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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

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
Authors
Issue Date2010
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://www.aacrmeetingabstracts.org/
Citation
The 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?
Abstract
Dysregulation 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
Persistent Identifierhttp://hdl.handle.net/10722/126716
ISSN

 

DC FieldValueLanguage
dc.contributor.authorChen, YWen_HK
dc.contributor.authorHu, XTen_HK
dc.contributor.authorLiang, ACTen_HK
dc.contributor.authorWong, MLYen_HK
dc.contributor.authorAu, WYen_HK
dc.contributor.authorWong, KYen_HK
dc.contributor.authorChoi, WWLen_HK
dc.contributor.authorWan, TSKen_HK
dc.contributor.authorChu, KMen_HK
dc.contributor.authorChim, CSen_HK
dc.contributor.authorChan, LCen_HK
dc.contributor.authorKwong, YLen_HK
dc.contributor.authorLiang, RHSen_HK
dc.contributor.authorSrivastava, Gen_HK
dc.date.accessioned2010-10-31T12:44:22Z-
dc.date.available2010-10-31T12:44:22Z-
dc.date.issued2010en_HK
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, 2010en_HK
dc.identifier.issn1948-3279-
dc.identifier.urihttp://hdl.handle.net/10722/126716-
dc.descriptionPoster Session 8 - Functional Identification of New Cancer Genes: abstract no. 258-
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.languageengen_HK
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://www.aacrmeetingabstracts.org/-
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 neoplasmen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailChen, YW: wywchen@pathology.hku.hken_HK
dc.identifier.emailWong, MLY: mmww2201@yahoo.comen_HK
dc.identifier.emailAu, WY: auwing@HKUCC.hku.hken_HK
dc.identifier.emailWong, KY: kywonga@HKUCC.hku.hken_HK
dc.identifier.emailChoi, WWL: wlchoi@pathology.hku.hken_HK
dc.identifier.emailWan, TSK: wantsk@HKUCC.hku.hken_HK
dc.identifier.emailChu, KM: chukm@hkucc.hku.hken_HK
dc.identifier.emailChim, CS: jcschim@hku.hken_HK
dc.identifier.emailChan, LC: chanlc@hkucc.hku.hken_HK
dc.identifier.emailKwong, YL: ylkwong@hku.hken_HK
dc.identifier.emailLiang, RHS: rliang@hku.hken_HK
dc.identifier.emailSrivastava, G: gopesh@pathology.hku.hken_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros173405en_HK
dc.publisher.placeUnited States-
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-

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