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Thessaloníki, Greece

Strefford J.C.,University of Southampton | Sutton L.-A.,Uppsala University | Baliakas P.,Uppsala University | Baliakas P.,HCT Unit | And 24 more authors.
Leukemia | Year: 2013

Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset #1, #2 and #8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset #2 (44%) versus subset #1 and #8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset #2 was only 8%, lower than the frequency observed in either subset #1 or #8 (19% and 14%, respectively; P=0.04 for subset #1 versus #2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy. © 2013 Macmillan Publishers Limited. Source

Agathangelidis A.,San Raffaele Scientific Institute | Vardi A.,HCT Unit | Baliakas P.,Uppsala University | Stamatopoulos K.,HCT Unit | And 2 more authors.
Leukemia and Lymphoma | Year: 2014

Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IGs) has proved to be a particularly fruitful field in chronic lymphocytic leukemia (CLL), not only for understanding disease pathogenesis but also for discriminating clinical subgroups with markedly distinct course and outcome. Of utmost importance was the identification of quasi-identical BcR IGs among unrelated patients with CLL, fittingly coined as "stereotypy," that set the wheels in motion for unraveling the role of antigen(s) in the selection and expansion of the leukemic clones. The categorization of CLL clones into "subsets" according to shared BcR IG structural characteristics provided a compartmentalized view of this otherwise heterogeneous disease, which eventually led to defining strikingly homogeneous groups of patients in terms of: (i) functional properties of the clonal BcR IGs, e.g. BcR reactivity and signaling; (ii) clonal genetic landscape, e.g. genomic aberrations, gene expression/methylation profiles, microRNA signatures; and (iii) clinical course and outcome. The remarkable restriction of the CLL IG gene repertoire, resulting to a great degree from the high impact of BcR IG stereotypy, may also prompt speculations regarding CLL ontogenesis. Overall, the BcR IG molecule justifiably lies at the heart of CLL clinical research, holding the promise of subset-tailored therapies. © 2014 Informa UK, Ltd. Source

Darzentas N.,Masaryk University | Darzentas N.,Center for Research and Technology Hellas | Stamatopoulos K.,Center for Research and Technology Hellas | Stamatopoulos K.,HCT Unit
Hematology/Oncology Clinics of North America | Year: 2013

Roughly 30% of patients with chronic lymphocytic leukemia (CLL) carry immunoglobulin receptors with highly similar primary sequences. Highly similar, quasi-identical immunoglobulins are termed stereotyped. Patients with CLL can be assigned to different subsets expressing different types of stereotyped immunoglobulin receptors. Reliable identification of stereotypy may assist in the molecular classification of CLL and thus better-guided, compartmentalized research. In several major subsets, stereotypy extends from shared primary sequences to shared clinicobiological features and outcome. Reliable identification of stereotypy in CLL may pave the way for tailored treatment strategies applicable to each major stereotyped subset. © 2013 Elsevier Inc.. Source

Navarro A.,University of Barcelona | Clot G.,University of Barcelona | Royo C.,University of Barcelona | Jares P.,University of Barcelona | And 32 more authors.
Cancer Research | Year: 2012

Mantle cell lymphoma (MCL) is a heterogeneous disease with most patients following an aggressive clinical course, whereas others having an indolent behavior. We conducted an integrative and multidisciplinary analysis of 177 MCL to determine whether the immunogenetic features of the clonotypic B-cell receptors (BcR) may identify different subsets of tumors. Truly unmutated (100% identity) IGHV genes were found in 24% cases, 40% were minimally/borderline mutated (99.9%-97%), 19% significantly mutated (96.9%-95%), and 17% hypermutated (<95%). Tumors with high or low mutational load used different IGHV genes, and their gene expression profiles were also different for several gene pathways. A gene set enrichment analysis showed that MCL with high and low IGHV mutations were enriched in memory and naive B-cell signatures, respectively. Furthermore, the highly mutated tumors had less genomic complexity, were preferentially SOX11-negative, and showed more frequent nonnodal disease. The best cut-off of germline identity of IGHV genes to predict survival was 97%. Patients with high and low mutational load had significant different outcome with 5-year overall survival (OS) of 59% and 40%, respectively (P = 0.004). Nodal presentation and SOX11 expression also predicted for poor OS. In a multivariate analysis, IGHV gene status and SOX11 expression were independent risk factors. In conclusion, these observations suggest the idea that MCL with mutated IGHV, SOX11-negativity, and nonnodal presentation correspond to a subtype of the disease with more indolent behavior. ©2012 AACR. Source

Langerak A.W.,Rotterdam University | Davi F.,University Pierre and Marie Curie | Ghia P.,Vita-Salute San Raffaele University | Hadzidimitriou A.,Center for Research and Technology Hellas | And 6 more authors.
Leukemia | Year: 2011

Immunoglobulin gene sequence analysis is widely utilized for prognostication in chronic lymphocytic leukemia (CLL) and the definition of standardized procedures has allowed reliable and reproducible results. Occasionally, a straightforward interpretation of the sequences is not possible because of the so-called problematic sequences that do not fit the classic interpretation and pose scientific questions at the cross-road between hematology and immunology. Thanks to a dedicated effort within the European Research Initiative on CLL (ERIC), we have now the possibility to present such cases, offer a scientific explanation and propose recommendations in terms of prognostication. © 2011 Macmillan Publishers Limited All rights reserved. Source

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