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IGHV3-21 Gene Frequency in a Swedish Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. (Molecular Haematology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. (Molecular Haematology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. (Rosenquist Brandell)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
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2012 (English)In: Clinical Lymphoma, Myeloma & Leukemia, ISSN 2152-2650, E-ISSN 2152-2669, Vol. 12, no 3, 201-206 p.Article in journal (Refereed) Published
Abstract [en]

The IGHV3-21 gene has been shown to be overrepresented in Scandinavian patients with chronic lymphocytic leukemia (CLL). By investigating a population-based cohort of 337 Swedish patients with CLL, a lower (6.5%) IGHV3-21 frequency was determined relative to our previous hospital-based studies (10.1%-12.7%), yet this frequency remained higher compared to other Western CLL cohorts (2.6%-4.1%). Furthermore, we confirmed the poor outcome for patients with IGHV3-21 to be independent of mutational and stereotypy status. Background: Scandinavian patients with CLL have shown an overrepresentation of the poor-prognostic IGHV3-21 gene. Furthermore, approximately 50% of patients with IGHV3-21 carry stereotyped B-cell receptors, which implicate antigen selection in leukemogenesis. These patients have also been reported to have shorter time to progression than patients with nonstereotyped IGHV3-21. Materials and Methods: To investigate the IGHV3-21 frequency and the clinical impact of IGHV3-21 stereotypy, 337 newly diagnosed Swedish CLL patients from a population-based cohort were analyzed. Results: Interestingly, the IGHV3-21 frequency was indeed lower (6.5%) in this indolent patient cohort than in our previous hospital-based cohort studies (10.1%-12.7%). Hence, a selection bias of more-aggressive cases rendered a higher proportion of IGHV3-21 cases in our original studies. Nevertheless, the Swedish IGHV3-21 frequency still remained higher when compared with other larger European or American studies (2.6%-4.1%). Finally, we confirmed the poor outcome for IGHV3-21 patients to be independent of mutational status and found stereotypy to have no impact on survival or time to treatment. Conclusion: The Swedish geographic bias in IGHV3-21 gene frequency was validated albeit at a lower frequency than previously reported. Moreover, no prognostic value could be attributed to IGHV3-21 stereotype status.

Place, publisher, year, edition, pages
2012. Vol. 12, no 3, 201-206 p.
Keyword [en]
IGHV3-21, stereotypy, Chronic lymphocytic leukemia, Immunoglobulin heavy-chain variable 3 21 gene frequency, Prognosis, Stereotyped B-cell receptors
National Category
Hematology Medical Genetics
Research subject
Biology with specialization in Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-168942DOI: 10.1016/j.clml.2012.01.009ISI: 000304495800008OAI: oai:DiVA.org:uu-168942DiVA: diva2:506152
Available from: 2012-02-27 Created: 2012-02-20 Last updated: 2018-01-12Bibliographically approved
In thesis
1. Molecular Genetic and DNA Methylation Profiling of Chronic Lymphocytic Leukaemia: A Focus on Divergent Prognostic Subgroups and Subsets
Open this publication in new window or tab >>Molecular Genetic and DNA Methylation Profiling of Chronic Lymphocytic Leukaemia: A Focus on Divergent Prognostic Subgroups and Subsets
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Advancements in prognostication have improved the subdivision of chronic lymphocytic leukaemia (CLL) into diverse prognostic subgroups. In CLL, IGHV unmutated and IGHV3-21 genes are associated with a poor-prognosis, conversely, IGHV mutated genes with a favourable outcome. The finding of multiple CLL subsets expressing ‘stereotyped’ B-cell receptors (BCRs) has suggested a role for antigen(s) in leukemogenesis. Patients belonging to certain stereotyped subsets share clinical and biological characteristics, yet limited knowledge exists regarding the genetic and epigenetic events that may influence their clinical behaviour. This thesis aimed to, further investigate Swedish IGHV3-21-utilising patients, screen for genetic and DNA-methylation events in CLL subgroups/subsets and study DNA methylation over time and within different CLL compartments.

In paper I, IGHV gene sequencing of 337 CLL patients from a Swedish population-based cohort revealed a lower (6.5%) IGHV3-21 frequency relative to previous Swedish hospital-based studies (10.1-12.7%). Interestingly, this frequency remained higher compared to other Western CLL (2.6-4.1%) hospital-based cohorts. Furthermore, we confirmed the poor-outcome for IGHV3-21 patients to be independent of mutational and stereotypy status.

In paper II, genomic events in stereotyped IGHV3-21-subset #2, IGHV4-34-subset #4 and subset #16 and their non-stereotyped counterparts were investigated via SNP arrays (n=101). Subset #2 and non-subset #2 carried a higher frequency of events compared to subset #4. A high frequency of del(11q) was evident in IGHV3-21 patients particularly subset #2 cases, which may partially explain their poor-prognosis. In contrast, the lower prevalence of aberrations and absence of poor-prognostic alterations may reflect the inherent low-proliferative disease seen in subset #4 cases.

In papers III and IV, differential methylation profiles in IGHV mutated and IGHV unmutated patients were identified using DNA-methylation microarrays. CLL prognostic genes (CLLU1, LPL), tumor-suppressor genes (TSGs) (ABI3, WISP3) and genes belonging to TGF-ß and NF-kB/TNFR1 pathways were differentially methylated between the subgroups. Additionally, the re-expression of methylated TSGs by use of methyl and deacetyl inhibitors was demonstrated. Interestingly, analysis of patient-paired diagnostic/follow-up samples and patient-matched lymph node (LN) and peripheral blood (PB) cases revealed global DNA methylation to be relatively stable over time and remarkably similar within the different compartments.

Altogether, this thesis provides insight into the aberrant genomic and DNA methylation events in divergent CLL subgroups. Moreover this thesis helps distinguish the extent to which DNA methylation changes with respect to time and microenvironment in CLL.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 102 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 745
Keyword
DNA methylation, Chronic lymphocytic leukemia, SNP, array, IGHV3-21, IGHV4-34
National Category
Hematology Medical Genetics
Research subject
Biology with specialization in Molecular Biology; Genetics; Medical Genetics; Molecular Biology; Molecular Genetics; Oncology
Identifiers
urn:nbn:se:uu:diva-168945 (URN)978-91-554-8289-3 (ISBN)
Public defence
2012-04-13, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-03-22 Created: 2012-02-20 Last updated: 2018-01-12
2. 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 815
Keyword
IGHV4-34, microenvironment, stereotypy, immunoglobulin, intraclonal diversification, clonal evolution
National Category
Hematology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-181602 (URN)978-91-554-8480-4 (ISBN)
Public defence
2012-11-09, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2012-10-18 Created: 2012-09-26 Last updated: 2018-01-12Bibliographically approved

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Cahill, NicolaSutton, Lesley-AnnJansson, MattiasMurray, FionaMansouri, LarryGunnarsson, RebeqaRosenquist, Richard

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