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Conference Paper: Molecular features and functional consequence of CD44 activation by a novel recurrent IGH translocation t(11;14) (p13;q32) in mature B-cell lymphoid neoplasm
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TitleMolecular features and functional consequence of CD44 activation by a novel recurrent IGH translocation t(11;14) (p13;q32) in mature B-cell lymphoid neoplasm
 
AuthorsChen, YW
Hu, XT
Liang, ACT
Wong, MLY
Au, WY
Wong, KY
Choi, WWL
Wan, TSK
Chu, KM
Chim, CS
Chan, LC
Kwong, YL
Liang, RHS
Srivastava, G
 
Issue Date2010
 
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://www.aacrmeetingabstracts.org/
 
CitationThe 101st Annual Meeting of the American Association for Cancer Research (AACR 2010), Washington D.C., 17-21 April 2010. In AACR Meeting Abstracts, 2010 [How to Cite?]
 
AbstractDysregulation of an oncogene by translocation to Ig locus is a common event in the pathogenesis of most non-Hodgkin’s lymphoma. Using inverse-PCR, CD44 on 11p13 was identified as a novel translocation partner of IgH in 9 of 114 cases of gastric, non-gastric extranodal, follicular and nodal diffuse large B-cell lymphomas (DLBCLs) analyzed. IgHSμ/CD44 translocation juxtaposes the enhancer of IgHSμ to the 5’ regulatory region of CD44 in a tail-to-head orientation, leading to the removal of exon 1 of CD44. Sequencing analysis showed microhomology sequences at the junction breakpoints of all the IGHSμ/CD44 translocations, suggesting that these translocations were the results of illegitimate switch recombination facilitated by homologous sequences present on both chromosomes. By interphase-FISH using home-grown CD44 dual-color break-apart probes (consisting of BACs RP4-607I7 and RP4-683L5), breakage at the CD44 locus in each of the nine IGHSμ/CD44 translocation-positive cases was confirmed. By 5’ RACE analysis, fusion Iμ-CD44ΔEx1 hybrid transcripts (with a splicing of the Iμ exon upstream of Sμ to exon 2 of CD44), were identified in all the nine lymphomas with IGHSμ/CD44 translocations. Notably, these translocations were detected exclusively in GCB-type DLBCLs. However, CD44 mRNA was minimally or not expressed in CD10+ microdissected reactive GCB cells. The IGHSμ/CD44 translocation substitute Sμ for the CD44 promoter and remove exon 1 of CD44, resulting in over-expression of the Iμ-CD44 hybrid transcript which encodes for a new CD44 variant lacking leader peptide sequence but retaining a unique C-terminus (CD44ΔEx1). The Iμ-CD44ΔEx1 ORF would encode for the CD44ΔEx1 protein starting from the ATG at nucleotide 254 with strong Kozak sequence. The new CD44ΔEx1 variant showed some similarity to CD44v5, but it lacked the leader peptide. The IGHSμ/CD44 translocation was detected in patients with advanced-stage disease (stages III and IV). When overexpressed in vitro in the CD44-negative GCB-DLBCL cell line BJAB, the CD44ΔEx1-GFP was localized to the cytoplasm and nucleus, while CD44s-GFP (standard form) was localized to the plasma membrane. The ectopic expression of CD44ΔEx1 in BJAB cells enhanced the cell proliferation rate and its clonogenic ability. These findings indicate a possible pathogenic role of the recurrent translocation in several malignant B-cell lymphomas.
 
DescriptionPoster Session 8 - Functional Identification of New Cancer Genes: abstract no. 258
 
ISSN1948-3279
 
DC FieldValue
dc.contributor.authorChen, YW
 
dc.contributor.authorHu, XT
 
dc.contributor.authorLiang, ACT
 
dc.contributor.authorWong, MLY
 
dc.contributor.authorAu, WY
 
dc.contributor.authorWong, KY
 
dc.contributor.authorChoi, WWL
 
dc.contributor.authorWan, TSK
 
dc.contributor.authorChu, KM
 
dc.contributor.authorChim, CS
 
dc.contributor.authorChan, LC
 
dc.contributor.authorKwong, YL
 
dc.contributor.authorLiang, RHS
 
dc.contributor.authorSrivastava, G
 
dc.date.accessioned2010-10-31T12:44:22Z
 
dc.date.available2010-10-31T12:44:22Z
 
dc.date.issued2010
 
dc.description.abstractDysregulation of an oncogene by translocation to Ig locus is a common event in the pathogenesis of most non-Hodgkin’s lymphoma. Using inverse-PCR, CD44 on 11p13 was identified as a novel translocation partner of IgH in 9 of 114 cases of gastric, non-gastric extranodal, follicular and nodal diffuse large B-cell lymphomas (DLBCLs) analyzed. IgHSμ/CD44 translocation juxtaposes the enhancer of IgHSμ to the 5’ regulatory region of CD44 in a tail-to-head orientation, leading to the removal of exon 1 of CD44. Sequencing analysis showed microhomology sequences at the junction breakpoints of all the IGHSμ/CD44 translocations, suggesting that these translocations were the results of illegitimate switch recombination facilitated by homologous sequences present on both chromosomes. By interphase-FISH using home-grown CD44 dual-color break-apart probes (consisting of BACs RP4-607I7 and RP4-683L5), breakage at the CD44 locus in each of the nine IGHSμ/CD44 translocation-positive cases was confirmed. By 5’ RACE analysis, fusion Iμ-CD44ΔEx1 hybrid transcripts (with a splicing of the Iμ exon upstream of Sμ to exon 2 of CD44), were identified in all the nine lymphomas with IGHSμ/CD44 translocations. Notably, these translocations were detected exclusively in GCB-type DLBCLs. However, CD44 mRNA was minimally or not expressed in CD10+ microdissected reactive GCB cells. The IGHSμ/CD44 translocation substitute Sμ for the CD44 promoter and remove exon 1 of CD44, resulting in over-expression of the Iμ-CD44 hybrid transcript which encodes for a new CD44 variant lacking leader peptide sequence but retaining a unique C-terminus (CD44ΔEx1). The Iμ-CD44ΔEx1 ORF would encode for the CD44ΔEx1 protein starting from the ATG at nucleotide 254 with strong Kozak sequence. The new CD44ΔEx1 variant showed some similarity to CD44v5, but it lacked the leader peptide. The IGHSμ/CD44 translocation was detected in patients with advanced-stage disease (stages III and IV). When overexpressed in vitro in the CD44-negative GCB-DLBCL cell line BJAB, the CD44ΔEx1-GFP was localized to the cytoplasm and nucleus, while CD44s-GFP (standard form) was localized to the plasma membrane. The ectopic expression of CD44ΔEx1 in BJAB cells enhanced the cell proliferation rate and its clonogenic ability. These findings indicate a possible pathogenic role of the recurrent translocation in several malignant B-cell lymphomas.
 
dc.description.naturelink_to_OA_fulltext
 
dc.descriptionPoster Session 8 - Functional Identification of New Cancer Genes: abstract no. 258
 
dc.description.otherThe 101st Annual Meeting of the American Association for Cancer Research (AACR 2010), Washington D.C., 17-21 April 2010. In AACR Meeting Abstracts, 2010
 
dc.identifier.citationThe 101st Annual Meeting of the American Association for Cancer Research (AACR 2010), Washington D.C., 17-21 April 2010. In AACR Meeting Abstracts, 2010 [How to Cite?]
 
dc.identifier.hkuros173405
 
dc.identifier.issn1948-3279
 
dc.identifier.urihttp://hdl.handle.net/10722/126716
 
dc.languageeng
 
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://www.aacrmeetingabstracts.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofAACR Meeting Abstracts
 
dc.titleMolecular features and functional consequence of CD44 activation by a novel recurrent IGH translocation t(11;14) (p13;q32) in mature B-cell lymphoid neoplasm
 
dc.typeConference_Paper
 
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<contributor.author>Liang, ACT</contributor.author>
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<description.abstract>Dysregulation of an oncogene by translocation to Ig locus is a common event in the pathogenesis of most non-Hodgkin&#8217;s lymphoma. Using inverse-PCR, CD44 on 11p13 was identified as a novel translocation partner of IgH in 9 of 114 cases of gastric, non-gastric extranodal, follicular and nodal diffuse large B-cell lymphomas (DLBCLs) analyzed. IgHS&#956;/CD44 translocation juxtaposes the enhancer of IgHS&#956; to the 5&#8217; regulatory region of CD44 in a tail-to-head orientation, leading to the removal of exon 1 of CD44. Sequencing analysis showed microhomology sequences at the junction breakpoints of all the IGHS&#956;/CD44 translocations, suggesting that these translocations were the results of illegitimate switch recombination facilitated by homologous sequences present on both chromosomes. By interphase-FISH using home-grown CD44 dual-color break-apart probes (consisting of BACs RP4-607I7 and RP4-683L5), breakage at the CD44 locus in each of the nine IGHS&#956;/CD44 translocation-positive cases was confirmed. By 5&#8217; RACE analysis, fusion I&#956;-CD44&#916;Ex1 hybrid transcripts (with a splicing of the I&#956; exon upstream of S&#956; to exon 2 of CD44), were identified in all the nine lymphomas with IGHS&#956;/CD44 translocations. Notably, these translocations were detected exclusively in GCB-type DLBCLs. However, CD44 mRNA was minimally or not expressed in CD10+ microdissected reactive GCB cells. The IGHS&#956;/CD44 translocation substitute S&#956; for the CD44 promoter and remove exon 1 of CD44, resulting in over-expression of the I&#956;-CD44 hybrid transcript which encodes for a new CD44 variant lacking leader peptide sequence but retaining a unique C-terminus (CD44&#916;Ex1). The I&#956;-CD44&#916;Ex1 ORF would encode for the CD44&#916;Ex1 protein starting from the ATG at nucleotide 254 with strong Kozak sequence. The new CD44&#916;Ex1 variant showed some similarity to CD44v5, but it lacked the leader peptide. The IGHS&#956;/CD44 translocation was detected in patients with advanced-stage disease (stages III and IV). When overexpressed in vitro in the CD44-negative GCB-DLBCL cell line BJAB, the CD44&#916;Ex1-GFP was localized to the cytoplasm and nucleus, while CD44s-GFP (standard form) was localized to the plasma membrane. The ectopic expression of CD44&#916;Ex1 in BJAB cells enhanced the cell proliferation rate and its clonogenic ability. These findings indicate a possible pathogenic role of the recurrent translocation in several malignant B-cell lymphomas.</description.abstract>
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