uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Extensive intraclonal diversification in a subgroup of chronic lymphocytic leukemia patients with stereotyped IGHV4-34 receptors: implications for ongoing interactions with antigen
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Show others and affiliations
2009 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 114, no 20, 4460-4468 p.Article in journal (Refereed) Published
Abstract [en]

Several studies indicate that the development of chronic lymphocytic leukemia (CLL) may be influenced by antigen recognition through the clonotypic B-cell receptors (BCRs). However, it is still unclear whether antigen involvement is restricted to the malignant transformation phase or whether the putative antigen(s) may continuously trigger the CLL clone and affect not only the progenitor cell but also the leukemic cells themselves. To address this issue, we conducted a large-scale subcloning study of rearranged immunoglobulin heavy variable (IGHV) genes of diverse mutational status from 71 CLL cases (total, 1496 subcloned sequences), belonging to both the common IgM/IgD variant and the rare IgG-positive variant. Although most cases showed no or low levels of intraclonal diversification (ID), we report intense ID in the IGHV genes of selected cases, especially a subgroup of 13 IgG-switched cases expressing stereotyped, mutated IGHV4-34 rearrangements (subset 4). We demonstrate that the ID evident in subset 4 cases cannot be attributed to IGHV4-34 usage, IGHV gene-mutated status, class-switch recombination, or BCR stereotypy in general; rather, it represents a unique phenomenon strongly correlated with the distinctive BCR of subset 4. In such cases, the observed ID patterns may imply a stereotyped response to an active, ongoing interaction with antigen(s).

Place, publisher, year, edition, pages
2009. Vol. 114, no 20, 4460-4468 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-112100DOI: 10.1182/blood-2009-05-221309ISI: 000271727500018PubMedID: 19713457OAI: oai:DiVA.org:uu-112100DiVA: diva2:284910
Available from: 2010-01-08 Created: 2010-01-08 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

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Rosenquist, Richard
By organisation
Department of Genetics and Pathology
In the same journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 308 hits
ReferencesLink to record
Permanent link

Direct link