Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1-positive leukemia

Gandemer, Virginie; Rio, Anne-Gaëlle; Tayrac, Marie de; Sibut, Vonnick; Mottier, Stéphanie; Sunnaram, Béatrice Ly; Henry, Cathérine; Monnier, Annabelle; Berthou, Christian; Gall, E. Le; Treut, A. Le; Schmitt, Claudine; Gall, Jean‐Yves Le; Mosser, Jean; Galibert, Marie‐Dominique

doi:10.1186/1471-2164-8-385

Cited by 60 publications

(56 citation statements)

References 28 publications

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“…This assumption is further supported by the specific expression signature of E/R-positive leukemias, which also suggests the involvement of other PI3K/AKT/mTOR-regulated processes, including above all cell adhesion and DNA damage response. 15,37 Pharmacological inhibition of the aberrantly activated PI3K/AKT/mTOR pathway has emerged as one of the therapeutic options for overcoming drug resistance. 13 Although E/R-positive leukemias are in general highly treatment-sensitive at initial presentation, a substantial proportion of them apparently become drug-resistant when they relapse.…”

Section: Discussionmentioning

confidence: 99%

Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts

Fuka

Grausenburger

et al. 2011

Leukemia

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The ETV6/RUNX1 (E/R) gene fusion is generated by the t(12;21) and found in approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia. In contrast to the overwhelming evidence that E/R is critical for the initiation of leukemia, its relevance for the maintenance of overt disease is less clear. To investigate this issue, we suppressed the endogenous E/R fusion protein with lentivirally transduced short hairpin RNA in the leukemia cell lines REH and AT-2, and found a distinct reduction of proliferation and cell survival. In line with the observed concurrent inactivation of the phosphoinositide 3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) pathway, pharmacological inhibition diminished the phosphorylation of AKT and ribosomal protein S6, and significantly increased the apoptosis rate in E/R-positive leukemias. Moreover, PI3K/mTOR inhibitors sensitized glucocorticoid-resistant REH cells to prednisolone, an observation of potential relevance for improving treatment of drug-resistant relapses. Of note, knockdown of the E/R fusion gene also severely impaired the repopulation capacity of REH cells in non-obese deficient/severe combined immunodeficient mice. Collectively, these data demonstrate that the E/R fusion protein activates the PI3K/AKT/mTOR pathway and is indispensible for disease maintenance. Importantly, these results provide a first rationale and justification for targeting the fusion gene and the PI3K/AKT/mTOR pathway therapeutically.

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Section: Discussionmentioning

confidence: 99%

Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts

Fuka

Grausenburger

et al. 2011

Leukemia

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“…The E/R fusion is suggested to function as an aberrant TF: The transactivating function of RUNX1 is lost, and the fusion protein is converted into a repressor through the ETV6 moiety that recruits corepressors (SIN3A or NCOR) and epigenetic modifiers (HDACs) (Hiebert et al 1996;Fears et al 1997;Fenrick et al 1999;Song et al 1999;Uchida et al 1999;Guidez et al 2000;Hiebert et al 2001;Morrow et al 2007). During the past decade, a number of microarray studies were performed exploring the gene expression profiles of E/R-positive patient samples (Yeoh et al 2002;Ross and Zhou 2003;Fine et al 2004;Andersson et al 2005Andersson et al , 2007Gandemer et al 2007). However, these studies generated only a limited number of common genomic targets of E/R, and the functions of E/R have remained elusive.…”

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confidence: 99%

Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia

et al. 2016

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Approximately 20%-25% of childhood acute lymphoblastic leukemias carry the ETV6-RUNX1 (E/R) fusion gene, a fusion of two central hematopoietic transcription factors, ETV6 (TEL) and RUNX1 (AML1). Despite its prevalence, the exact genomic targets of E/R have remained elusive. We evaluated gene loci and enhancers targeted by E/R genome-wide in precursor B acute leukemia cells using global run-on sequencing (GRO-seq). We show that expression of the E/R fusion leads to widespread repression of RUNX1 motif-containing enhancers at its target gene loci. Moreover, multiple super-enhancers from the CD19 + /CD20 + -lineage were repressed, implicating a role in impediment of lineage commitment. In effect, the expression of several genes involved in B cell signaling and adhesion was down-regulated, and the repression depended on the wild-type DNA-binding Runt domain of RUNX1. We also identified a number of E/R-regulated annotated and de novo noncoding genes. The results provide a comprehensive genome-wide mapping between E/R-regulated key regulatory elements and genes in precursor B cell leukemia that disrupt normal B lymphopoiesis.

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“…TNFAIP6 also identified by [11] was involved in intracellular signaling (integral to plasma membrane, receptor activity, signal transducer activity, cell surface receptor-linked signal transduction, cell motility, G-proteincoupled receptor protein signaling pathway, cell-cell signaling, development, and organogenesis, morphogenesis and extracellular region). TCFL5 is one of the nine selected genes reported by [48] as being the most biologically relevant and being able to independently differentiate between TEL/AML1 positive and TEL/AML1 negative patients. The lymphoid specific gene, MME that is highly expressed in ALL samples and under expressed in MLL samples has a function in early B-cell development [34].…”

Section: Performing Biomedical Literature Search To Validate the Resultsmentioning

confidence: 99%

Association Rule Based Similarity Measures for the Clustering of Gene Expression Data

Sethi¹

2010

TOMINFOJ

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Abstract:In life threatening diseases, such as cancer, where the effective diagnosis includes annotation, early detection, distinction, and prediction, data mining and statistical approaches offer the promise for precise, accurate, and functionally robust analysis of gene expression data. The computational extraction of derived patterns from microarray gene expression is a non-trivial task that involves sophisticated algorithm design and analysis for specific domain discovery. In this paper, we have proposed a formal approach for feature extraction by first applying feature selection heuristics based on the statistical impurity measures, the Gini Index, Max Minority, and the Twoing Rule and obtaining the top 100-400 genes. We then analyze the associative dependencies between the genes and assign weights to the genes based on their degree of participation in the rules. Consequently, we present a weighted Jaccard and vector cosine similarity measure to compute the similarity between the discovered rules. Finally, we group the rules by applying hierarchical clustering. To demonstrate the usability and efficiency of the concept of our technique, we applied it to three publicly available, multiclass cancer gene expression datasets and performed a biomedical literature search to support the effectiveness of our results.

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Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1-positive leukemia

Cited by 60 publications

References 28 publications

Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts

Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts

Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia

Association Rule Based Similarity Measures for the Clustering of Gene Expression Data

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