The Leukemia-Specific Fusion Gene ETV6/RUNX1 Perturbs Distinct Key Biological Functions Primarily by Gene Repression
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{"title"=>"The leukemia-specific fusion gene etv6/runx1 perturbs distinct key biological functions primarily by gene repression", "type"=>"journal", "authors"=>[{"first_name"=>"Gerhard", "last_name"=>"Fuka", "scopus_author_id"=>"25947406600"}, {"first_name"=>"Maximilian", "last_name"=>"Kauer", "scopus_author_id"=>"7003295522"}, {"first_name"=>"Reinhard", "last_name"=>"Kofler", "scopus_author_id"=>"7004864063"}, {"first_name"=>"Oskar A.", "last_name"=>"Haas", "scopus_author_id"=>"7103157876"}, {"first_name"=>"Renate", "last_name"=>"Panzer-Grümayer", "scopus_author_id"=>"6507561995"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"80054789892", "pmid"=>"22028862", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "scopus"=>"2-s2.0-80054789892", "issn"=>"19326203", "pui"=>"362778267", "doi"=>"10.1371/journal.pone.0026348"}, "id"=>"a6858c57-4b93-388c-8cef-a4520772c143", "abstract"=>"BACKGROUND: ETV6/RUNX1 (E/R) (also known as TEL/AML1) is the most frequent gene fusion in childhood acute lymphoblastic leukemia (ALL) and also most likely the crucial factor for disease initiation; its role in leukemia propagation and maintenance, however, remains largely elusive. To address this issue we performed a shRNA-mediated knock-down (KD) of the E/R fusion gene and investigated the ensuing consequences on genome-wide gene expression patterns and deducible regulatory functions in two E/R-positive leukemic cell lines.\\n\\nFINDINGS: Microarray analyses identified 777 genes whose expression was substantially altered. Although approximately equal proportions were either up- (KD-UP) or down-regulated (KD-DOWN), the effects on biological processes and pathways differed considerably. The E/R KD-UP set was significantly enriched for genes included in the \"cell activation\", \"immune response\", \"apoptosis\", \"signal transduction\" and \"development and differentiation\" categories, whereas in the E/R KD-DOWN set only the \"PI3K/AKT/mTOR signaling\" and \"hematopoietic stem cells\" categories became evident. Comparable expression signatures obtained from primary E/R-positive ALL samples underline the relevance of these pathways and molecular functions. We also validated six differentially expressed genes representing the categories \"stem cell properties\", \"B-cell differentiation\", \"immune response\", \"cell adhesion\" and \"DNA damage\" with RT-qPCR.\\n\\nCONCLUSION: Our analyses provide the first preliminary evidence that the continuous expression of the E/R fusion gene interferes with key regulatory functions that shape the biology of this leukemia subtype. E/R may thus indeed constitute the essential driving force for the propagation and maintenance of the leukemic process irrespective of potential consequences of associated secondary changes. Finally, these findings may also provide a valuable source of potentially attractive therapeutic targets.", "link"=>"http://www.mendeley.com/research/leukemiaspecific-fusion-gene-etv6runx1-perturbs-distinct-key-biological-functions-primarily-gene-rep", "reader_count"=>45, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>8, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>1, "Student > Master"=>14, "Other"=>2, "Student > Bachelor"=>5, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>8, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>1, "Student > Master"=>14, "Other"=>2, "Student > Bachelor"=>5, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>6, "Agricultural and Biological Sciences"=>27, "Medicine and Dentistry"=>8, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>8}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>27}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Czech Republic"=>1, "United States"=>1, "Brazil"=>1, "Mexico"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/721927"], "description"=>"<p>Meta-groups were curated based on gene-clustering of annotation terms. A: Top 100 annotation terms from KD-UP genes, their <i>P</i>-values and their affiliation to meta-groups. Similarity of the meta-groups was based on the number of shared genes. For distance calculations between the meta-groups genes from all contributing terms were taken together. B: Change in expression of individual genes in meta-groups that contain significant annotation terms. The color code at the bottom of the figure indicates the extent of log2-fold changes in gene expression.</p>", "links"=>[], "tags"=>["annotations", "up-regulated", "genes"], "article_id"=>392286, "categories"=>["Molecular Biology", "Biological Sciences", "Cancer", "Genetics", "Hematology"], "users"=>["Gerhard Fuka", "Maximilian Kauer", "Reinhard Kofler", "Oskar A. Haas", "Renate Panzer-Grümayer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026348.g003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Meta_groups_of_functional_annotations_for_up_regulated_genes_upon_E_R_KD_/392286", "title"=>"Meta-groups of functional annotations for up-regulated genes upon E/R KD.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:38:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/722107"], "description"=>"<p>Depicted are genes found to be significantly and concordantly de-regulated by E/R in KD experiments and <i>E/R</i>-positive vs. <i>E/R</i>-negative primary BCP ALL from Ross et al. <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026348#pone.0026348-Ross1\" target=\"_blank\">[8]</a>. Columns 1–3: Gene identifiers; columns 4–5: log2-fold change values for the mean of AT-2 and REH (column 4) and <i>E/R</i>-positive vs. <i>E/R</i>-negative primary BCP ALL (column 5).</p>", "links"=>[], "tags"=>["50", "regulated", "genes", "microarray", "kd", "experiments"], "article_id"=>392460, "categories"=>["Molecular Biology", "Biological Sciences", "Cancer", "Genetics", "Hematology"], "users"=>["Gerhard Fuka", "Maximilian Kauer", "Reinhard Kofler", "Oskar A. Haas", "Renate Panzer-Grümayer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026348.t002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Top_50_E_R_regulated_genes_from_microarray_analysis_of_KD_experiments_and_primary_ALL_/392460", "title"=>"Top 50 E/R regulated genes from microarray analysis of KD experiments and primary ALL.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-20 00:41:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/365222", "https://ndownloader.figshare.com/files/365277", "https://ndownloader.figshare.com/files/365306", "https://ndownloader.figshare.com/files/365322", "https://ndownloader.figshare.com/files/365357", "https://ndownloader.figshare.com/files/365383", "https://ndownloader.figshare.com/files/365418", "https://ndownloader.figshare.com/files/365446", "https://ndownloader.figshare.com/files/365467"], "description"=>"<div><h3>Background</h3><p><em>ETV6/RUNX1</em> (<em>E/R</em>) (also known as <em>TEL/AML1</em>) is the most frequent gene fusion in childhood acute lymphoblastic leukemia (ALL) and also most likely the crucial factor for disease initiation; its role in leukemia propagation and maintenance, however, remains largely elusive. To address this issue we performed a shRNA-mediated knock-down (KD) of the <em>E/R</em> fusion gene and investigated the ensuing consequences on genome-wide gene expression patterns and deducible regulatory functions in two <em>E/R</em>-positive leukemic cell lines.</p> <h3>Findings</h3><p>Microarray analyses identified 777 genes whose expression was substantially altered. Although approximately equal proportions were either up- (KD-UP) or down-regulated (KD-DOWN), the effects on biological processes and pathways differed considerably. The E/R KD-UP set was significantly enriched for genes included in the “cell activation”, “immune response”, “apoptosis”, “signal transduction” and “development and differentiation” categories, whereas in the E/R KD-DOWN set only the “PI3K/AKT/mTOR signaling” and “hematopoietic stem cells” categories became evident. Comparable expression signatures obtained from primary <em>E/R</em>-positive ALL samples underline the relevance of these pathways and molecular functions. We also validated six differentially expressed genes representing the categories “stem cell properties”, “B-cell differentiation”, “immune response”, “cell adhesion” and “DNA damage” with RT-qPCR.</p> <h3>Conclusion</h3><p>Our analyses provide the first preliminary evidence that the continuous expression of the <em>E/R</em> fusion gene interferes with key regulatory functions that shape the biology of this leukemia subtype. E/R may thus indeed constitute the essential driving force for the propagation and maintenance of the leukemic process irrespective of potential consequences of associated secondary changes. Finally, these findings may also provide a valuable source of potentially attractive therapeutic targets.</p> </div>", "links"=>[], "tags"=>["leukemia-specific", "fusion", "perturbs", "functions", "repression"], "article_id"=>132186, "categories"=>["Molecular Biology", "Biological Sciences", "Cancer", "Genetics", "Hematology"], "users"=>["Gerhard Fuka", "Maximilian Kauer", "Reinhard Kofler", "Oskar A. Haas", "Renate Panzer-Grümayer"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0026348.s001", "https://dx.doi.org/10.1371/journal.pone.0026348.s002", "https://dx.doi.org/10.1371/journal.pone.0026348.s003", "https://dx.doi.org/10.1371/journal.pone.0026348.s004", "https://dx.doi.org/10.1371/journal.pone.0026348.s005", "https://dx.doi.org/10.1371/journal.pone.0026348.s006", "https://dx.doi.org/10.1371/journal.pone.0026348.s007", "https://dx.doi.org/10.1371/journal.pone.0026348.s008", "https://dx.doi.org/10.1371/journal.pone.0026348.s009"], "stats"=>{"downloads"=>28, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/The_Leukemia_Specific_Fusion_Gene_ETV6_RUNX1_Perturbs_Distinct_Key_Biological_Functions_Primarily_by_Gene_Repression/132186", "title"=>"The Leukemia-Specific Fusion Gene <em>ETV6/RUNX1</em> Perturbs Distinct Key Biological Functions Primarily by Gene Repression", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-10-20 00:36:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/721726"], "description"=>"<p>Each dot represents the mean regulation value (log2-fold change of E/R-repressed versus control cells) of three and two replicas, for REH and AT-2 cell lines, respectively. x-axis: REH cell line, y-axis: AT-2 cell line. Negative values indicate a decrease and positive values an increase in gene expression upon fusion gene KD. Green and red dots depict concordantly and significantly modulated genes in a joint analysis of both cell lines.</p>", "links"=>[], "tags"=>["differential", "kd"], "article_id"=>392090, "categories"=>["Molecular Biology", "Biological Sciences", "Cancer", "Genetics", "Hematology"], "users"=>["Gerhard Fuka", "Maximilian Kauer", "Reinhard Kofler", "Oskar A. Haas", "Renate Panzer-Grümayer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026348.g001", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Scatter_plot_of_differential_gene_expression_values_upon_E_R_KD_in_two_cell_lines_/392090", "title"=>"Scatter plot of differential gene expression values upon E/R KD in two cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:34:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/722008"], "description"=>"<p>Quantification of transcripts of differentially expressed genes. A: Concordantly de-regulated by E/R in the KD and primary leukemias. B: Only regulated in the KD experiments. Boxes cover the median and the interquartile range (25–75th percentiles) and whiskers the minimum and maximum values. *, <i>P</i>≤0.05; **, <i>P</i>≤0.01; ***, <i>P</i>≤0.001 (paired t-test).</p>", "links"=>[], "tags"=>["differentially", "genes", "kd", "experiments"], "article_id"=>392368, "categories"=>["Molecular Biology", "Biological Sciences", "Cancer", "Genetics", "Hematology"], "users"=>["Gerhard Fuka", "Maximilian Kauer", "Reinhard Kofler", "Oskar A. Haas", "Renate Panzer-Grümayer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026348.g004", "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Validation_of_selected_differentially_expressed_genes_from_the_KD_experiments_by_RT_qPCR_/392368", "title"=>"Validation of selected differentially expressed genes from the KD experiments by RT-qPCR.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:39:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/722067"], "description"=>"<p>Depicted are genes found to be significantly de-regulated in the E/R knockdown. Columns 1–3: Gene identifiers; columns 4–6: log2-fold change values for the mean of AT-2 and REH (column 4), REH (column 5), AT-2 (column 6).</p>", "links"=>[], "tags"=>["50", "regulated", "genes", "microarray"], "article_id"=>392427, "categories"=>["Molecular Biology", "Biological Sciences", "Cancer", "Genetics", "Hematology"], "users"=>["Gerhard Fuka", "Maximilian Kauer", "Reinhard Kofler", "Oskar A. Haas", "Renate Panzer-Grümayer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026348.t001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Top_50_regulated_genes_from_microarray_analysis_upon_E_R_KD_/392427", "title"=>"Top 50 regulated genes from microarray analysis upon E/R KD.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-20 00:40:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/721831"], "description"=>"<p>Visualization of the similarity of functional annotations that were determined by DAVID for down- (left) and up-regulated (right) genes upon E/R KD. The 100 most significant terms (ranked by <i>P</i>-value) are shown for both sets of annotation terms. Significance levels of functional terms are indicated by a color code shown at the bottom of the figure. Due to large differences in the range of <i>P</i>-values for the functional groups resulting from up- and down-regulated genes upon KD, a different color-scheme was used in each panel.</p>", "links"=>[], "tags"=>["annotation", "clustering", "differentially", "genes"], "article_id"=>392188, "categories"=>["Molecular Biology", "Biological Sciences", "Cancer", "Genetics", "Hematology"], "users"=>["Gerhard Fuka", "Maximilian Kauer", "Reinhard Kofler", "Oskar A. Haas", "Renate Panzer-Grümayer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026348.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_annotation_clustering_of_differentially_expressed_genes_upon_E_R_KD_/392188", "title"=>"Functional annotation clustering of differentially expressed genes upon E/R KD.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-20 00:36:28"}

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Relative Metric

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