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Telomere length in mature B cell malignancies - correlation with cellular origin with respect to the germinal center
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-92921OAI: oai:DiVA.org:uu-92921DiVA: diva2:166240
Available from: 2005-04-22 Created: 2005-04-22 Last updated: 2010-01-13Bibliographically approved
In thesis
1. 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 29
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
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
Available from: 2005-04-22 Created: 2005-04-22 Last updated: 2013-07-24Bibliographically approved

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