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Conference Paper: ID3 is a novel tumor suppressor gene in Burkitt lymphoma

TitleID3 is a novel tumor suppressor gene in Burkitt lymphoma
Authors
Issue Date2012
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
The 54th Annual Meeting and Exposition of the American Society of Hematology (ASH 2012), Atlanta, GA., 8-11 December 2012. In Blood, 2012, v. 120 n. 21, abstract 898 How to Cite?
AbstractBurkitt Lymphoma (BL) is a highly proliferative form of non-Hodgkin lymphoma and is characterized by translocation of the C-MYC gene to the immunoglobulin gene loci resulting in deregulation. The role of collaborating gene mutations in BL is largely unknown. We performed whole exome sequencing and gene expression profiling of 57 Burkitt lymphoma and 94 DLBCL exomes. Mutational analysis revealed that ID3 is recurrently mutated in 38% of Burkitt lymphoma samples. ID3 mutations did not occur in any of the 94 DLBCL cases. ID3 gene expression was also found to be a distinguishing feature of Burkitt lymphomas (P<10–6), compared to DLBCL. We found a total of 27 distinct mutations in the ID3 genes among the 22 BL cases. These included five frameshift, four nonsense, and 18 missense mutations. We validated 16 of these events with Sanger sequencing with over 90% concordance. All of these mutations were located in the highly conserved helix-loop-helix region located on Exon 1. We explored the biological significance of ID3 mutations by initially comparing the gene expression profiles of BL cases that had mutated and wild-type ID3. Gene set enrichment analysis showed that those samples with mutated ID3 had higher expression of genes that were involved in cell cycle regulation, specifically those involved in the G1-S transition (P=0.01). In order to experimentally investigate the functional consequences of ID3 mutation, we generated mutant constructs corresponding to six different ID3 mutations observed in BLs. These mutant constructs were cloned into lentiviral vectors and overexpressed in BL cells that were wild type for ID3. We then performed cell cycle analysis for these wild type cells expressing GFP controls or the mutant constructs. We found that BL cells expressing each of the six mutant constructs demonstrated significant cell cycle progression from G1 to S phase compared to wild-type (P=0.01). Separately, we tested the effects of expressing mutant ID3 in cell proliferation assays and found that cells expressing mutant ID3 were considerably more proliferative than those expressing wild type (P=0.03). Conversely, we over-expressed the wild type form of ID3 in BL cells that had mutated ID3. These experiments completely rescued the observed phenotypes of the mutant ID3 constructs, with reduced cell cycle progression through increased G1 phase and decreased S-phase (P=0.04). We also noted decreased cell proliferation in these cells (P=0.03). These experiments support a role for ID3 as a novel tumor suppressor gene in Burkitt lymphoma. ID3 is a basic helix loop helix (bHLH) protein that binds to other E-proteins, blocking their ability to bind DNA. ID3 has been shown to be involved in a variety of biological processes including development and T and B cell differentiation. ID3 knockout mice have been shown to develop T cell as well as B cell lymphomas. Our data implicates this gene for the first time as a tumor suppressor in human cancer.
DescriptionOpen Access Journal
This journal issue is proceedings of ASH Conference 2012
Oral Sessions - 622. Non-Hodgkin Lymphoma - Biology, excluding Therapy: Highly Aggressive Lymphomas
Persistent Identifierhttp://hdl.handle.net/10722/181791
ISSN
2015 Impact Factor: 11.841
2015 SCImago Journal Rankings: 6.395

 

DC FieldValueLanguage
dc.contributor.authorLove, CLen_US
dc.contributor.authorJima, Den_US
dc.contributor.authorSun, Zen_US
dc.contributor.authorMiles, RRen_US
dc.contributor.authorDunphy, CHen_US
dc.contributor.authorChoi, WWLen_US
dc.contributor.authorAu, WYen_US
dc.contributor.authorSrivastava, Gen_US
dc.contributor.authorLugar, Pen_US
dc.contributor.authorRizzieri, DAen_US
dc.contributor.authorLagoo, ASen_US
dc.contributor.authorBernal-Mizrachi, Len_US
dc.contributor.authorMann, KPen_US
dc.contributor.authorFlowers, CRen_US
dc.contributor.authorNaresh, Ken_US
dc.contributor.authorEvens, AMen_US
dc.contributor.authorChadburn, Aen_US
dc.contributor.authorGordon, LIen_US
dc.contributor.authorCzader, Men_US
dc.contributor.authorGill, Jen_US
dc.contributor.authorHsi, EDen_US
dc.contributor.authorZhang, Jen_US
dc.contributor.authorGrubor, Ven_US
dc.contributor.authorLevy, Sen_US
dc.contributor.authorBunerjee, Aen_US
dc.contributor.authorDunson, Den_US
dc.contributor.authorLi, Gen_US
dc.contributor.authorMoffitt, Aen_US
dc.contributor.authorGreenough, Aen_US
dc.contributor.authorMcKinney, MSen_US
dc.contributor.authorDave, SSen_US
dc.date.accessioned2013-03-19T03:57:52Z-
dc.date.available2013-03-19T03:57:52Z-
dc.date.issued2012en_US
dc.identifier.citationThe 54th Annual Meeting and Exposition of the American Society of Hematology (ASH 2012), Atlanta, GA., 8-11 December 2012. In Blood, 2012, v. 120 n. 21, abstract 898en_US
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/181791-
dc.descriptionOpen Access Journal-
dc.descriptionThis journal issue is proceedings of ASH Conference 2012-
dc.descriptionOral Sessions - 622. Non-Hodgkin Lymphoma - Biology, excluding Therapy: Highly Aggressive Lymphomas-
dc.description.abstractBurkitt Lymphoma (BL) is a highly proliferative form of non-Hodgkin lymphoma and is characterized by translocation of the C-MYC gene to the immunoglobulin gene loci resulting in deregulation. The role of collaborating gene mutations in BL is largely unknown. We performed whole exome sequencing and gene expression profiling of 57 Burkitt lymphoma and 94 DLBCL exomes. Mutational analysis revealed that ID3 is recurrently mutated in 38% of Burkitt lymphoma samples. ID3 mutations did not occur in any of the 94 DLBCL cases. ID3 gene expression was also found to be a distinguishing feature of Burkitt lymphomas (P<10–6), compared to DLBCL. We found a total of 27 distinct mutations in the ID3 genes among the 22 BL cases. These included five frameshift, four nonsense, and 18 missense mutations. We validated 16 of these events with Sanger sequencing with over 90% concordance. All of these mutations were located in the highly conserved helix-loop-helix region located on Exon 1. We explored the biological significance of ID3 mutations by initially comparing the gene expression profiles of BL cases that had mutated and wild-type ID3. Gene set enrichment analysis showed that those samples with mutated ID3 had higher expression of genes that were involved in cell cycle regulation, specifically those involved in the G1-S transition (P=0.01). In order to experimentally investigate the functional consequences of ID3 mutation, we generated mutant constructs corresponding to six different ID3 mutations observed in BLs. These mutant constructs were cloned into lentiviral vectors and overexpressed in BL cells that were wild type for ID3. We then performed cell cycle analysis for these wild type cells expressing GFP controls or the mutant constructs. We found that BL cells expressing each of the six mutant constructs demonstrated significant cell cycle progression from G1 to S phase compared to wild-type (P=0.01). Separately, we tested the effects of expressing mutant ID3 in cell proliferation assays and found that cells expressing mutant ID3 were considerably more proliferative than those expressing wild type (P=0.03). Conversely, we over-expressed the wild type form of ID3 in BL cells that had mutated ID3. These experiments completely rescued the observed phenotypes of the mutant ID3 constructs, with reduced cell cycle progression through increased G1 phase and decreased S-phase (P=0.04). We also noted decreased cell proliferation in these cells (P=0.03). These experiments support a role for ID3 as a novel tumor suppressor gene in Burkitt lymphoma. ID3 is a basic helix loop helix (bHLH) protein that binds to other E-proteins, blocking their ability to bind DNA. ID3 has been shown to be involved in a variety of biological processes including development and T and B cell differentiation. ID3 knockout mice have been shown to develop T cell as well as B cell lymphomas. Our data implicates this gene for the first time as a tumor suppressor in human cancer.-
dc.languageengen_US
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlooden_US
dc.titleID3 is a novel tumor suppressor gene in Burkitt lymphomaen_US
dc.typeConference_Paperen_US
dc.identifier.emailChoi, WWL: choiwl@hkucc.hku.hken_US
dc.identifier.emailAu, WY: auwing@hkucc.hku.hken_US
dc.identifier.emailSrivastava, G: gopesh@pathology.hku.hken_US
dc.identifier.authorityChoi, WWL=rp00247en_US
dc.identifier.authoritySrivastava, G=rp00365en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros213565en_US
dc.identifier.volume120-
dc.identifier.issue21-
dc.publisher.placeUnited States-
dc.customcontrol.immutablesml 130326-

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