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1.
  • Baliakas, Panagiotis, et al. (författare)
  • Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study
  • 2014
  • Ingår i: Lancet Haematology. - Elsevier. - 2352-3026. ; 1:2, s. 74-84
  • Tidskriftsartikel (refereegranskat)abstract
    • Background About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptor immunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggests that B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never been explored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn. Methods For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogenetic data were available. These patients were followed up in 15 academic institutions throughout Europe (in Czech Republic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collected between June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptor immunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressing unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain variable genes. The primary outcome of our analysis was time to first treatment, defined as the time between diagnosis and date of first treatment. Findings 2878 patients were assigned to a stereotyped subset, of which 1122 patients belonged to one of 14 major subsets. Stereotyped subsets showed significant differences in terms of age, sex, disease burden at diagnosis, CD38 expression, and cytogenetic aberrations of prognostic significance. Patients within a specific subset generally followed the same clinical course, whereas patients in different stereotyped subsets-despite having the same immunoglobulin heavy variable gene and displaying similar immunoglobulin mutational status-showed substantially different times to first treatment. By integrating B-cell receptor immunoglobulin stereotypy (for subsets 1, 2, and 4) into the well established Dohner cytogenetic prognostic model, we showed these, which collectively account for around 7% of all cases of CLL and represent both U-CLL and M-CLL, constituted separate clinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2). Interpretation The molecular classification of chronic lymphocytic leukaemia based on B-cell receptor immunoglobulin stereotypy improves the Dohner hierarchical model and refines prognostication beyond immunoglobulin mutational status, with potential implications for clinical decision making, especially within prospective clinical trials.
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3.
  • Baliakas, Panagiotis, et al. (författare)
  • Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations.
  • 2015
  • Ingår i: Blood. - American Society of Hematology. - 1528-0020. ; 125:5, s. 856-859
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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4.
  • Baliakas, Panagiotis, et al. (författare)
  • Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia
  • 2019
  • Ingår i: Haematologica. - Ferrata Storti Foundation. - 1592-8721. ; 104:2, s. 360-369
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL.
5.
  • Bhoi, Sujata, et al. (författare)
  • Prognostic impact of epigenetic classification in chronic lymphocytic leukemia : The case of subset #2
  • 2016
  • Ingår i: Epigenetics. - Landes Bioscience. - 1559-2294. ; 11:6, s. 449-455
  • Tidskriftsartikel (refereegranskat)abstract
    • ABSTRACT: Based on the methylation status of 5 single CpG sites, a novel epigenetic classification of chronic lymphocytic leukemia (CLL) was recently proposed, classifying CLL patients into 3 clinico-biological subgroups with different outcome, termed memory like CLL (m-CLL), naïve like CLL (n-CLL), and a third intermediate CLL subgroup (i-CLL). While m-CLL and n-CLL patients at large corresponded to patients carrying mutated and unmutated IGHV genes, respectively, limited information exists regarding the less defined i-CLL group. Using pyrosequencing, we investigated the prognostic impact of the proposed 5 CpG signature in a well-characterized CLL cohort (135 cases), including IGHV-mutated and unmutated patients as well as clinically aggressive stereotyped subset #2 patients. Overall, we confirmed the signature's association with established prognostic markers. Moreover, in the presence of the IGHV mutational status, the epigenetic signature remained independently associated with both time-to-first-treatment and overall survival in multivariate analyses. As a prime finding, we observed that subset #2 patients were predominantly classified as i-CLL, probably reflecting their borderline IGHV mutational status (97–99% germline identity), though having a similarly poor prognosis as n-CLL patients. In summary, we validated the epigenetic classifier as an independent factor in CLL prognostication and provide further evidence that subset #2 is a member of the i-CLL group, hence supporting the existence of a third, intermediate epigenetic subgroup.
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6.
7.
  • Cahill, Nicola, et al. (författare)
  • IGHV3-21 Gene Frequency in a Swedish Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia
  • 2012
  • Ingår i: Clinical Lymphoma, Myeloma & Leukemia. - CIG Media Group. - 2152-2650. ; 12:3, s. 201-206
  • Tidskriftsartikel (refereegranskat)abstract
    • 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. Clinical Lymphoma, Myeloma & Leukemia, Vol. 12, No. 3, 201-6 (C) 2012 Elsevier Inc. All rights reserved.
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8.
  • Deneberg, Stefan, et al. (författare)
  • microRNA-34b/c on chromosome 11q23 is aberrantly methylated in chronic lymphocytic leukemia
  • 2014
  • Ingår i: Epigenetics. - 1559-2294 .- 1559-2308. ; 9:6, s. 910-917
  • Tidskriftsartikel (refereegranskat)abstract
    • A commonly deleted region in chronic lymphocytic leukemia (CLL) is the 11q22-23 region, which encompasses the ATM gene. Evidence suggests that tumor suppressor genes other than ATM are likely to be involved in CLL with del(11q). A microRNA (miR) cluster including the miR-34b and miR-34c genes is located, among other genes, within the commonly deleted region (CDR) at 11q. Interestingly, these miRs are part of the TP53 network and have been shown to be epigenetically regulated. In this study, we investigated the expression and methylation status of these miRs in a well-characterized cohort of CLL, including cases with/without 11q-deletion. We show that the miR-34b/c promoter was aberrantly hypermethylated in a large proportion of CLL cases (48%, 25/52 cases). miR-34b/c expression correlated inversely to DNA methylation (P = 0.003), and presence of high H3K37me3 further suppressed expression regardless of methylation status. Furthermore, increased miR-34b/c methylation inversely correlated with the presence of 11q-deletion, indicating that methylation and del(11q) independently silence these miRs. Finally, 5-azacytidine and trichostatin A exposure synergistically increased the expression of miR-34b/c in CLL cells, and transfection of miR-34b or miR-34c into HG3 CLL cells significantly increased apoptosis. Altogether, our novel data suggest that miR-34b/c is a candidate tumor suppressor that is epigenetically silenced in CLL.
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9.
  • Gunnarsson, Rebeqa, et al. (författare)
  • Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia
  • 2011
  • Ingår i: Haematologica. - Ferrata Storti Foundation. - 1592-8721. ; 96:8, s. 1161-1169
  • Tidskriftsartikel (refereegranskat)abstract
    • Background High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution. Design and Methods We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years. Results At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV. Conclusions Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
10.
  • Halldorsdottir, Anna Margret, et al. (författare)
  • Mantle cell lymphoma displays a homogenous methylation profile: A comparative analysis with chronic lymphocytic leukemia
  • 2012
  • Ingår i: American Journal of Hematology. - John Wiley and Sons Inc.. - 0361-8609. ; 87:4, s. 361-367
  • Tidskriftsartikel (refereegranskat)abstract
    • Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL. Am. J. Hematol., 2012. (C) 2012 Wiley Periodicals, Inc.
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