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Immunoglobulin Gene Analysis in Different B cell Lymphomas: With Focus on Cellular Origin and Antigen Selection
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

B cell lymphoma (BCL) comprises a biologically and clinically heterogeneous group of tumors deriving from different stages of B cell development. The immunoglobulin (Ig) variable heavy chain (VH) gene rearrangement is unique for each BCL and can be used to reveal cellular origin, to study signs of antigen selection and to quantify tumor cell load.

The normal counterpart of mantle cell lymphoma (MCL) has been postulated to be a naïve B cell and in hairy cell leukemia (HCL) it is considered to be a post-germinal centre B cell. We analyzed the VH gene rearrangements in 110 MCLs and 32 HCLs by PCR amplification and sequencing. Most MCLs (84%) displayed VH genes lacking somatic hypermutation (SHM), thus correlating to a naïve cell origin, whereas a subgroup (16%) showed SHM, implying derivation from a more differentiated B cell. In HCL, a majority of cases (84%) displayed SHM with signs of intraclonal heterogeneity and 16% had unmutated VH genes, thus questioning the cell of origin in HCL. Biased usage of particular VH genes was detected in both HCL (VH3-30) and MCL (VH3-21 and VH4-34), which indicates that antigen selection may be involved in lymphoma development. Furthermore, VH3-21+ MCLs showed a highly restricted Vλ3-19 gene use and they also had a superior outcome compared to other MCLs.

Rearrangement analysis of 67 VH3-21+ chronic lymphocytic leukemia (CLL) cases from three different countries verified, regardless of geographical origin, the short and highly homologous complementarity determining region 3s and the strikingly biased usage of the Vλ2-14 gene (75%), as previously reported in CLL. This further supports that antigen selection by a common antigenic epitope may have occurred in VH3-21+ CLLs.

In an autologous transplantation study of 30 multiple myeloma patients, we quantified the tumor content in the autografts before and after stem cell selection using clone-specific PCR. We conclude that stem cell selection reduced the number of clonal cells linearly, but purging could not totally eliminate the tumor cells from the graft, thus increasing the risk of a relapse.

Altogether, our data allowed us to define new BCL subsets and to gain insights into the potential role of antigen selection in BCL development as well as the monitoring of tumor cell load using Ig gene rearrangements analysis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 65
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1375
Keywords [en]
Genetics, B cell lymphoma, Immunoglobulin, V gene, somatic hypermutation, antigen selection, quantitative PCR
Keywords [sv]
Genetik
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-4567ISBN: 91-554-6044-5 (print)OAI: oai:DiVA.org:uu-4567DiVA, id: diva2:165147
Public defence
2004-10-15, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-09-24 Created: 2004-09-24 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Somatic hypermutation and V(H) gene usage in mantle cell lymphoma
Open this publication in new window or tab >>Somatic hypermutation and V(H) gene usage in mantle cell lymphoma
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2002 In: European Journal of Haematology, Vol. 68, p. 217-24Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92164 (URN)
Available from: 2004-09-24 Created: 2004-09-24Bibliographically approved
2. Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma
Open this publication in new window or tab >>Mutated VH genes and preferential VH3-21 use define new subsets of mantle cell lymphoma
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2003 In: Blood, Vol. 101, p. 4057-54Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92165 (URN)
Available from: 2004-09-24 Created: 2004-09-24Bibliographically approved
3. Strikingly homologous VH3-21/Vλ2-14 gene rearrangements in chronic lymphocytic leukemia despite different geographical origin
Open this publication in new window or tab >>Strikingly homologous VH3-21/Vλ2-14 gene rearrangements in chronic lymphocytic leukemia despite different geographical origin
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-92166 (URN)
Available from: 2004-09-24 Created: 2004-09-24 Last updated: 2010-01-13Bibliographically approved
4. Heterogeneous somatic hypermutation status confounds the cell of origin in hairy cell leukemia
Open this publication in new window or tab >>Heterogeneous somatic hypermutation status confounds the cell of origin in hairy cell leukemia
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2005 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 29, no 2, p. 153-158Article in journal (Refereed) Published
Abstract [en]

Hairy cell leukemia (HCL) is thought to arise from a post-germinal center (GC) B-cell, however the exact normal counterpart remains unclear. We performed VH gene analysis of 32 HCL cases, revealing somatically mutated VH genes (<98% homology) in 27 cases and unmutated VH genes in five cases, four of which displayed germline VH genes. Intraclonal heterogeneity was evident in the majority of eight mutated HCLs investigated, although at a lower level compared to GC-derived lymphomas. A novel finding of preferential VH3-30 gene usage was detected (19% of HCLs). Our data confounds the postulated post-GC origin in HCL considering (1) the finding of unmutated HCLs, generally correlating with a pre-GC origin, and (2) the presence of intraclonal variation in mutated HCLs. The latter suggests that the transformed B-cell was frozen when it still had an active mutation process, implying a closer relation to the GC than previously assumed. Furthermore, restricted VH3-30 usage indicates that antigen selection could be a promoting factor in HCL development.

Keywords
Adult, Aged, Aged; 80 and over, Base Sequence, Female, Gene Rearrangement; B-Lymphocyte; Heavy Chain, Humans, Immunoglobulin Heavy Chains/analysis/*genetics, Leukemia; B-Cell/genetics/immunology/pathology, Leukemia; Hairy Cell/*genetics/immunology/pathology, Male, Middle Aged, Molecular Sequence Data, Research Support; Non-U.S. Gov't, Somatic Hypermutation; Immunoglobulin/*genetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92167 (URN)10.1016/j.leukres.2004.05.016 (DOI)15607363 (PubMedID)
Available from: 2004-09-24 Created: 2004-09-24 Last updated: 2017-12-14Bibliographically approved
5. Linear reduction of clonal cells in stem cell enriched grafts in transplanted multiple myeloma
Open this publication in new window or tab >>Linear reduction of clonal cells in stem cell enriched grafts in transplanted multiple myeloma
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1999 In: British Journal of Heamatology, Vol. 104, p. 546-52Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92168 (URN)
Available from: 2004-09-24 Created: 2004-09-24Bibliographically approved

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