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Conference Paper: Alternative splicing is a major mechanism of gene regulation in diffuse large B cell lymphoma

TitleAlternative splicing is a major mechanism of gene regulation in diffuse large B cell lymphoma
Authors
Issue Date2010
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
The 52nd Annual Meeting and Exposition of the American Society of Hematology (ASH 2010), Orlando, FL., 4-7 December 2010. In Blood, 2010, v. 116 n. 21, abstract 803 How to Cite?
AbstractDiffuse large B-cell lymphomas (DLBCL) is the most common form of lymphoma and these tumors demonstrate a striking molecular and clinical heterogeneity. Gene expression profiling has shown that these tumors can be divided into at least two groups, activated B cell-like (ABC) and germinal B cell-like (GCB), as well as a number of other cellular processes underlying survival and tumor biology. However, the molecular mechanisms which lead to the differential gene expression patterns are not well understood. Alternative splicing is a process through which individual exons that comprise genes that are assembled into different gene isoforms with potentially different function. Alternative splicing has been shown to be a ubiquitous mechanism of gene regulation in eukaryotes and a number of cancers. The role of alternative splicing in DLBCL is unknown. We hypothesized that alternative splicing might play an important role in DLBCL. We measured genome-wide expression of over 1 million exons in 106 primary DLBCL tumors using Affymetrix Exon 1.0 ST microarrays. The same cases were also profiled for gene expression using a conventional Affymetrix Gene microarray for comparison, and further sub-classified as the molecular subgroups of DLBCL and for independent assessment of gene expression associated with known biological processes. We identified those genes as alternatively spliced which had at least one exon that was significantly different (P<0.01) compared with the comparison group. Through examination of exon-level expression data, we found evidence for splicing events in over 10,000 genes that affect at least 10% of DLBCL cases. We identified over 200 genes that have differential exon usage between ABC and GCB DLBCL. The expression of selected alternatively spliced exons was confirmed by real-time PCR. We further examined the occurrence of alternative splicing in a number of cellular processes including each of the survival associated gene expression signatures. We found that alternative splicing regulates a significant number of genes underlying the survival-associated proliferation, stromal response and germinal center differentiation gene expression signatures (P<10–6 in all cases). In addition, a number of processes that are known to be important in oncogenesis appeared to be highly regulated by alternative splicing including transcription factor activity, DNA-repair and apoptosis (P<0.001). These data confirm that alternative splicing plays a significant role in regulating genes that are important mediators of DLBCL biology. We further investigated whether lineage-specific effects were responsible for some of the observed differences in splicing in the molecular subgroups of DLBCLs. We obtained normal resting B cells from healthy donors and stimulated them with IgM and CD40-ligand to generate activated B cells. We found that the gene-isoforms expressed highly in activated normal B cells were significantly enriched in ABC-DLBCLS (P<0.01), suggesting that lineage-derived differences in isoform splicing are preserved in their malignant counterparts. Our data indicate that alternative splicing provides an additional and significant component of regulation that encompasses nearly every biological process that is known to be important in DLBCL. Future studies that examine the role gene expression will need to recognize the specific isoforms that result in proteins with altered function.
DescriptionOpen Access Journal
This journal issue is proceedings of ASH Conference 2010
Oral Session - Non-Hodgkin Lymphoma - Biology, excluding Therapy: Advanced Technology in Non-Hodgkin Lymphoma Genetics
Persistent Identifierhttp://hdl.handle.net/10722/129872
ISSN
2015 Impact Factor: 11.841
2015 SCImago Journal Rankings: 6.395

 

DC FieldValueLanguage
dc.contributor.authorJacobs, CLen_US
dc.contributor.authorPatel, Aen_US
dc.contributor.authorJima, Den_US
dc.contributor.authorLiu, Qen_US
dc.contributor.authorGreenough, Aen_US
dc.contributor.authorZhang, Jen_US
dc.contributor.authorDunphy, Cen_US
dc.contributor.authorRichards, Ken_US
dc.contributor.authorChoi, WLen_US
dc.contributor.authorSrivastava, Gen_US
dc.contributor.authorAu, WYen_US
dc.contributor.authorEvens, AMen_US
dc.contributor.authorGordon, LIen_US
dc.contributor.authorCzader, Men_US
dc.contributor.authorRizzieri, DAen_US
dc.contributor.authorLagoo, ASen_US
dc.contributor.authorMann, KPen_US
dc.contributor.authorFlowers, CRen_US
dc.contributor.authorBernal-Mizrachi, Len_US
dc.contributor.authorNaresh, Ken_US
dc.contributor.authorLuftig, Men_US
dc.contributor.authorChadburn, Aen_US
dc.contributor.authorHsi, Een_US
dc.contributor.authorThompson, MAen_US
dc.contributor.authorGill, Jen_US
dc.contributor.authorDave, S-
dc.date.accessioned2010-12-23T08:43:27Z-
dc.date.available2010-12-23T08:43:27Z-
dc.date.issued2010en_US
dc.identifier.citationThe 52nd Annual Meeting and Exposition of the American Society of Hematology (ASH 2010), Orlando, FL., 4-7 December 2010. In Blood, 2010, v. 116 n. 21, abstract 803en_US
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/129872-
dc.descriptionOpen Access Journal-
dc.descriptionThis journal issue is proceedings of ASH Conference 2010-
dc.descriptionOral Session - Non-Hodgkin Lymphoma - Biology, excluding Therapy: Advanced Technology in Non-Hodgkin Lymphoma Genetics-
dc.description.abstractDiffuse large B-cell lymphomas (DLBCL) is the most common form of lymphoma and these tumors demonstrate a striking molecular and clinical heterogeneity. Gene expression profiling has shown that these tumors can be divided into at least two groups, activated B cell-like (ABC) and germinal B cell-like (GCB), as well as a number of other cellular processes underlying survival and tumor biology. However, the molecular mechanisms which lead to the differential gene expression patterns are not well understood. Alternative splicing is a process through which individual exons that comprise genes that are assembled into different gene isoforms with potentially different function. Alternative splicing has been shown to be a ubiquitous mechanism of gene regulation in eukaryotes and a number of cancers. The role of alternative splicing in DLBCL is unknown. We hypothesized that alternative splicing might play an important role in DLBCL. We measured genome-wide expression of over 1 million exons in 106 primary DLBCL tumors using Affymetrix Exon 1.0 ST microarrays. The same cases were also profiled for gene expression using a conventional Affymetrix Gene microarray for comparison, and further sub-classified as the molecular subgroups of DLBCL and for independent assessment of gene expression associated with known biological processes. We identified those genes as alternatively spliced which had at least one exon that was significantly different (P<0.01) compared with the comparison group. Through examination of exon-level expression data, we found evidence for splicing events in over 10,000 genes that affect at least 10% of DLBCL cases. We identified over 200 genes that have differential exon usage between ABC and GCB DLBCL. The expression of selected alternatively spliced exons was confirmed by real-time PCR. We further examined the occurrence of alternative splicing in a number of cellular processes including each of the survival associated gene expression signatures. We found that alternative splicing regulates a significant number of genes underlying the survival-associated proliferation, stromal response and germinal center differentiation gene expression signatures (P<10–6 in all cases). In addition, a number of processes that are known to be important in oncogenesis appeared to be highly regulated by alternative splicing including transcription factor activity, DNA-repair and apoptosis (P<0.001). These data confirm that alternative splicing plays a significant role in regulating genes that are important mediators of DLBCL biology. We further investigated whether lineage-specific effects were responsible for some of the observed differences in splicing in the molecular subgroups of DLBCLs. We obtained normal resting B cells from healthy donors and stimulated them with IgM and CD40-ligand to generate activated B cells. We found that the gene-isoforms expressed highly in activated normal B cells were significantly enriched in ABC-DLBCLS (P<0.01), suggesting that lineage-derived differences in isoform splicing are preserved in their malignant counterparts. Our data indicate that alternative splicing provides an additional and significant component of regulation that encompasses nearly every biological process that is known to be important in DLBCL. Future studies that examine the role gene expression will need to recognize the specific isoforms that result in proteins with altered function.-
dc.languageengen_US
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlood-
dc.titleAlternative splicing is a major mechanism of gene regulation in diffuse large B cell lymphomaen_US
dc.typeConference_Paperen_US
dc.identifier.emailChoi, WL: wlchoi@pathology.hku.hken_US
dc.identifier.emailSrivastava, G: gopesh@pathology.hku.hken_US
dc.identifier.emailAu, WY: auwing@hkucc.hku.hk-
dc.identifier.authorityChoi, WL=rp00247en_US
dc.identifier.authoritySrivastava, G=rp00365en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros183559en_US
dc.identifier.volume116-
dc.identifier.issue21-
dc.publisher.placeUnited States-
dc.customcontrol.immutablesml 130326-

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