Dicer1 imparts essential survival cues in Notch-driven T-ALL via miR-21–mediated tumor suppressor Pdcd4 repression

Junker, Fabian; Chabloz, Antoine; Koch, Ute; Radtke, Freddy

doi:10.1182/blood-2014-12-618892

Cited by 26 publications

(22 citation statements)

References 67 publications

(90 reference statements)

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“…Microarray-based miRNA profiling revealed that miR-21 was deregulated in mouse and human T-ALL cells. Furthermore, miR-21 was shown to regulate T-ALL cell survival via repression of the tumor suppressor PDCD4 (46). In addition, the tumor suppressor Spry2 was revealed to be negatively correlated with miR-21 expression in myeloma cells.…”

Section: Mir-21 and Hematological Malignanciesmentioning

confidence: 98%

Emerging role of microRNA-21 in cancer

2016

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Abstract. MicroRNAs (miRs) are a class of single-stranded RNA molecules of 15-27 nucleotides in length that regulate gene expression at the post-translational level. miR-21 is one of the earliest identified cancer-promoting 'oncomiRs', targeting numerous tumor suppressor genes associated with proliferation, apoptosis and invasion. The regulation of miR-21 and its role in carcinogenesis have been extensively investigated. Recent studies have focused on the diagnostic and prognostic value of miR-21 as well as its implication in the drug resistance of human malignancies. The further use of miR-21 as a biomarker and target for cancer treatments is likely to improve the outcome for patients with cancer. The present review highlights recent findings associated with the importance of miR-21 in hematological and non-hematological malignancies. IntroductionMicroRNAs (miRs) are a class of naturally occurring short non-coding RNA molecules of 15-27 nucleotides in length that regulate eukaryotic gene expression at the post-transcriptional level. Almost 2,000 human miRNAs have been identified through cloning and/or sequence analysis (1). They have key regulatory roles in the development, differentiation and apoptosis of normal cells, as well as in the determination of the final phenotype of cancer cells, affecting carcinogenesis and metastatic potential (2). miR-21 is an abundantly expressed miRNA in mammalian cells, whose upregulation is associated with numerous types of cancer (3,4). By generation of a conditional miR-21 knock-in mouse, it was demonstrated that miR-21 functions as an oncogene with its overexpression resulting in malignant B-cell lymphoma (5). Indeed, miR-21 was found to be the only consistently upregulated miRNA in a study that profiled 540 clinical samples from cancer patients (6). The majority of studies on miR-21 have focused on its role in carcinogenesis and its clinical application. miR-21 is also expressed in hematopoietic cells of the immune system, including B/T cells, monocytes, macrophages and dendritic cells. High miR-21 levels are, therefore, considered to be a marker of immune cell activation (7). Regarding pathological necrosis, miR-21 enhances cellular necrosis by negatively regulating tumor suppressor genes associated with the death receptor-mediated intrinsic apoptotic pathway (8). Biological function of miR-21The biological functions of various miRNAs, including miR-21, have been extensively investigated and miR-21 is

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Section: Mir-21 and Hematological Malignanciesmentioning

confidence: 98%

Emerging role of microRNA-21 in cancer

2016

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“…Junker et al showed that the leukemia onset of this mouse model is dependent on Dicer1 -mediated biogenesis of miRNAs [101]. When HPCs with ICN1 overexpression were injected in conditional Dicer1 knockout mice, where Dicer1 is inactivated when thymocytes or leukemic cells transit from the double negative to double positive (CD4 + CD8 + ) stage, there was no leukemic onset compared with control mice that all developed leukemia in less than 100 days.…”

Section: Methodological Approaches In Mirna and Long Noncoding Rna Rementioning

confidence: 99%

T-ALL and thymocytes: a message of noncoding RNAs

et al. 2017

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In the last decade, the role for noncoding RNAs in disease was clearly established, starting with microRNAs and later expanded towards long noncoding RNAs. This was also the case for T cell acute lymphoblastic leukemia, which is a malignant blood disorder arising from oncogenic events during normal T cell development in the thymus. By studying the transcriptomic profile of protein-coding genes, several oncogenic events leading to T cell acute lymphoblastic leukemia (T-ALL) could be identified. In recent years, it became apparent that several of these oncogenes function via microRNAs and long noncoding RNAs. In this review, we give a detailed overview of the studies that describe the noncoding RNAome in T-ALL oncogenesis and normal T cell development.

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“…To further confirm the function of miR-21, we tested the protein levels of PTEN (phosphatase and tensin homolog deleted on chromosome ten) and PDCD4 (programmed cell death protein 4), which were the target genes of miR-21 ( Junker et al, 2015;Xu et al, 2015). The data showed that miR-21 suppressed the protein levels of PTEN and PDCD4, and the protein levels of PTEN and PDCD4 decreased apparently at ratios RNAiMAX:miR-21 = 3:5, 4:5, 5:5 (Fig.…”

Section: Protein Levels Of Pten and Pdcd4mentioning

confidence: 99%

Establishment of Lipofection Protocol for Efficient miR-21 Transfection into Cortical Neurons In Vitro

Han

Tan

et al. 2015

DNA and Cell Biology

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Dysregulated microRNAs in neurons could cause many nervous system diseases. The therapeutic manipulation of these pathogenic microRNAs necessitates novel, efficient delivery systems to facilitate microRNA modulators targeting neurons with minimal off-target effects. The study aimed to establish a lipofection protocol to upregulate expression levels of miR-21 in neurons under different conditions, including different serum-free medium, transfection conditions, and reagent concentration, by evaluating the expression levels of miR-21 and neuron injury. The expression levels of miR-21 were higher in neurons transfected by Neurobasal-A than by DMEM. Expression levels of miR-21 were already the highest at the ratio RNAiMAX:miR-21 = 3:5, but the increase of RNAiMAX's concentration had not caused the further upregulation of expression level of miR-21. Neuron injury was condition dependent and dose dependent after transfection. Compared to S-Neurobasal groups, neurons have a smaller injury in N-Neurobasal groups, and compared to ratios RNAiMAX:miR-21 = 4:5, 5:5, neuron injury was smaller at ratios of RNAiMAX:miR-21 = 1:5, 2:5, 3:5. Without the pretreatment of starvation in vitro, the lipofection protocol was that RNAiMAX/miR-21 agomir complexes were diluted in Neurobasal-A at the ratio of RNAiMAX:miR-21 = 3:5.

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Dicer1 imparts essential survival cues in Notch-driven T-ALL via miR-21–mediated tumor suppressor Pdcd4 repression

Abstract: Key Points Dicer1-mediated miRNA biogenesis is essential for induction and maintenance of Notch1-driven T-ALL. miR-21 regulates survival of T-ALL, in part through the repression of the tumor suppressor gene Pdcd4.

Cited by 26 publications

References 67 publications

Emerging role of microRNA-21 in cancer

Emerging role of microRNA-21 in cancer

T-ALL and thymocytes: a message of noncoding RNAs

Establishment of Lipofection Protocol for Efficient miR-21 Transfection into Cortical Neurons In Vitro

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