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Intraclonal diversification of immunoglobulin light chains in a subset of chronic lymphocytic leukemia alludes to antigen-driven clonal evolution
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2010 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 24, no 7, 1317-1324 p.Article in journal (Refereed) Published
Abstract [en]

The study of intraclonal diversification (ID) in immunoglobulin (IG) genes offers valuable insight into the role of ongoing interactions with antigen in lymphomagenesis. We recently showed that ID in the IG heavy chain genes of patients with chronic lymphocytic leukemia (CLL) was generally limited; however, intense ID was evident in selected cases, especially those expressing stereotyped IGHV4-34 rearrangements and assigned to subset 4. Here, we report results from a large-scale subcloning study of IG light variable genes, in a total of 1008 subcloned sequences from 56 CLL cases. Multiple analogies were noted between heavy and light chains regarding the occurrence and molecular features of ID. More specifically, the impact of ID on the clonotypic light chains was generally low, with the significant exception of subset 4. Similar to the IGHV4-34 heavy chains of this subset, their partner IGKV2-30 light chains were affected by an active and precisely targeted ID process. Altogether, these findings strengthen the argument that stereotypy in subset 4 extends to stereotyped ID patterns for both heavy and light chains through persistent antigenic stimulation. Furthermore, they strongly suggest that light chains have an active role in the antigen selection process, at least for certain subsets of CLL cases.

Place, publisher, year, edition, pages
2010. Vol. 24, no 7, 1317-1324 p.
Keyword [en]
intraclonal diversification, antigen, superantigen, subcloning, stereotyped receptor, somatic hypermutation
National Category
Medical and Health Sciences Biological Sciences
URN: urn:nbn:se:uu:diva-135654DOI: 10.1038/leu.2010.90ISI: 000279892900011OAI: oai:DiVA.org:uu-135654DiVA: diva2:375654
Available from: 2010-12-08 Created: 2010-12-07 Last updated: 2013-01-23Bibliographically approved
In thesis
1. Molecular and Genetic Evidence for Antigen Selection in the Pathogenesis of Chronic Lymphocytic Leukemia
Open this publication in new window or tab >>Molecular and Genetic Evidence for Antigen Selection in the Pathogenesis of Chronic Lymphocytic Leukemia
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antigens play a critical role in the development of chronic lymphocytic leukemia (CLL) by binding to and stimulating leukemic precursor cells at some point during CLL ontogeny. Nevertheless, much remains unknown and further studies are necessary before an accurate model of antigen-drive can be ascertained. In this context, intraclonal diversification (ID) analysis of immunoglobulin (IG) genes could shed light on whether antigen involvement is restricted to the malignant transformation phase or if the triggering antigen(s) continuously stimulates the CLL clone. Hence, in Paper I we conducted a large-scale analysis of 71 CLL cases and revealed that 28/71 cases carried intraclonally diversified IGHV-IGHD-IGHJ genes. Although most cases showed no or low levels of ID, intense ID was evident within all subset #4 (IGHV4-34/IGKV2-30) cases. Subsequent analysis, in Paper II, of the clonotypic light chains revealed that the outstanding exception again related to subset #4. In such cases, the expressed IGKV2-30 gene was affected by targeted ID, analogous to their partner IGHV4-34 gene. Whilst these results convincingly argued for the role of antigen(s) in the development and evolution of CLL subset #4, this analysis was limited to depicting what was occurring at a single time-point and could not provide insight into the temporal dynamics of the CLL clones. Thus, in Paper III we conducted a longitudinal study of 8 subset #4 cases which enabled us to establish a hierarchical pattern of subclonal evolution. The observed ‘stepwise’ accumulation of mutations strongly supports a role for antigen selection in the pathogenesis of CLL subset #4. In Paper IV we reported a subset of IgG-switched CLL patients with coexisting trisomies of 12 and 19, and propose that the emergence of trisomy 18 in such cases represents a clonal evolution event suggestive of selection due to a clonal advantage. Paper V focused on the IGHV3-21 gene, an adverse prognostic factor in CLL. Since ~60% of IGHV3-21-expressing cases carry stereotyped B cell receptors, recognition of a common antigenic epitope, perhaps of pathogenic significance, is envisaged. Therefore, we investigated IGHV3-21 gene frequency within a Swedish population-based cohort and assessed the impact of stereotypy on clinical outcome. Taken collectively, this thesis provides molecular and genetic evidence for the role of antigen in CLL pathogenesis by convincingly demonstrating that clonal evolution, at least for certain subsets of CLL, is functionally driven rather than a consequence of clonal expansion promoted by nonspecific stimuli.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 65 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 815
IGHV4-34, microenvironment, stereotypy, immunoglobulin, intraclonal diversification, clonal evolution
National Category
Hematology Medical Genetics
urn:nbn:se:uu:diva-181602 (URN)978-91-554-8480-4 (ISBN)
Public defence
2012-11-09, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 13:15 (English)
Available from: 2012-10-18 Created: 2012-09-26 Last updated: 2013-01-23Bibliographically approved

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