A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma
Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic...
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| Veröffentlicht in: | Leukemia 2014-05, Vol.28 (5), p.1092-1102 |
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| creator | Horvilleur, E Sbarrato, T Hill, K Spriggs, R V Screen, M Goodrem, P J Sawicka, K Chaplin, L C Touriol, C Packham, G Potter, K N Dirnhofer, S Tzankov, A Dyer, M J S Bushell, M MacFarlane, M Willis, A E |
| description | Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5′-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis. |
| doi_str_mv | 10.1038/leu.2013.295 |
| format | Article |
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Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5′-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2013.295</identifier><identifier>PMID: 24135829</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>5' Untranslated Regions ; 631/337/574 ; 692/420/755 ; 692/699/67/1990/291/1621/1915 ; Cancer Research ; Care and treatment ; Cell Line, Tumor ; Cellular proteins ; Critical Care Medicine ; Development and progression ; DNA repair ; Electrophoresis, Polyacrylamide Gel ; Eukaryotic Initiation Factors - metabolism ; Gene expression ; Genetic aspects ; Health aspects ; Hematology ; Humans ; Intensive ; Internal Medicine ; Leukemia ; Lymphoma ; Lymphoma, Large B-Cell, Diffuse - metabolism ; Lymphoma, Large B-Cell, Diffuse - pathology ; Lymphomas ; Medical prognosis ; Medicine ; Medicine & Public Health ; Oligonucleotide Array Sequence Analysis ; Oncology ; Original ; original-article ; Pathogenesis ; Patients ; Protein synthesis ; Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; Sucrose ; Toxicology ; Up-Regulation</subject><ispartof>Leukemia, 2014-05, Vol.28 (5), p.1092-1102</ispartof><rights>The Author(s) 2014</rights><rights>COPYRIGHT 2014 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 2014</rights><rights>Copyright © 2014 Macmillan Publishers Limited 2014 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c608t-82718379959fa97f84c5d0d7ab058bd9484790d5edc686c5c4bf4c91645fb4463</citedby><cites>FETCH-LOGICAL-c608t-82718379959fa97f84c5d0d7ab058bd9484790d5edc686c5c4bf4c91645fb4463</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2013.295$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2013.295$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24135829$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Horvilleur, E</creatorcontrib><creatorcontrib>Sbarrato, T</creatorcontrib><creatorcontrib>Hill, K</creatorcontrib><creatorcontrib>Spriggs, R V</creatorcontrib><creatorcontrib>Screen, M</creatorcontrib><creatorcontrib>Goodrem, P J</creatorcontrib><creatorcontrib>Sawicka, K</creatorcontrib><creatorcontrib>Chaplin, L C</creatorcontrib><creatorcontrib>Touriol, C</creatorcontrib><creatorcontrib>Packham, G</creatorcontrib><creatorcontrib>Potter, K N</creatorcontrib><creatorcontrib>Dirnhofer, S</creatorcontrib><creatorcontrib>Tzankov, A</creatorcontrib><creatorcontrib>Dyer, M J S</creatorcontrib><creatorcontrib>Bushell, M</creatorcontrib><creatorcontrib>MacFarlane, M</creatorcontrib><creatorcontrib>Willis, A E</creatorcontrib><title>A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5′-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis.</description><subject>5' Untranslated Regions</subject><subject>631/337/574</subject><subject>692/420/755</subject><subject>692/699/67/1990/291/1621/1915</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Cell Line, Tumor</subject><subject>Cellular proteins</subject><subject>Critical Care Medicine</subject><subject>Development and progression</subject><subject>DNA repair</subject><subject>Electrophoresis, Polyacrylamide Gel</subject><subject>Eukaryotic Initiation Factors - metabolism</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Hematology</subject><subject>Humans</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Leukemia</subject><subject>Lymphoma</subject><subject>Lymphoma, Large B-Cell, Diffuse - 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Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5′-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. 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| ispartof | Leukemia, 2014-05, Vol.28 (5), p.1092-1102 |
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| source | MEDLINE; Springer Journals; Springer Nature - Connect here FIRST to enable access; Elektronische Zeitschriftenbibliothek - Freely accessible e-journals |
| subjects | 5' Untranslated Regions 631/337/574 692/420/755 692/699/67/1990/291/1621/1915 Cancer Research Care and treatment Cell Line, Tumor Cellular proteins Critical Care Medicine Development and progression DNA repair Electrophoresis, Polyacrylamide Gel Eukaryotic Initiation Factors - metabolism Gene expression Genetic aspects Health aspects Hematology Humans Intensive Internal Medicine Leukemia Lymphoma Lymphoma, Large B-Cell, Diffuse - metabolism Lymphoma, Large B-Cell, Diffuse - pathology Lymphomas Medical prognosis Medicine Medicine & Public Health Oligonucleotide Array Sequence Analysis Oncology Original original-article Pathogenesis Patients Protein synthesis Proteins Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Sucrose Toxicology Up-Regulation |
| title | A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma |
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