Integrative Analysis of MicroRNA-Mediated Gene Signatures and Pathways Modulating White Blood Cell Count in Childhood Acute Lymphoblastic Leukemia

Ramani, Ritika; Megason, Gail; Schallheim, Jason; Karlson, Cynthia; Vijayakumar, Vani; Vijayakumar, Srinivasan; Hicks, Chindo

doi:10.1177/1177271917702895

Cited by 10 publications

(13 citation statements)

References 36 publications

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“…More recently, however, they have been implicated in a variety of cancers, including ALL, and are increasingly recognized as potential crucial biomarkers and treatment targets 27,28 . In 2017, Ramani et al discovered signatures of differentially expressed miRNAs in ALL to better risk stratify pediatric patients and identified several dysregulated miRNA-mediated molecular networks, including VEGF, IGF-1, and JAK/STAT 29 . Additionally, Correia et al found in 2016 that downregulation of miR-146b by oncogene TAL1 promotes aggressive phenotypes of T-cell ALL (T-ALL), suggesting that exogenous miR-146b can potentially contribute to treatment strategies 30 .…”

Section: Discussionmentioning

confidence: 99%

NET1 Enhances Proliferation and Chemoresistance in Acute Lymphoblastic Leukemia Cells

et al. 2019

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Acute lymphoblastic leukemia (ALL) is the most prevalent of pediatric cancers. Neuroepithelial cell-transforming 1 (NET1) has been associated with malignancy in a number of cancers, but the role of NET1 in ALL development is unclear. In the present study, we investigated the effect of NET1 gene in ALL cell proliferation and chemoresistance. We analyzed GEO microarray data comparing bone marrow expression profiles of pediatric B-cell ALL samples and those of age-matched controls. MTT and colony formation assays were performed to analyze cell proliferation. ELISA assays, Western blot analyses, and TUNEL staining were used to detect chemoresistance. We confirmed that NET1 was targeted by miR-206 using Western blot and luciferase reporter assays. We identified NET1 gene as one of the most significantly elevated genes in pediatric B-ALL. MTT and colony formation assays demonstrated that NET1 overexpression increases B-ALL cell proliferation in Nalm-6 cells. ELISA assays, Western blot analyses, and TUNEL staining showed that NET1 contributes to ALL cell doxorubicin resistance, whereas NET1 inhibition reduces resistance. Using the TargetScan database, we found that several microRNAs (miRNAs) were predicted to target NET1, including microRNA-206 (miR-206), which has been shown to regulate cancer development. To determine whether miR-206 targets NET1 in vitro, we transfected Nalm-6 cells with miR-206 or its inhibitor miR-206-in. Western blot assays showed that miR-206 inhibits NET1 expression and miR-206-in increases NET1 expression. Luciferase assays using wild-type or mutant 3′-untranslated region (3′-UTR) of NET1 confirmed these findings. We ultimately found that miR-206 inhibits B-ALL cell proliferation and chemoresistance induced by NET1. Taken together, our results provide the first evidence that NET1 enhances proliferation and chemoresistance in B-ALL cells and that miR-206 regulates these effects by targeting NET1. This study therefore not only contributes to a greater understanding of the molecular mechanisms underlying B-ALL progression but also opens the possibility for developing curative interventions.

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Section: Discussionmentioning

confidence: 99%

NET1 Enhances Proliferation and Chemoresistance in Acute Lymphoblastic Leukemia Cells

et al. 2019

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“…The resultant differentially expressed miRNAs between Austrians and Japanese were analyzed using Ingenuity Pathway Analysis (IPA) (Ingenuity Pathway Analysis: QIAGEN Inc. https://www.qiagenbioinformatics.com/products/ingenuitypathway-analysis ) 55 . Putative miRNA targets were found using Ingenuity miRNA target filter for experimentally validated and putative predicted targets (high confidence level) through in silico analysis 56 . After linking miRNAs with mRNA target genes, mRNA target genes that differed between the countries were considered.…”

Section: Methodsmentioning

confidence: 99%

Blood levels of microRNAs associated with ischemic heart disease differ between Austrians and Japanese: a pilot study

Wakabayashi

Eguchi

Sotoda

et al. 2020

Sci Rep

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Mortality from ischemic heart disease (IHD) is significantly lower in Japan than in Western countries. The purpose of this study was to investigate differences in circulating microRNA (miRNA) levels related to IHD in Austrians and Japanese. Participants were middle-aged healthy male Austrians (n = 20) and Japanese (n = 20). Total miRNAs in serum from each participant were analyzed using the 3D-Gene miRNA Oligo chip. Twenty-one miRNAs, previously reported as associated with IHD, were compared between Austrians and Japanese. The expression levels of miR-106a-5p, miR-135a-3p, miR-150-3p, miR-16-5p, miR-17-5p. miR-191-5p, miR-320b, miR-451a, miR-486-5p, miR-663b, and miR-92a-3p were significantly higher, while the miR-2861 expression level was significantly lower in Austrians as compared to Japanese. Both in Austrians and Japanese, there were significant positive correlations between serum expression levels of each pair of the above miRNAs except for miR-2861. The expression level of miR-2861 showed significant positive correlations with the expression levels of miR-106a-5p, miR-150-3p, miR-17-5p, miR-486-5p, miR-663b and miR-92a-3p in Austrians but not in Japanese. In pathway analysis, proinflammatory cytokine production in foam cells and collagen synthesis in vascular smooth muscle cells were associated with differentially expressed miRNAs. Difference in miRNA levels may contribute to lower cardiovascular risk in Japan than in Western countries.

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“…The same study pointed out that JAK1 inhibitor ruxolitinib can rescue phenotypic changes induced by low miR-24-2 [ 134 ]. Significant downregulation of miR-25 has been also reported in pediatric ALL cases compared with healthy controls [ 59 , 62 ]. miR-24-2 belongs to a family comprising miR-92a-1, miR-92a-2 and miR-92b, whereas it is found clustered with miR-93 and miR-106b.…”

Section: Resultsmentioning

confidence: 99%

MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools

Kyriakidis

Tsezou

2022

Cancers

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MicroRNAs (miRNAs) have been implicated in childhood acute lymphoblastic leukemia (ALL) pathogenesis. We performed a systematic review and meta-analysis of miRNA single-nucleotide polymorphisms (SNPs) in childhood ALL compared with healthy children, which revealed (i) that the CC genotype of rs4938723 in pri-miR-34b/c and the TT genotype of rs543412 in miR-100 confer protection against ALL occurrence in children; (ii) no significant association between rs2910164 genotypes in miR-146a and childhood ALL; and (iii) SNPs in DROSHA, miR-449b, miR-938, miR-3117 and miR-3689d-2 genes seem to be associated with susceptibility to B-ALL in childhood. A review of published literature on differential expression of miRNAs in children with ALL compared with controls revealed a significant upregulation of the miR-128 family, miR-130b, miR-155, miR-181 family, miR-210, miR-222, miR-363 and miR-708, along with significant downregulation of miR-143 and miR-148a, seem to have a definite role in childhood ALL development. MicroRNA signatures among childhood ALL subtypes, along with differential miRNA expression patterns between B-ALL and T-ALL cases, were scrutinized. With respect to T-ALL pediatric cases, we reanalyzed RNA-seq datasets with a robust and sensitive pipeline and confirmed the significant differential expression of hsa-miR-16-5p, hsa-miR-19b-3p, hsa-miR-92a-2-5p, hsa-miR-128-3p (ranked first), hsa-miR-130b-3p and -5p, hsa-miR-181a-5p, -2-3p and -3p, hsa-miR-181b-5p and -3p, hsa-miR-145-5p and hsa-miR-574-3p, as described in the literature, along with novel identified miRNAs.

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Integrative Analysis of MicroRNA-Mediated Gene Signatures and Pathways Modulating White Blood Cell Count in Childhood Acute Lymphoblastic Leukemia

Cited by 10 publications

References 36 publications

NET1 Enhances Proliferation and Chemoresistance in Acute Lymphoblastic Leukemia Cells

NET1 Enhances Proliferation and Chemoresistance in Acute Lymphoblastic Leukemia Cells

Blood levels of microRNAs associated with ischemic heart disease differ between Austrians and Japanese: a pilot study

MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools

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