AIMS: This is a nation-wide survey of chronic lymphocytic leukemia (CLL) patients at six large hematology centers in the Czech Republic. The aim was to identify specific populations, social, and health characteristics of CLL subgroups divided according to the immunogenetic features of their B cell receptors (BCRs) and clonality. PATIENTS AND METHODS: Questionnaires directed to specific health, social, and environmental conditions were collected in a cohort of 573 CLL patients. For these patients, immunoglobulin heavy chain gene rearrangements were also analyzed in order to gain information about their clonality, IGHV mutational status, and the presence of stereotyped BCRs. Data extracted from the questionnaires were analyzed statistically in the context of immunogenetic features of the cohort. RESULTS: There were no statistically significant differences in the data collected in the survey between patients with mutated and patients with unmutated IGHV. However, patients with oligoclonal CLL reported health conditions such as hypercholesterolemia, hypertension, herpes simplex, tumors, and also, separately, CLL in 1st degree relatives, more often than their monoclonal counterparts. In patients with stereotyped BCRs, we found more frequent alcohol consumption and gastric infections in subset #1 cases and frequent cholecystectomies and familial CLL in subset #2 cases. CONCLUSION: To the best of our knowledge, this study is the first to investigate CLL immunogenetic features and clonality in the context of epidemiological data. We reported statistically significant associations suggesting the influence of certain health and social conditions on a number of clonal populations expanding in CLL and also on characteristic BCR features, especially stereotypy.
- MeSH
- biologické faktory * MeSH
- chronická lymfatická leukemie epidemiologie genetika imunologie MeSH
- dospělí MeSH
- genetická variace * MeSH
- genetika člověka MeSH
- genotyp MeSH
- imunogenetika * MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- receptory antigenů B-buněk genetika MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
- MeSH
- alely MeSH
- analýza jednotlivých buněk metody MeSH
- chronická lymfatická leukemie diagnóza farmakoterapie genetika MeSH
- genotyp MeSH
- klonální evoluce genetika MeSH
- lidé MeSH
- mutační analýza DNA metody MeSH
- nádorový supresorový protein p53 genetika MeSH
- receptor Notch1 genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.
- MeSH
- analýza přežití MeSH
- B-lymfocyty účinky léků imunologie patologie MeSH
- čas zasáhnout při rozvinutí nemoci MeSH
- chronická lymfatická leukemie diagnóza farmakoterapie genetika mortalita MeSH
- genetická heterogenita MeSH
- lidé středního věku MeSH
- lidé MeSH
- přestavba genů pro těžké řetězce B-lymfocytů imunologie MeSH
- prognóza MeSH
- protinádorové látky terapeutické užití MeSH
- regulace genové exprese u leukemie * MeSH
- senioři MeSH
- somatická hypermutace imunoglobulinových genů MeSH
- těžké řetězce imunoglobulinů genetika MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
To further our understanding about antigen involvement in mantle cell lymphoma (MCL), we analyzed the expression levels of activation-induced cytidine deaminase (AID), a key player in B-cell responses to antigen triggering, in 133 MCL cases; assessed the functionality of AID by evaluating in vivo class switch recombination in 52 MCL cases; and sought for indications of ongoing antigen interactions by exploring intraclonal diversification within 14 MCL cases. The AID full-length transcript and the most frequent splice variants (AID-ΔE4a, AID-ΔE) were detected in 128 (96.2%), 96 (72.2%), and 130 cases (97.7%), respectively. Higher AID full-length transcript levels were significantly associated (P < 0.001) with lack of somatic hypermutation within the clonotypic immunoglobulin heavy variable (IGHV) genes. Median AID transcript levels were higher in lymph node material compared to cases in which peripheral blood was analyzed, implying that clonal behavior is influenced by the microenvironment. Switched tumor-derived IGHV-IGHD-IGHJ transcripts were identified in 5 of 52 cases (9.6%), all of which displayed somatic hypermutation and AID-mRNA expression. Finally, although most cases exhibited low levels of intraclonal diversification, analysis of the mutational activity revealed a precise targeting of somatic hypermutation indicative of an active, ongoing interaction with antigen(s). Collectively, these findings strongly allude to antigen involvement in the natural history of MCL, further challenging the notion of antigen naivety.
- MeSH
- B-lymfocyty imunologie metabolismus patologie MeSH
- cytidindeaminasa metabolismus MeSH
- lidé MeSH
- lymfom z plášťových buněk imunologie metabolismus patologie MeSH
- somatická hypermutace imunoglobulinových genů * MeSH
- variabilní oblast imunoglobulinu * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
