Functional enrichment analysis identified that upregulated DEGs, including marker of proliferation Ki-67, cyclin F and nucleolar and spindle associated protein 1, were significantly enriched in mesenchymal cell differentiation and development processes, whilst downregulated DEGs, including bone marrow morphogenetic protein 2, semaphoring 3F and ephrin B1 were enriched in cell cycle process. Amongst the DEGs, 169 PPIs were identified. Notably, carbimazole and quinostatin were associated with DEGs. Additionally, a number of DEGs were targeted by the two drugs, including signal transducer and activator of transcription 3, nucleolar and spindle associated protein 1 and cell division cycle 20. Mesenchymal cell differentiation and development as well as cell cycle processes may be important for pediatric ALL. Quinostatin may be used as a potent supplementary drug for treating pediatric ALL.

The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?

“…Oliveira and colleagues reported that PLK1 expression was heterogeneous in pediatric ALL cases, with no differences between the overall population and normal bone marrow cells [68]. Moreover, genes involved in spindle organization ( SPC25 , KIF11 , ESPL1 , UBE2C , TACC3 ), chromosome segregation ( SPC25 , NUSAP1 , BIRC5 , CENPE , ESPL1 , PTTG1 ), and cell division (KIF11, CCNF , NUSAP1 , CENPE , CDC20 ) have been found to be upregulated in pediatric B cell precursor ALL compared with normal B cell progenitors, highlighting their potential for use as therapeutic targets [69]. With regard to adult ALL cases, mRNA levels of two negative regulators of CDK1-cyclin B1 complex, WEE1 and PKMYT1, are significantly upregulated in leukemic samples with respect to normal hematopoietic precursors [70] .…”

A drug repurposing method based on inhibition effect on gene regulatory network

“…Quinostatin was also regarded as an inhibitor of cellular S6 phosphorylation [73] . Kong et al found that quinostatin had been predicted as a potential supplementary agent for the treatment of pediatric acute lymphoblastic leukemia [74] . Yang et al [75] presented that quinostatin potently inhibited the mTOR signaling pathway by directly targeting the lipid-kinase activity of the catalytic subunits of class Ia PI3K.…”

The Clinical Relevance of the EPH/Ephrin Signaling Pathway in Pediatric Solid and Hematologic Malignancies

“…Specifically, the observation that a high expression of EPHA2 in neuroblastoma [103], EPHB1 in glioma [79], EPHB6, ephrin-B2, and ephrin-B3 in neuroblastoma [101] correlates with a better prognosis is in line with a tumor-suppressive role of these EPHs. EFNB1 has been identified among downregulated DEGs in children diagnosed with AML [134], while bone marrow samples from pediatric AML patients are characterized by EPHB1 promoter hypermethylation with subsequent decreased EPHB1 expression [136], while analogously for the case of pediatric ALL, the observed increased EPHB4 methylation resulting in decreased EPHB4 expression may contribute to leukemia development and progression [131]. Interestingly, as it is observed for the case of EPHB4, the same EPH can exert either a pro-tumorigenic (i.e., in neuroblastoma and rhabdomyosarcoma [106,120]) or anti-tumorigenic function (i.e., in ALL [131]) depending on the type of neoplasm it is expressed.…”

“…Furthermore, EPHB6-expressing cells were shown to be significantly selected in minimal residual disease up to 30 days from the standard treatments, while they also presented increased markers related to cell proliferation and poor clinical outcome, such as cyclin B1 (CCNB1) and kinesin family member 20A (KIF20A) [133]. For the case of pediatric B-cell ALL (B-ALL), Kong et al identified EFNB1 among the downregulated differentially expressed genes (DEGs) enriched in the cell cycle process [134]. El-Sisi et al investigated the expression of EPHA4 by RT-PCR in peripheral blood samples of a cohort that included 58 acute myeloid leukemia (AML) patients, among whom 19 were children, demonstrating a positive expression in 36.8% of pediatric AML patients [135].…”