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Heterogeneous somatic hypermutation status confounds the cell of origin in hairy cell leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
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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, 153-158 p.Article 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.

Place, publisher, year, edition, pages
2005. Vol. 29, no 2, 153-158 p.
Keyword [en]
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: urn:nbn:se:uu:diva-92167DOI: 10.1016/j.leukres.2004.05.016PubMedID: 15607363OAI: oai:DiVA.org:uu-92167DiVA: diva2:165145
Available from: 2004-09-24 Created: 2004-09-24 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Immunoglobulin Gene Analysis in Different B cell Lymphomas: With Focus on Cellular Origin and Antigen Selection
Open this publication in new window or tab >>Immunoglobulin Gene Analysis in Different B cell Lymphomas: With Focus on Cellular Origin and Antigen Selection
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. 65 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1375
Keyword
Genetics, B cell lymphoma, Immunoglobulin, V gene, somatic hypermutation, antigen selection, quantitative PCR, Genetik
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-4567 (URN)91-554-6044-5 (ISBN)
Public defence
2004-10-15, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-09-24 Created: 2004-09-24Bibliographically approved
2. Analysis of Immunoglobulin Genes and Telomeres in B cell Lymphomas and Leukemias
Open this publication in new window or tab >>Analysis of Immunoglobulin Genes and Telomeres in B cell Lymphomas and Leukemias
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

B cell lymphomas and leukemias are heterogeneous tumors with different cellular origins. Analysis of immunoglobulin (Ig) genes enables insight into the B cell progenitor, as Ig somatic hypermutation correlates with antigen-related B cell transit through the germinal center (GC). Also, restricted Ig variable heavy chain (VH) gene repertoires in B cell malignancies could imply antigen selection during tumorigenesis. The length of telomeres has been shown to differ between GC B cells and pre/post-GC B cells, possibly representing an alternative angle to investigate B cell tumor origin.

Mantle cell lymphoma (MCL), previously postulated to derive from a naïve, pre-GC B cell, was shown to have an Ig-mutated subset (18/110 MCLs, 16%), suggestive of divergent cellular origin and GC exposure. Another subset of MCL (16/110, 15%), characterized by VH3-21/Vλ3-19 gene usage, alludes to a role for antigen(s) in pathogenesis, also possible for hairy cell leukemia (HCL) in which the VH3-30 gene (6/32, 19%) was overused. HCL consisted mainly of Ig-mutated cases (27/32, 84%) with low level intraclonal heterogeneity, contrasting with the proposed post-GC origin, for both Ig-mutated and Ig-unmutated HCLs. For MCL and HCL, derivation from naïve or memory marginal zone B cells which may acquire mutations without GC transit are tempting speculations, but currently little is known about this alternative immunological pathway. Heavily mutated Ig genes without intraclonal heterogeneity were demonstrated in lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (13/14, 93%), confirming that the precursor cell was transformed after GC affinity maturation. Telomere length analysis within 304 B cell tumors revealed variable lengths; shortest in the Ig-unmutated subset of chronic lymphocytic leukemia, longest in the GC-like subtype of diffuse large B cell lymphoma, and homogeneous in MCL regardless of Ig mutation status. However, telomere length is complex with regard to GC-related origin.

In summary, this thesis has provided grounds for speculation that antigens play a role in MCL and HCL pathogenesis, although the potential antigens involved are currently unknown. It has also enabled a more informed postulation about the cellular origin of B cell tumors, which will ultimately enhance understanding of the biological background of the diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 29
Keyword
Genetics, B cell lymphoma/leukemia, mantle cell lymphoma, hairy cell leukemia, lymphoplasmacytic lymphoma, immunoglobulin genes, antigen selection, telomeres, cellular origin, somatic hypermutation, Genetik
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-5748 (URN)91-554-6217-0 (ISBN)
Public defence
2005-05-21, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, 13:15
Opponent
Supervisors
Available from: 2005-04-22 Created: 2005-04-22 Last updated: 2013-07-24Bibliographically approved

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Thunberg, UlfHagberg, HansSundström, ChristerRosenquist, Richard

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