Differential MiRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features

Oliveira, Jaqueline Carvalho de; Scrideli, Carlos Alberto; Brassesco, María Sol; Morales, Andressa Gois; Pezuk, Julia Alejandra; Queiroz, Rosane de Paula; Yunes, José Andrés; Brandalise, Sílvia Regina; Tone, Luíz Gonzaga

doi:10.1016/j.leukres.2011.10.005

Cited by 87 publications

(98 citation statements)

References 48 publications

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“…mir-125a-5p is downregulated in many cancers (de Oliveira et al ., 2012; Sand et al ., 2012), which strongly suggests that mir-125a-5p functions as a suppressor of proliferation and migration in cancer cells. In noncancer cells, mir-125a-5p mediates lipid uptake, decreases the secretion of inflammatory cytokines (IL-2, IL-6 and TNF-α) and the expression of oxysterol binding protein-like-9 (ORP9) in human monocytic cells (Chen et al ., 2009), and suppresses ET-1 expression in human umbilical vascular endothelial cells (HUVECs) (Li et al ., 2010).…”

Section: Discussionmentioning

confidence: 99%

miR‐125a‐5p impairs endothelial cell angiogenesis in aging mice via RTEF ‐1 downregulation

Che

Zhang

et al. 2014

Aging Cell

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Increasing evidence suggests that microRNAs (miRNAs) play important roles in impaired endothelial cell (EC) angiogenesis during aging. However, their exact roles in the aging process remain unclear. We aimed to determine whether miRNAs cause angiogenesis defects in ECs during aging and to uncover the underlying mechanisms. To study the miRNA-induced changes in ECs during aging, we performed microarray analyses on arterial ECs collected from young and aging mice. Using qRT–PCR, we showed that microRNA-125a-5p (mir-125a-5p) expression was approximately 2.9 times higher in old endothelial cells (OECs) compared with samples collected from young animals. Western blot assays showed a lower expression level of an mir-125a-5p target known as related transcriptional enhancer factor-1 (RTEF-1) in OECs compared with its expression levels in young cells. Overexpression of mir-125a-5p in young endothelial cells (YECs) using pre-mir-125a-5p caused the downregulation of RTEF-1, endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) and resulted in impaired angiogenesis, as evidenced by spheroid sprouting and tube formation assays in vitro. Conversely, repression of mir-125a-5p in OECs using anti-mir-125a-5p increased RTEF-1, eNOS and VEGF expression and improved EC angiogenesis. Importantly, impaired angiogenesis caused by knock-down of RTEF-1 was not efficiently rescued by anti-mir-125a-5p. Dual-luciferase reporter gene analysis showed that RTEF-1 is a direct target of mir-125a-5p, which regulates angiogenesis by repressing RTEF-1 expression and modulating eNOS and VEGF expression. These findings indicate that mir-125a-5p and RTEF-1 are potential therapeutic targets for improving EC-mediated angiogenesis in elderly individuals.

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Section: Discussionmentioning

confidence: 99%

miR‐125a‐5p impairs endothelial cell angiogenesis in aging mice via RTEF ‐1 downregulation

Che

Zhang

et al. 2014

Aging Cell

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“…Alterations in miRNA expression patterns and their respective targets have been documented in various tumors [12] including different types of leukemias such as chronic lymphocytic leukemia [13], acute myeloid leukemia [14] and ALL [15], thus suggesting a possible correlation between miRNA expression status and the development of hematological malignancies.…”

Section: Introductionmentioning

confidence: 99%

miR-2909-mediated regulation of KLF4: a novel molecular mechanism for differentiating between B-cell and T-cell pediatric acute lymphoblastic leukemias

et al. 2014

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BackgroundmicroRNAs (miRNAs) play both oncogenic and oncostatic roles in leukemia. However, the molecular details underlying miRNA-mediated regulation of their target genes in pediatric B- and T-cell acute lymphoblastic leukemias (ALLs) remain unclear. The present study investigated the relationship between miR-2909 and Kruppel-like factor 4 (KLF4), and its functional relevance to cell cycle progression and immortalization in patients with pediatric ALL.MethodsElevated levels of miR-2909 targeted the tumor suppressor gene KLF4 in pediatric B-cell, but not pediatric T-cell ALL, as detected by pMIR-GFP reporter assay. Expression levels of genes including apoptosis-antagonizing transcription factor (AATF), MYC, B-cell lymphoma (BCL3), P21 CIP , CCND1 and SP1 in B- and T-cells from patients with pediatric ALL were compared with control levels using real-time quantitative reverse transcription polymerase chain reaction, western blotting, and reporter assays.ResultsWe identified two novel mutations in KLF4 in pediatric T-ALL. A mutation in the 3′ untranslated region of the KLF4 gene resulted in loss of miR-2909-mediated regulation, while mutation in its first or third zinc-finger motif (Zf1/Zf3) rendered KLF4 transcriptionally inactive. This mutation was a frameshift mutation resulting in alteration of the Zf3 motif sequence in the mutant KLF4 protein in all pediatric T-ALL samples. Homology models, docking studies and promoter activity of its target gene P21 CIP confirmed the lack of function of the mutant KLF4 protein in pediatric T-ALL. Moreover, the inability of miR-2909 to regulate KLF4 and its downstream genes controlling cell cycle and apoptosis in T-cell but not in B-ALL was verified by antagomiR-2909 transfection. Comprehensive sequence analysis of KLF4 identified the predominance of isoform 1 (~55 kDa) in most patients with pediatric B-ALL, while those with pediatric T-ALL expressed isoform 2 (~51 kDa).ConclusionsThis study identified a novel miR-2909-KLF4 molecular axis able to differentiate between the pathogeneses of pediatric B- and T-cell ALLs, and which may represent a new diagnostic/prognostic marker.

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“…The association between the lower expression of miR-128 and steroid resistance was not evaluated in the present study. In these and other previous studies, miR-128 expression did not correlate with other biological and clinical features (28,31). The role of miR-128 insufficiency in the pathogenesis and response to treatment in patients with IKZF1-deletion ALL should be additionally examined with large-scale pediatric patients with ALL.…”

Section: Discussionmentioning

confidence: 54%

“…In a comparison between normal controls and patients with AML, an increased expression of miR-128 in patients with ALL has been suggested (26). Altered miR-128 expression may discriminate ALL from adult myeloid leukemia and normal bone marrow samples (27)(28)(29)(30). Notably, Mi et al (27) revealed that the differential expression of miR-128 in acute leukemia is not a consequence of an altered genomic DNA copy number, and suggested that this miRNA is also under other types of DNA epigenetic regulation.…”

Section: Discussionmentioning

confidence: 99%

Selected miRNA levels are associated with IKZF1 microdeletions in pediatric acute lymphoblastic leukemia

et al. 2017

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Abstract.The clinical outcome of children with high-risk relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is poor. The present study assessed the utility and prognostic value of selected microRNA (miRNA/miR) in BCP-ALL. The changes in the expression levels of these miRNAs regarding known gene lesions affecting lymphoid development [early B-cell factor 1 (EBF1), ETS variant 6 (ETV6), IKAROS family zinc finger 1 (IKZF1), paired box 5 (PA X5), cyclin dependent kinase inhibitor (CDKN) 2A/CDKN2B, retinoblastoma 1 (RB1), pseudoautosomal region 1 (PAR1), B-cell translocation gene 1 protein (BTG1)] were analyzed. The following miRNAs were analyzed: miR-24, miR-31, miR-128, miR-542, and miR-708. The present study focused on patients with deletions of the IKAROS transcriptional factor gene IKZF1, which is currently considered to be an independent negative prognostic factor for ALL outcome. It was demonstrated that the expression level of miR-128 was significantly lower in patients with IKZF1 deletion compared with patients without IKZF1 deletion. Additionally, low expression of miR-542 was associated with CDKN2A/B and miR-31deletions, and low expression of miR-24 was associated with miR-31 deletion. Low expression of miR-31, miR-24, miR-708 and miR-128 was associated with PAX5 deletion, high expression of miR-24 and miR-542 was associated with PAR1 deletion and high expression of miR-708 was associated with ETV6 deletion. The expression of the selected miRNAs was not associated with deletions of BTG1, EBF1 and RB1. These data, by emphasizing the association of miRNAs expression level with microdeletions, may assist to elucidate ALL biology and contribute to future studies on the possible applications of the miRNA profile for diagnosis.

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Differential MiRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features

Cited by 87 publications

References 48 publications

miR‐125a‐5p impairs endothelial cell angiogenesis in aging mice via RTEF ‐1 downregulation

miR‐125a‐5p impairs endothelial cell angiogenesis in aging mice via RTEF ‐1 downregulation

miR-2909-mediated regulation of KLF4: a novel molecular mechanism for differentiating between B-cell and T-cell pediatric acute lymphoblastic leukemias

Selected miRNA levels are associated with IKZF1 microdeletions in pediatric acute lymphoblastic leukemia

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