Author: "Pospisilova, Sarka" / Database: OpenAIRE - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Pospisilova, Sarka"' showing total 35 results

Start Over Author "Pospisilova, Sarka" Database OpenAIRE

35 results on '"Pospisilova, Sarka"'

1. Comparative analysis of targeted next-generation sequencing panels for the detection of gene mutations in chronic lymphocytic leukemia: an ERIC multi-center study

Author: Sutton, Lesley-Ann, Ljungström, Viktor, Enjuanes, Anna, Cortese, Diego, Skaftason, Aron, Tausch, Eugen, Kozubik, Katerina Stano, Nadeu, Ferran, Armand, Marine, Malcikova, Jikta, Djureinovic, Tatjana, Forster, Jade, Davis, Zadie, Oscier, David, Rossi, Davide, Ghia, Paolo, Strefford, Jonathan C., Pospisilova, Sarka, Stilgenbauer, Stephan, Davi, Frederic, Campo, Elias, Stamatopoulos, Kostas, Rosenquist, Richard, Karolinska Institutet [Stockholm], Uppsala University, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), University of Ulm (UUlm), Central European Institute of Technology [Brno] (CEITEC MU), Brno University of Technology [Brno] (BUT), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), University of Southampton, Oncology Institute of Southern Switzerland (IOSI), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), IRCCS Ospedale San Raffaele [Milan, Italy], Karolinska University Hospital [Stockholm], Sutton, Lesley-Ann, Ljungström, Viktor, Enjuanes, Anna, Cortese, Diego, Skaftason, Aron, Tausch, Eugen, Stano Kozubik, Katerina, Nadeu, Ferran, Armand, Marine, Malcikova, Jikta, Pandzic, Tatjana, Forster, Jade, Davis, Zadie, Oscier, David, Rossi, Davide, Ghia, Paolo, Strefford, Jonathan C, Pospisilova, Sarka, Stilgenbauer, Stephan, Davi, Frederic, Campo, Elia, Stamatopoulos, Kosta, and Rosenquist, Richard
Subjects: Cytogenetics and Molecular Genetics, [SDV]Life Sciences [q-bio], Mutation, Next-generation sequencing, High-Throughput Nucleotide Sequencing, Humans, Chronic Lymphocytic Leukemia, Hematology, Hematologi, Genomics, Precision Medicine, Leukemia, Lymphocytic, Chronic, B-Cell, Article
Abstract: International audience; Next-generation sequencing (NGS) has transitioned from research to clinical routine, yet the comparability of different technologies for mutation profiling remains an open question. We performed a European multicenter (n=6) evaluation of three amplicon-based NGS assays targeting 11 genes recurrently mutated in chronic lymphocytic leukemia. Each assay was assessed by two centers using 48 pre-characterized chronic lymphocytic leukemia samples; libraries were sequenced on the Illumina MiSeq instrument and bioinformatics analyses were centralized. Across all centers the median percentage of target reads ≥100x ranged from 94.2- 99.8%. In order to rule out assay-specific technical variability, we first assessed variant calling at the individual assay level i.e., pairwise analysis of variants detected amongst partner centers. After filtering for variants present in the paired normal sample and removal of PCR/sequencing artefacts, the panels achieved 96.2% (Multiplicom), 97.7% (TruSeq) and 90% (HaloPlex) concordance at a variant allele frequency (VAF) >0.5%. Reproducibility was assessed by looking at the inter-laboratory variation in detecting mutations and 107 of 115 (93% concordance) mutations were detected by all six centers, while the remaining eight variants (7%) were undetected by a single center. Notably, 6 of 8 of these variants concerned minor subclonal mutations (VAF 5%, after rigorous validation, the use of unique molecular identifiers may be necessary to reach a higher sensitivity and ensure consistent and accurate detection of low-frequency variants.
Published: 2020

2. Additional file 1 of Evolution of TP53 abnormalities during CLL disease course is associated with telomere length changes

Author: Olbertova, Helena, Plevova, Karla, Pavlova, Sarka, Malcikova, Jitka, Kotaskova, Jana, Stranska, Kamila, Spunarova, Michaela, Trbusek, Martin, Navrkalova, Veronika, Dvorackova, Barbara, Tom, Nikola, Pal, Karol, Jarosova, Marie, Brychtova, Yvona, Panovska, Anna, Doubek, Michael, and Pospisilova, Sarka
Abstract: Additional file 1: Supplementary Table 1. Antibodies used for BCR signaling activity assessment. Supplementary Table 2. Results of relative telomere length (RTL) quantification in the basic CLL cohort (n = 198). Supplementary Table 3. TP53 mutation evolution cohort �� overview of clinico-biological features and results in baseline and follow-up samples, PART A Abbreviations: ALZ �� alemtuzumab; BR - bendamustine and rituximab; CLB �� chlorambucil; CR - cyclophosphamide and rituximab; del - deletion; F �� female; FCR - fludarabine, cyclophosphamide, and rituximab; FISH - fluorescence in situ hybridization; hyper CVAD - hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; IGHV �� immunoglobulin heavy chain variable region; M �� male; M �� mutated; mo �� months; U �� unmutated; yrs �� years. Supplementary Table 3. TP53 mutation evolution cohort �� overview of clinico-biological features and results in baseline and follow-up samples, PART B Abbreviations: LTD �� lymphocyte doubling time; mo �� months; mut �� mutated; p �� phosphorylated; RTL �� relative telomere length; VAF �� variant allele frequency; wt �� wildtype. Supplementary Figure 1. RTL of the entire CLL cohort was compared to the telomere length of a control DNA sample pooled from healthy individuals, arbitrarily set to RTL = 1 (green line). Median RTL of CLL cases (black line) was 0.81, range 0.46 �� 1.25. Supplementary Figure 2. A) Rai (n = 130) and B) Binet (n = 133) stages at diagnosis in untreated CLL samples and their associations with RTL. The significant associations were P 0 vs III-IV = 0.0018; P I-II vs III-IV = 0.0108; P A vs C = 0.0043. Supplementary Figure 3. Overall survival (OS) of A) the entire CLL cohort (n = 198) divided by RTL above (��RTL long��) and below (��RTL short��) median RTL value (median RTL = 0.84; OS long RTL = 119; OS short RTL = 91; OS P = 0.0004); and B) of CLL patients with mutated TP53 status (n = 40) divided by RTL above (��RTL long��) and below (��RTL short��) median RTL value in this subgroup (median RTL = 0.78; OS long RTL = 86; OS short RTL = 55; OS P = 0.046). Supplementary Figure 4. hTERT expression in A) the baseline samples (P shortening vs. stable = 0.66; P stable vs. prolonging = 0.08; P shortening vs. prolonging = 0.45) and in B) the follow-up samples (P shortening vs. stable = 0.77; P stable vs. prolonging = 0.52; P shortening vs. prolonging = 0.82), (RTL shortening n = 10; stable n = 10; prolonging n = 6). C) Comparison of hTERT values in serial samples. hTERT expression did not associate with RTL prolongation. Supplementary Figure 5. Lymphocyte doubling time did not correlate with a change of RTL time during the disease course (Pearson r = -0.175; P = 0.45). Supplementary Figure 6. p-ZAP70/SYK significantly correlated with p-ERK1/2 in A) baseline samples (Pearson R = 0.82; P = 0.002) and B) follow-up samples (Pearson R = 0.92; P < 0.001).
Published: 2022
Full Text: View/download PDF

3. Additional file 1 of KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

Author: Limberger, Tanja, Schlederer, Michaela, Trachtová, Karolina, Garces de los Fayos Alonso, Ines, Yang, Jiaye, Högler, Sandra, Sternberg, Christina, Bystry, Vojtech, Oppelt, Jan, Tichý, Boris, Schmeidl, Margit, Kodajova, Petra, Jäger, Anton, Neubauer, Heidi A., Oberhuber, Monika, Schmalzbauer, Belinda S., Pospisilova, Sarka, Dolznig, Helmut, Wadsak, Wolfgang, Culig, Zoran, Turner, Suzanne D., Egger, Gerda, Lagger, Sabine, and Kenner, Lukas
Abstract: Additional file 1: Supplementary Figure 1. related to Figure 1. Supplementary Figure 2. related to Figure 2. Supplementary Figure 3. related to Figure 3. Supplementary Figure 4. related to Figure 4. Supplementary Figure 5. related to Figure 6.
Published: 2022
Full Text: View/download PDF

4. Additional file 2 of KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

Author: Limberger, Tanja, Schlederer, Michaela, Trachtová, Karolina, Garces de los Fayos Alonso, Ines, Yang, Jiaye, Högler, Sandra, Sternberg, Christina, Bystry, Vojtech, Oppelt, Jan, Tichý, Boris, Schmeidl, Margit, Kodajova, Petra, Jäger, Anton, Neubauer, Heidi A., Oberhuber, Monika, Schmalzbauer, Belinda S., Pospisilova, Sarka, Dolznig, Helmut, Wadsak, Wolfgang, Culig, Zoran, Turner, Suzanne D., Egger, Gerda, Lagger, Sabine, and Kenner, Lukas
Abstract: Additional file 2. Supplementary Methods.
Published: 2022
Full Text: View/download PDF

5. Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5A promoter and undetectable expression of WNT5A gene

Author: Poppova, Lucie, Pavlova, Sarka, Gonzalez, Beatriz, Kotaskova, Jana, Plevova, Karla, Dumbovic, Gabrijela, Janovska, Pavlina, Bystry, Vojtech, Panovska, Anna, Bezdekova, Lucie, Maslejova, Stanislava, Brychtova, Yvona, Doubek, Michael, Krzyzankova, Marcela, Borsky, Marek, Mayer, Jiri, Bryja, Vitezslav, Alonso, Sergio, and Pospisilova, Sarka
Subjects: immune system diseases, hemic and lymphatic diseases, embryonic structures, sense organs, neoplasms
Abstract: Genome methylation profiles define na��ve-like (n-CLL), memory-like (m-CLL), and intermediate (i-CLL) subsets of chronic lymphocytic leukaemia (CLL). The profiles can be easily determined by the analysis of the five-CpG signature. m-CLL, i-CLL, and n-CLL with the good, intermediate, and poor prognoses, respectively, differ by the somatic hypermutation status of the immunoglobulin heavy chain variable gene (IGHV), a widely used prognostic predictor in CLL. We have previously shown that the expression of WNT5A, encoding a ROR1 ligand, distinguishes patients with the worse outcome within the prognostically favourable IGHV-mutated subgroup. To analyse the mechanisms controlling WNT5A expression, we investigated the methylation status of 54 CpG sites within the WNT5A promoter and its relation to the WNT5A gene expression. In a cohort of 59 CLL patients balanced for combinations of IGHV and WNT5A statuses, we identified three promoter CpG sites whose methylation level correlated with the WNT5A expression within the IGHV-mutated subgroup. Further, we complemented our data with the methylation status of the five-CpG signature. IGHV-mutated/WNT5A-negative and IGHV-mutated/WNT5A-positive cases overlapped with m��CLL and i��CLL methylation subgroups, respectively, while most IGHV��unmutated samples were assigned to n-CLL. Median methylation levels of all the three CpG sites in the WNT5A promoter were lowest in i-CLL. Finally, a detailed analysis of m-CLL and i-CLL showed that undetectable WNT5A expression predicts longer treatment-free survival with higher statistical significance than the classification according to the five-CpG signature. To conclude, a favourable m-CLL subgroup is associated with mutated IGHV and undetectable WNT5A expression due to its promoter methylation.
Published: 2022
Full Text: View/download PDF

6. MZ lymphoproliferations: shared and unique characteristics

Author: Xochelli, Aliki, Bikos, Vasilis, Polychronidou, Eleftheria, Galigalidou, Chrysi, Agathangelidis, Andreas, Charlotte, Frédéric, Moschonas, Panagiotis, Davis, Zadie, Colombo, Monica, Roumelioti, Maria, Sutton, Lesley-Ann, Groenen, Patricia, van den Brand, Michiel, Boudjoghra, Myriam, Algara, Patricia, Traverse-Glehen, Alexandra, Ferrer, Ana, Stalika, Evangelia, Karypidou, Maria, Kanellis, George, Kalpadakis, Christina, Mollejo, Manuella, Pangalis, Gerasimos, Vlamos, Panayiotis, Amini, Rose-Marie, Pospisilova, Sarka, Gonzalez, David, Ponzoni, Maurilio, Anagnostopoulos, Achilles, Giudicelli, Véronique, Lefranc, Marie-Paule, Espinet, Blanca, Panagiotidis, Panagiotis, Piris, Miguel Angel, Du, Ming-Qing, Rosenquist, Richard, Papadaki, Theodora, Belessi, Chrysoula, Ferrarini, Manlio, Oscier, David, Tzovaras, Dimitrios, Ghia, Paolo, Davi, Frederic, Hadzidimitriou, Anastasia, Stamatopoulos, Kostas, Apollo - University of Cambridge Repository, Institute of Applied Biosciences, CERTH, Thessaloniki, Greece., Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden, Central European Institute of Technology [Brno] (CEITEC MU), Brno University of Technology [Brno] (BUT), Information Technologies Institute, CERTH, Thessaloniki, Greece., Department of Informatics, Ionian University, Corfu, Greece, Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy., Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de pathologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Information Technologies Institute, CERTH, Thessaloniki, Greece, Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK., Molecular Pathology, Ospedale Policlinico SanMartino, Genoa, Italy., First Department of Propaedeutic Medicine, University of Athens, Athens, Greece, Uppsala Universitet [Uppsala], Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands., Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospital Virgen de la Salud, Toledo, Spain, Department of Pathology and Hematology, Hospices Civils de Lyon (HCL), Laboratori de Citologia Hematològica i Citogenètica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain, Centre for Research and Technology Hellas (CERTH), Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece, Hematopathology Department, Evangelismos Hospital, Athens, Greece., Department of Haematology, University of Crete, Heraklion, Greece., Department of Haematology, Athens Medical Center, Athens, Greece, Department of Informatics [Ionian University], Ionian University [Corfu], Department of Informatics, Ionian University, Corfu, Greece., Department of Genetics and Pathology, Uppsala University Hospital, CEITEC-Central European Institute of Technology, MasarykBrno, Czech Republic., Pathology Unit, Unit of Lymphoid Malignancies, San Raffaele H Scientific Institute, Pathology Unit, San Raffaele Scientific Institute, Milan, Italy, Laboratoire d'ImmunoGénétique Moléculaire (LIGM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoris de Citologia Hematológica/Citogenética Molecular. Servei de Patologia, GRETNHE, IMIM-Hospital del Mar, Laboratori de Citologia Hematològica i Citogenètica Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain., Pathology Department, IIS 'Fundacion Jimenez Diaz', Madrid, Spain, Pathology, University of Cambridge [UK] (CAM), Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK, Hematology Department, Nikea General Hospital, Piraeus, Greece, Direzione Scientifica, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera Universitaria (AOU) San Martino-IST, Genoa, Italy., Informatics & Telematics Institute (ITI), CERTH, Università Vita e Salute, San Raffaele, Milano, Italy, Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Applied Biosciences, Centre for Research and Technology-Hellas, Thessaloniki, Greece, Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden, Xochelli, Aliki, Bikos, Vasili, Polychronidou, Eleftheria, Galigalidou, Chrysi, Agathangelidis, Andrea, Charlotte, Frédéric, Moschonas, Panagioti, Davis, Zadie, Colombo, Monica, Roumelioti, Maria, Sutton, Lesley-Ann, Groenen, Patricia, van den Brand, Michiel, Boudjoghra, Myriam, Algara, Patricia, Traverse-Glehen, Alexandra, Ferrer, Ana, Stalika, Evangelia, Karypidou, Maria, Kanellis, George, Kalpadakis, Christina, Mollejo, Manuella, Pangalis, Gerasimo, Vlamos, Panayioti, Amini, Rose-Marie, Pospisilova, Sarka, Gonzalez, David, Ponzoni, Maurilio, Anagnostopoulos, Achille, Giudicelli, Véronique, Lefranc, Marie-Paule, Espinet, Blanca, Panagiotidis, Panagioti, Piris, Miguel Angel, Du, Ming-Qing, Rosenquist, Richard, Papadaki, Theodora, Belessi, Chrysoula, Ferrarini, Manlio, Oscier, David, Tzovaras, Dimitrio, Ghia, Paolo, Davi, Frederic, Hadzidimitriou, Anastasia, and Stamatopoulos, Kostas
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, Genes, Immunoglobulin, Genes, Immunoglobulin Heavy Chain, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], [SDV]Life Sciences [q-bio], Immunoglobulin Variable Region, Receptors, Antigen, B-Cell, Lymphoma, B-Cell, Marginal Zone, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Complementarity Determining Regions, marginal zone lymphoma, immunoglobulin gene, antigen, ontogeny, Marginal zone lymphoma, Mutation, Tumor Microenvironment, Humans, Gene Rearrangement, B-Lymphocyte
Abstract: Contains fulltext : 203155.pdf (Publisher’s version ) (Closed access) The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Published: 2019

7. Thyroid and androgen receptor signaling are antagonized by μ-Crystallin in prostate cancer

Author: Aksoy, Osman, Pencik, Jan, Hartenbach, Markus, Moazzami, Ali A, Schlederer, Michaela, Balber, Theresa, Varady, Adam, Philippe, Cecile, Baltzer, Pascal A, Mazumder, Bismoy, Whitchurch, Jonathan B, Roberts, Christopher J, Haitel, Andrea, Herac, Merima, Susani, Martin, Mitterhauser, Markus, Marculescu, Rodrig, Stangl-Kremser, Judith, Hassler, Melanie R, Kramer, Gero, Shariat, Shahrokh F, Turner, Suzanne D, Tichy, Boris, Oppelt, Jan, Pospisilova, Sarka, Hartenbach, Sabrina, Tangermann, Simone, Egger, Gerda, Neubauer, Heidi A, Moriggl, Richard, Culig, Zoran, Greiner, Georg, Hoermann, Gregor, Hacker, Marcus, Heery, David M, Merkel, Olaf, Kenner, Lukas, Aksoy, Osman [0000-0002-3068-455X], and Apollo - University of Cambridge Repository
Subjects: Male, μ-Crystallin, Down-Regulation, urologic and male genital diseases, Choline, Cohort Studies, PSMA-PET, androgen receptor, Cell Line, Tumor, Positron Emission Tomography Computed Tomography, mu-Crystallins, Humans, Metabolomics, Neoplasm Staging, Receptors, Thyroid Hormone, Sequence Analysis, RNA, Gene Expression Profiling, thyroid hormone receptor, Prostatic Neoplasms, prostate cancer, Prognosis, Crystallins, Gene Expression Regulation, Neoplastic, Receptors, Androgen, Tissue Array Analysis, PC-3 Cells, Triiodothyronine, Signal Transduction
Abstract: Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3'-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRα/TRβ) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen-mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.
Published: 2020
Full Text: View/download PDF

8. Functional analysis of germline ETV6 W380R mutation causing inherited thrombocytopenia and secondary acute lymphoblastic leukemia or essential thrombocythemia

Author: Kozubik, Katerina Stano, Radova, Lenka, Reblova, Kamila, Smida, Michal, Kubricanova, Marketa Zaliova, Baloun, Jiri, Pesova, Michaela, Vrzalova, Zuzana, Folber, Frantisek, Mejstrikova, Sona, Pospisilova, Sarka, and Doubek, Michael
Subjects: hemic and lymphatic diseases
Abstract: Germline mutations in ETV6 gene cause inherited thrombocytopenia with leukemia predisposition. Here, we report on functional validation of ETV6 W380R mutation segregating with thrombocytopenia in a family where two family members also suffered from acute lymphoblastic leukemia (ALL) or essential thrombocythemia (ET). In-silico analysis predicted impaired DNA binding due to W380R mutation. Functional analysis showed that this mutation prevents the ETV6 protein from localizing into the cell nucleus and impairs the transcriptional repression activity of ETV6. Based on the germline ETV6 mutation, ET probably started with somatic JAK2 V617F mutation, whereas ALL could be caused by diverse mechanisms: high-hyperdiploidity; somatic deletion of exon 1 IKZF1 gene; or somatic mutations of other genes found by exome sequencing of the ALL sample taken at the diagnosis.
Published: 2020
Full Text: View/download PDF

9. Transcription Factor YY1 Can Control AID-mediated Mutagenesis

Author: Zaprazna, Kristina, Basu, Arindam, Tom, Nikola, Jha, Vibha, Hodawadekar, Suchita, Radova, Lenka, Malcikova, Jitka, Tichy, Boris, Pospisilova, Sarka, and Atchison, Michael L.
Subjects: Male, Mice, Knockout, B-Lymphocytes, Ubiquitination, Mice, Transgenic, Lymphocyte Activation, Immunoglobulin Class Switching, Article, Mice, Inbred C57BL, Mice, Mutagenesis, Cytidine Deaminase, Mutation, Animals, DNA Breaks, Double-Stranded, Female, Somatic Hypermutation, Immunoglobulin, YY1 Transcription Factor, Protein Binding
Abstract: Activation-induced cytidine deminase (AID) is crucial for controlling the immunoglobulin (Ig) diversification processes of somatic hypermutation (SHM) and class switch recombination (CSR). AID initiates these processes by deamination of cytosine, ultimately resulting in mutations or double strand DNA breaks needed for SHM and CSR. Levels of AID control mutation rates, and off-target non-Ig gene mutations can contribute to lymphomagenesis. Therefore, factors that control AID levels in the nucleus can regulate SHM and CSR, and may contribute to disease. We previously showed that transcription factor YY1 can regulate the level of AID in the nucleus and Ig CSR. Therefore, we hypothesized that conditional knock-out of YY1 would lead to reduction in AID localization at the Ig locus, and reduced AID-mediated mutations. Using mice that overexpress AID (IgκAID yy1f/f) or that express normal AID levels (yy1f/f), we found that conditional knock-out of YY1 results in reduced AID nuclear levels, reduced localization of AID to the Sμ switch region, and reduced AID-mediated mutations. We find that the mechanism of YY1 control of AID nuclear accumulation is likely due to YY1-AID physical interaction which blocks AID ubiquitination.
Published: 2017

10. Reappraising Immunoglobulin Repertoire Restrictions in Chronic Lymphocytic Leukemia: Focus on Major Stereotyped Subsets and Closely Related Satellites

Author: Agathangelidis, Andreas Hadzidimitriou, Anastasia Minga, Eva and Sutton, Lesley-Ann Polychronidou, Eleftheria Shanafelt, Tait D. and Davis, Zadie Yan, Xiao-Jie Plevova, Karla Boudjoghra, Myriam Navarro, Alba Rossi, Davide Pedersen, Lone Bredo and Bikos, Vasilis Baliakas, Panagiotis Scarfo, Lydia Mattsson, Mattias Xochelli, Aliki di Celle, Paola Francia and Giannopoulos, Krzysztof Vanura, Katrina Evers, Ludo and Veronese, Silvio Facco, Monica Moschonas, Panagiotis Bystry, Vojtech Karan-Djurasevic, Teodora Roumelioti, Maria and Pavlovic, Sonja Mansouri, Larry Chu, Charles Stalika, Evangelia Giudicelli, Veronique Panagiotidis, Panagiotis and Sudarikov, Andrey Anagnostopoulos, Achilles Trentin, Livio and Catherwood, Mark Montillo, Marco Stavroyianni, Niki Gaidano, Gianluca Campo, Elias Niemann, Carsten Utoft Langerak, Anton W. Pospisilova, Sarka Lefranc, Marie-Paule Jaeger, Ulrich and Kater, Arnon Pott, Christiane Chiorazzi, Nicholas and Oscier, David Jelinek, Diane F. Stilgenbauer, Stephan and Hallek, Michael Tzovaras, Dimitrios Darzentas, Nikos and Belessi, Chrysoula Davi, Frederic Rosenquist, Richard Ghia, Paolo Stamatopoulos, Kostas
Published: 2016

11. Oxidative stress as a therapeutic perspective for ATM-deficient chronic lymphocytic leukemia patients

Author: Navrkalova, Veronika, Kafkova, Leona Raskova, Divoky, Vladimir, and Pospisilova, Sarka
Subjects: Oxidative Stress, Cell Transformation, Neoplastic, Editorials, Humans, Epistasis, Genetic, Ataxia Telangiectasia Mutated Proteins, Molecular Targeted Therapy, Leukemia, Lymphocytic, Chronic, B-Cell
Published: 2015

12. Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: A systematic reappraisal of classic cytogenetic data

Author: Baliakas, Panagiotis, Iskas, Michalis, Gardiner, Anne, Davis, Zadie, Plevova, Karla, Nguyen-Khac, Florence, Malcikova, Jitka, Anagnostopoulos, Achilles, Glide, Sharron, Mould, Sarah, Stepanovska, Kristina, Brejcha, Martin, Belessi, Chrysoula, Davi, Frederic, Pospisilova, Sarka, Athanasiadou, Anastasia, Stamatopoulos, Kostas, and Oscier, David
Subjects: Chromosome Aberrations, Male, Karyotype, Cell Culture Techniques, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell, Translocation, Genetic, Chromosome Breakpoints, Karyotyping, Tumor Cells, Cultured, Chromosomes, Human, Humans, Female, Chromosome Deletion, Interphase, In Situ Hybridization, Fluorescence, Proportional Hazards Models
Abstract: The significance of chromosomal translocations (CTRAs) and karyotype complexity (KC) in chronic lymphocytic leukemia (CLL) remains uncertain. To gain insight into these issues, we evaluated a series of 1001 CLL cases with reliable classic cytogenetic data obtained within 6 months from diagnosis before any treatment. Overall, 320 cases were found to carry ≥ 1 CTRAs. The most frequent chromosome breakpoints were 13q, followed by 14q, 18q, 17q, and 17p; notably, CTRAs involving chromosome 13q showed a wide spectrum of translocation partners. KC (≥ 3 aberrations) was detected in 157 cases and significantly (P0.005) associated with unmutated IGHV genes and aberrations of chromosome 17p. Furthermore, it was identified as an independent prognostic factor for shorter time-to-first-treatment. CTRAs were assigned to two categories (i) CTRAs present in the context of KC, often with involvement of chromosome 17p aberrations, occurring mostly in CLL with unmutated IGHV genes; in such cases, we found that KC rather than the presence of CTRAs per se negatively impacts on survival; (ii) CTRAs in cases without KC, having limited if any impact on survival. On this evidence, we propose that all CTRAs in CLL are not equivalent but rather develop by different processes and are associated with distinct clonal behavior.
Published: 2014
Full Text: View/download PDF

13. Bone Marrow Stromal Cells Protect Lymphoma B-cells from Rituximab-Induced Apoptosis and Targeting Integrin alfa-4-beta-1 (VLA-4) with Natalizumab can Overcome this Resistance

Author: Mraz, Marek, Zent, Clive S., Church, Amy K., Jelinek, Diane F., Wu, Xiaosheng, Pospisilova, Sarka, Ansell, Stephen M., Novak, Anne J., Kay, Neil E., Witzig, Thomas E., and Nowakowski, Grzegorz S.
Subjects: B-Lymphocytes, Lymphoma, B-Cell, Natalizumab, Antineoplastic Agents, Apoptosis, Bone Marrow Cells, Integrin alpha4beta1, Antibodies, Monoclonal, Humanized, Article, Coculture Techniques, Antibodies, Monoclonal, Murine-Derived, immune system diseases, Drug Resistance, Neoplasm, hemic and lymphatic diseases, Cell Adhesion, Tumor Cells, Cultured, Tumor Microenvironment, Humans, Stromal Cells, Rituximab
Abstract: Rituximab improves the outcome of patients with non-Hodgkin lymphoma, but does not completely eradicate residual B-cell populations in the microenvironment of the bone marrow and lymph nodes. Adhesion to stromal cells can protect B-cells from apoptosis induced by chemotherapy drugs [(cell adhesion-mediated drug resistance (CAM-DR)]. A similar mechanism of resistance to rituximab has not, to our knowledge, been described. We tested the hypothesis that the microenvironment protects malignant B-cells from rituximab-induced apoptosis, and that blocking these interactions with natalizumab, an antibody targeting VLA-4 (integrin alfa-4-beta-1/CD49d), can overcome this protection. VLA-4 is an adhesion molecule constitutively expressed on malignant B-cells and is important for pro-survival signalling in the bone marrow and lymph node microenvironment. The human bone marrow stromal cell line HS-5 was shown to strongly protect B-cell lymphoma cells from rituximab cytotoxicity, suggesting the existence of a stromal cell adhesion-mediated antibody resistance (CAM-AR) mechanism analogous to CAM-DR. Natalizumab decreased B-lymphocyte adherence to fibronectin by 75-95% and partially overcame stromal protection against rituximab and cytotoxic drugs. These pre-clinical findings suggest that the addition of stromal adhesion-disruptive drugs to rituximab-containing therapy could improve treatment efficacy.
Published: 2011

14. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

Author: Mansouri, Larry, Thorvaldsdottir, Birna, Sutton, Lesley-Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Catherwood, Mark, Kotaskova, Jana, Delgado, Julio, Rodríguez-Vicente, Ana E., Benito, Rocío, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Miras, Fatima, Martinez-Lopez, Joaquín, de la Serna, Javier, Rivas, Jesús María Hernández, Thornton, Patrick, Larráyoz, María José, Calasanz, M.J, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Bosch José, Francesc Xavier, Tazón-Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Terol, Maria Jose, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elias, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas, Rosenquist, Richard, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Mansouri L, Thorvaldsdottir B, Sutton LA] Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. [Karakatsoulis G] Centre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, Greece. Department of Mathematics, University of Ioannina, Ioannina, Greece. [Meggendorfer M] MLL Munich Leukemia Laboratory, Munich, Germany. [Parker H] Cancer Genomics, School for Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK. [Bosch F, Tazón-Vega B] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Karolinska Institutet [Stockholm], Institute of Applied Biosciences [Thessaloniki, Greece] (IAB), University of Ioannina, Munich Leukemia Laboratory [Munich, Germany] (M2L), University of Southampton, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Copenhagen University Hospital, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Oncology Institute of Southern Switzerland (IOSI), Institute Of Oncology Research [Bellinzona, Switzerland] (IOL), Queen's University [Belfast] (QUB), University Hospital Brno, Masaryk University [Brno] (MUNI), Clinic Barcelona Hospital Universitari, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Università degli Studi di Ferrara = University of Ferrara (UniFE), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Uppsala University, University Hospitals Dorset NHS Foundation Trust [Bournemouth, UK] (UHD), All India Institute of Medical Sciences [New Delhi], Hospital Universitario 12 de Octubre [Madrid], Spanish National Cancer Research Center (CNIO), Hôpital de Beaumont [Dublin, Ireland] (HB), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], Semmelweis University [Budapest], South-Pest Hospital Centre [Budapest, Hungary] (SPHC), IMIM-Hospital del Mar, Generalitat de Catalunya, Humboldt University Of Berlin, Universitat Autònoma de Barcelona (UAB), Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Hôpital Avicenne HUPSSD - Service d'Hématologie Biologique, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Zürich [Zürich] = University of Zurich (UZH), University hospital of Zurich [Zurich], Universitat de València (UV), Centre for Research and Technology Hellas (CERTH), Karolinska University Hospital [Stockholm], and Baran-Marszak, Fanny
Subjects: Cancer Research, Otros calificadores::Otros calificadores::/genética [Otros calificadores], [SDV]Life Sciences [q-bio], Leucèmia limfocítica crònica - Aspectes genètics, Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], Hematology, [SDV] Life Sciences [q-bio], Anomalies cromosòmiques, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Leukemia, B-Cell::Leukemia, Lymphocytic, Chronic, B-Cell [DISEASES], Oncology, Genetics research, Other subheadings::Other subheadings::/genetics [Other subheadings], Cancer genetics, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], neoplasias::neoplasias por tipo histológico::leucemia::leucemia linfoide::leucemia de células B::leucemia linfocítica crónica de células B [ENFERMEDADES]
Abstract: Cancer genetics; Genetics research Genètica del càncer; Recerca genètica Genética del cáncer; Investigación genética Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3–9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management. The European Research Initiative on CLL (ERIC) is a partner in the HARMONY Alliance, the EHA Scientific Working group on CLL and the ELN Workpackage 7 on CLL. This work was in part supported by; Associazione Italiana per la Ricerca sul Cancro—AIRC, Milano, Italy (Investigator Grant #20246 and Special Program on Metastatic Disease—5 per mille #21198); ERA NET TRANSCAN-2 Joint Transnational Call for Proposals: JTC 2014 (project #143 GCH-CLL) and JTC 2016 (project #179 NOVEL), project code (MIS) 5041673; Bando della Ricerca Finalizzata 2018, Ministero della Salute, Roma, Italy (progetto RF-2018–12368231); “la Caixa” Foundation (Health Research 2017 Program HR17-00221); the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE), the European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245), and the Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022, LADY_TATA_21_3223); the Hellenic Precision Medicine Network in Oncology; project ODYSSEAS (Intelligent and Automated Systems for enabling the Design, Simulation and Development of Integrated Processes and Products) implemented under the “Action for the Strategic Development on the Research and Technological Sector”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) and co-financed by Greece and the European Union, with grant agreement no: MIS 5002462”; MH CZ—DRO (FNBr, 65269705), NV19-03-00091 and the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union—Next-Generation EU; Instituto de Salud Carlos III (ISCIII), “PI21/00983”, co-funded by the European Union; the EU’s Horizon 2020 research and innovation program under grant agreement No. 739593, by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the K21_137948, FK20_134253, TKP2021-EGA-24 and TKP2021-NVA-15 funding schemes, and Elixir Hungary; Instituto de Salud Carlos III (ISCIII), “PI21/00983”, co-funded by the European Union; Fondo di Ateneo per la Ricerca (FAR) 2019, 2020 and 2021 of the University of Ferrara (GMR; AC), Associazione Italiana contro le Leucemie-Linfomi e Mieloma ONLUS Ferrara (AC; GMR), BEAT Leukemia Foundation Milan Italy (AC); the Danish Cancer Society and the CLL-CLUE project under the frame of ERA PerMed; Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087, and programme C2750/A23669); the Swedish Cancer Society (19 0425 Pj 01 H), the Swedish Research Council (2020-01750), the Knut and Alice Wallenberg Foundation (2016.0373), Region Stockholm (ALF/FoUI-962423), and Radiumhemmets Forskningsfonder (194133), Stockholm; and Lion’s Cancer Research Foundation, Uppsala.
Full Text: View/download PDF

15. Clustering Adult ACUTE Lymphoblastic Leukemia (ALL) Philadelphia Negative (Ph-) By Whole Exome Sequencing (WES) Analysis

Author: Ferrari, Anna, Di Rora, Andrea Chelli Luserna, Do Valle, Italo, Garonzi, Marianna, Robustelli, Valentina, Maria Hernandez-Rivas, Jesus, Santoro, Alessandra, Pospisilova, Sarka, Haferlach, Torsten, Padella, Antonella, Simonetti, Giorgia, CRISTINA PAPAYANNIDIS, Abbenante, Maria Chiara, Sazzini, Marco, Ferrarini, Alberto, Schira, Julien, Delledonne, Massimo, Castellani, Gastone, Remondini, Daniel, Martinelli, Giovanni, Ferrari, Anna, Di Rora, Andrea Chelli Luserna, FARIA DO VALLE, Italo, Garonzi, Marianna, Robustelli, Valentina, Maria Hernandez-Rivas, Jesu, Santoro, Alessandra, Pospisilova, Sarka, Haferlach, Torsten, Padella, Antonella, Simonetti, Giorgia, Papayannidis, Cristina, Abbenante, Mariachiara, Sazzini, Marco, Ferrarini, Alberto, Schira, Julien, Delledonne, Massimo, Castellani, Gastone, Remondini, Daniel, and Martinelli, Giovanni
Subjects: leucemia linfoblastica acuta, sequenziamento dell'esoma

16. Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations

Author: Xochelli, Aliki, Bikos, Vasilis, Polychronidou, Eleftheria, Galigalidou, Chrysi, Agathangelidis, Andreas, Charlotte, Frédéric, Moschonas, Panagiotis, Davis, Zadie, Colombo, Monica, Roumelioti, Maria, Sutton, Lesley-Ann, Groenen, Patricia, Van Den Brand, Michiel, Boudjoghra, Myriam, Algara, Patricia, Traverse-Glehen, Alexandra, Ferrer, Ana, Stalika, Evangelia, Karypidou, Maria, Kanellis, George, Kalpadakis, Christina, Mollejo, Manuella, Pangalis, Gerasimos, Vlamos, Panayiotis, Amini, Rose-Marie, Pospisilova, Sarka, Gonzalez, David, Ponzoni, Maurilio, Anagnostopoulos, Achilles, Giudicelli, Véronique, Lefranc, Marie-Paule, Espinet, Blanca, Panagiotidis, Panagiotis, Piris, Miguel Angel, Du, Ming-Qing, Rosenquist, Richard, Papadaki, Theodora, Belessi, Chrysoula, Ferrarini, Manlio, Oscier, David, Tzovaras, Dimitrios, Ghia, Paolo, Davi, Frederic, Hadzidimitriou, Anastasia, and Stamatopoulos, Kostas
Subjects: immunoglobulin gene, antigen, ontogeny, Marginal zone lymphoma, 3. Good health
Abstract: The B cell receptor immunoglobulin (BcR IG) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n=488) i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL) as well as provisional entities (n=76) according to the World Health Organization classification. The most striking IG gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different IG gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ IG sequence dataset with a large dataset of IG sequences (MZ-related or not; n=65,837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia but also rheumatoid factors and non-malignant spleen MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms, may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments.

17. Casein Kinase 1 delta/epsilon inhibition blocks CLL chemotaxis and delays leukemia onset in the E mu-TCL1 mouse model of chronic lymphocytic leukemia

Author: Janovska, Pavlina, Jan Verner, Kohoutek, Jiri, Bryjoval, Lenka, Dzimkova, Marta, Skabrahova, Hana, Radaszkiewicz, Tomasz, Nemcova, Tereza, Hoferova, Zuzana, Vasickova, Katerina, Smyckova, Lucie, Gregorova, Michaela, Egle, Alexander, Pavlova, Sarka, Poppova, Lucie, Pospisilova, Sarka, and Bryja, Viterslav

18. miR-34a, miR-29c and miR-17-5p expression in chronic lymphocytic leukemia patients is dependent on p53 functionality

Author: Mraz, Marek, Kotaskova, Jana, Malinova, Karla, Sarka Pavlova, Tichy, Boris, Malcikova, Jitka, Trbusek, Martin, Mayer, Jiri, and Pospisilova, Sarka

19. Cellular localization of epilepsy-related microRNAs in P12 and P60 rat hippocampi

Author: Peskova, Marie Kudlickova, Totkova, Tereza, Bencurova, Petra, Brazdil, Milan, Hana Kubova, and Pospisilova, Sarka

20. Minor-clone TP53 mutations in CLL patients entering first-line treatment: clonal evolution and clinical impact

Author: Malcikova, Jitka, Sarka Pavlova, Vonkova, Barbara, Kotaskova, Jana, Radova, Lenka, Plevova, Karla, Zenatova, Marcela, Hynst, Jakub, Dvorackova, Barbara, Panovska, Anna, Brychtova, Yvona, Tichy, Boris, Navrkalova, Veronika, Pal, Karol, Mayer, Jiri, Doubek, Michael, and Pospisilova, Sarka

21. Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target

Author: Larose, Hugo, Prokoph, Nina, Matthews, Jamie D, Schlederer, Michaela, Högler, Sandra, Alsulami, Ali F, Ducray, Stephen P, Nuglozeh, Edem, Fazaludeen, Feroze MS, Elmouna, Ahmed, Ceccon, Monica, Mologni, Luca, Gambacorti-Passerini, Carlo, Hoefler, Gerald, Lobello, Cosimo, Pospisilova, Sarka, Janikova, Andrea, Woessmann, Wilhelm, Damm-Welk, Christine, Zimmermann, Martin, Federova, Alina, Malone, Andrea, Smith, Owen, Wasik, Mariusz, Inghirami, Giorgio, Lamant, Laurence, Blundell, Tom L, Klapper, Wolfram, Merkel, Olaf, Burke, Amos GA, Mian, Shahid, Ashankyty, Ibraheem, Kenner, Lukas, and Turner, Suzanne D
Subjects: hemic and lymphatic diseases, Cell Line, Tumor, Mutation, Exome Sequencing, Humans, Lymphoma, Large-Cell, Anaplastic, Receptor Protein-Tyrosine Kinases, Neoplasm Recurrence, Local, Protein-Tyrosine Kinases, Receptor, Notch1, 3. Good health
Abstract: Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.

22. Higher-order connections between stereotyped subsets

Author: Andrea Patriarca, Marco Montillo, Niki Stavroyianni, Claudia Haferlach, Lesley-Ann Sutton, Livio Trentin, Franco Fais, Raphael Sandaltzopoulos, Arnon P. Kater, Anton W. Langerak, Marine Armand, Davide Rossi, Diane F. Jelinek, Davide Bagnara, Lydia Scarfò, Andreas Agathangelidis, Krzysztof Giannopoulos, Eugen Tausch, Andrey Sudarikov, Silvio Veronese, Salem H. Alshemmari, B V Biderman, Zadie Davis, Chrysoula Belessi, Lisa Bonello, Achilles Anagnostopoulos, Gerlinde Mitterbauer-Hohendanner, David Oscier, Sofia Kossida, Lone Bredo Pedersen, Paolo Ghia, Csaba Bödör, Christian Brieghel, Andrea Visentin, Véronique Giudicelli, Matthias Ritgen, Panagiotis Panagiotidis, Panagiotis Baliakas, Stephan Stilgenbauer, Ellen J van Gastel, Renee C. Tschumper, Christiane Pott, Frederic Davi, Katerina Gemenetzi, Valentina Guido, Elias Campo, Gianluca Gaidano, Irina Panovska, Sabine Jeromin, Karla Plevová, Kostas Stamatopoulos, Kamila Brázdilová, Maria Karypidou, Alba Navarro, Christof W. Schneider, Theodoros Moysiadis, Larry Mansouri, Darko Antic, Cristina Tresoldi, Constance Baer, Šárka Pospíšilová, Maria Roumelioti, Katrina Vanura, Xiao-Jie Yan, Hana Skuhrová Francová, Richard Rosenquist, Blanca Espinet, Paola Francia di Celle, Monica Facco, Paul Costeas, Michael Hallek, Carsten Utoft Niemann, Teodora Karan-Djurasevic, Manja Meggendorfer, Kirsten Fischer, Aleksandar Dimovski, Letizia Foroni, Marie-Paule Lefranc, Mark Catherwood, Anne de Septenville, Anastasia Chatzidimitriou, Sarah Lawless, Nicholas Chiorazzi, Agathangelidis, Andrea, Chatzidimitriou, Anastasia, Gemenetzi, Katerina, Giudicelli, Veronique, Karypidou, Maria, Plevova, Karla, Davis, Zadie A, Yan, Xiao-Jie, Jeromin, Sabine, Schneider, Christof, Pedersen, Lone Bredo, Tschumper, Renee, Sutton, Lesley A, Baliakas, Panagioti, Scarfò, Lydia, van Gastel, Ellen J, Armand, Marine, Tausch, Eugen, Biderman, Bella, Baer, Constance, Bagnara, Davide, Navarro, Alba, de Septenville, Anne, Guido, Valentina, Mitterbauer-Hohendanner, Gerlinde, Dimovski, Aleksandar, Brieghel, Christian, Lawless, Sarah, Meggendorfer, Manja, Stranska, Kamila, Ritgen, Matthia, Facco, Monica, Tresoldi, Cristina, Visentin, Andrea, Patriarca, Andrea, Catherwood, Mark, Bonello, Lisa, Sudarikov, Andrey, Vanura, Katrina, Roumelioti, Maria, Skuhrova Francova, Hana, Moysiadis, Theodoro, Veronese, Silvio M, Giannopoulos, Krzysztof, Mansouri, Larry, Karan-Djurasevic, Teodora, Sandaltzopoulos, Raphael, Bödör, Csaba, Fais, Franco, Kater, Arnon P, Panovska-Stavridis, Irina, Rossi, Davide, Alshemmari, Salem, Panagiotidis, Panagioti, Costeas, Paul A, Espinet, Blanca, Antic, Darko, Foroni, Letizia, Montillo, Marco, Trentin, Livio, Stavroyianni, Niki, Gaidano, Gianluca, Francia di Celle, Paola, Niemann, Carsten Utoft, Campo, Elía, Anagnostopoulos, Achille, Pott, Christiane, Fischer, Kirsten, Hallek, Michael, Oscier, David Graham, Stilgenbauer, Stephan, Haferlach, Claudia, Jelinek, Diane F, Chiorazzi, Nichola, Pospisilova, Sarka, Lefranc, Marie-Paule, Kossida, Sofia, Langerak, Anton W, Belessi, Chrysoula, Davi, Frederic, Rosenquist, Richard, Ghia, Paolo, Stamatopoulos, Kostas, Experimental Immunology, Clinical Haematology, AII - Cancer immunology, CCA - Cancer biology and immunology, and Immunology
Subjects: Chronic lymphocytic leukemia, Immunology, B-cell receptor, Immunoglobulin Variable Region, Disease, Computational biology, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, hemic and lymphatic diseases, Immunoglobulin, medicine, Humans, Chronic, 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Leukemia, Lymphoid Neoplasia, Repertoire, B-Cell, breakpoint cluster region, Cell Biology, Hematology, Gene rearrangement, Somatic Hypermutation, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic, Stereotypy (non-human), Immunoglobulin Heavy Chains, Somatic Hypermutation, Immunoglobulin, 030220 oncology & carcinogenesis, IGHV@
Abstract: Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL. Key Points: • In a series of 29 856 CLL patients, the incidence of BcR stereotypy peaked at 41%. • Higher-order relations exist between stereotyped subsets, particularly for those from U-CLL, for which satellite subsets were identified.
Published: 2021

23. STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma

Author: Geeta G. Sharma, Daniel Filip, Marek Mráz, Ivonne-Aidee Montes-Mojarro, Falko Fend, Šárka Pospíšilová, Andrea Janíková, David Belada, Boris Tichy, Nina Prokoph, Katerina Kamaradova, Vojtech Bystry, Luca Mologni, Hugo Larose, Carlo Gambacorti-Passerini, Suzanne D. Turner, Cosimo Lobello, Lenka Radová, Olaf Merkel, Huan-Chang Liang, Lobello, C, Tichy, B, Bystry, V, Radova, L, Filip, D, Mraz, M, Montes-Mojarro, I, Prokoph, N, Larose, H, Liang, H, Sharma, G, Mologni, L, Belada, D, Kamaradova, K, Fend, F, Gambacorti Passerini, C, Merkel, O, Turner, S, Janikova, A, Pospisilova, S, Lobello, Cosimo [0000-0003-1329-2113], Prokoph, Nina [0000-0002-6429-9895], Larose, Hugo [0000-0003-4678-6048], Liang, Huan-Chang [0000-0003-2612-3714], Fend, Falko [0000-0002-5496-293X], Gambacorti-Passerini, Carlo [0000-0001-6058-515X], Turner, Suzanne D. [0000-0002-8439-4507], Pospisilova, Sarka [0000-0001-7136-2680], Apollo - University of Cambridge Repository, and Turner, Suzanne D [0000-0002-8439-4507]
Subjects: Adult, Male, STAT3 Transcription Factor, Cancer Research, Letter, Anaplastic Lymphoma, Adolescent, 45/22, 45/23, 631/67/69, CHOP, medicine.disease_cause, Tp53 mutation, ALK P53, Young Adult, hemic and lymphatic diseases, Genetics research, Cancer genomics, medicine, Humans, Young adult, 631/208/69, STAT3, Child, Anaplastic large-cell lymphoma, Aged, Aged, 80 and over, Mutation, biology, business.industry, 692/308/2056, 45/77, Hematology, Middle Aged, medicine.disease, Prognosis, Lymphoma, Oncology, Child, Preschool, 13/51, biology.protein, Cancer research, Lymphoma, Large-Cell, Anaplastic, Female, Tumor Suppressor Protein p53, business
Abstract: Funder: European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712 Czech Science Foundation (GA CR), junior project no. 19-23424Y MEYS CZ project CEITEC 2020 (LQ1601), Funder: MEYS CZ project CEITEC 2020 (LQ1601) NCMG research infrastructure (LM22018132 funded by MEYS CR), Funder: European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712., Funder: MH CZ-RVO 65269705
Published: 2021
Full Text: View/download PDF

24. HIGHER ORDER IMMUNOGLOBULIN REPERTOIRE RESTRICTIONS IN CLL: THE ILLUSTRATIVE CASE OF STEREOTYPED SUBSETS #2 AND #169

Author: Panagiotis Baliakas, Maria Gounari, Massimo Degano, Paolo Ghia, Konstantinos Pasentsis, Šárka Pospíšilová, Claudia Minici, Raphael Sandaltzopoulos, Frederic Davi, Kostas Stamatopoulos, Maria Tsagiopoulou, Alejandra Carriles, Achilles Anagnostopoulos, Katerina Gemenetzi, Richard Rosenquist, Fotis Psomopoulos, Anastasia Chatzidimitriou, Karla Plevová, Lesley A Sutton, Gemenetzi, Katerina, Psomopoulos, Foti, Carriles, Alejandra, Gounari, Maria, Minici, Claudia, Plevova, Karla, Sutton, Lesley A, Tsagiopoulou, Maria, Baliakas, Panagioti, Pasentsis, Konstantino, Anagnostopoulos, Achille, Sandaltzopoulos, Raphael, Rosenquist, Richard, Davi, Frederic B, Pospisilova, Sarka, Ghia, Paolo, Stamatopoulos, Kosta, Degano, Massimo, and Chatzidimitriou, Anastasia
Subjects: Models, Molecular, Genes, Immunoglobulin Heavy Chain, Chronic lymphocytic leukemia, Immunology, Receptors, Antigen, B-Cell, Somatic hypermutation, Context (language use), Computational biology, Crystallography, X-Ray, Immunoglobulin light chain, Biochemistry, Protein Domains, medicine, Humans, Gene Rearrangement, biology, Gene Expression Regulation, Leukemic, Repertoire, Cell Biology, Hematology, Gene rearrangement, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, HEK293 Cells, biology.protein, Somatic Hypermutation, Immunoglobulin, Antibody, IGHV@
Abstract: Chronic lymphocytic leukemia (CLL) major stereotyped subset 2 (IGHV3-21/IGLV3-21, ∼2.5% of all cases of CLL) is an aggressive disease variant, irrespective of the somatic hypermutation (SHM) status of the clonotypic IGHV gene. Minor stereotyped subset 169 (IGHV3-48/IGLV3-21, ∼0.2% of all cases of CLL) is related to subset 2, as it displays a highly similar variable antigen-binding site. We further explored this relationship through next-generation sequencing and crystallographic analysis of the clonotypic B-cell receptor immunoglobulin. Branching evolution of the predominant clonotype through intraclonal diversification in the context of ongoing SHM was evident in both heavy and light chain genes of both subsets. Molecular similarities between the 2 subsets were highlighted by the finding of shared SHMs within both the heavy and light chain genes in all analyzed cases at either the clonal or subclonal level. Particularly noteworthy in this respect was a ubiquitous SHM at the linker region between the variable and the constant domain of the IGLV3-21 light chains, previously reported as critical for immunoglobulin homotypic interactions underlying cell-autonomous signaling capacity. Notably, crystallographic analysis revealed that the IGLV3-21–bearing CLL subset 169 immunoglobulin retains the same geometry and contact residues for the homotypic intermolecular interaction observed in subset 2, including the SHM at the linker region, and, from a molecular standpoint, belong to a common structural mode of autologous recognition. Collectively, our findings document that stereotyped subsets 2 and 169 are very closely related, displaying shared immunoglobulin features that can be explained only in the context of shared functional selection.
Published: 2020

25. TP53 aberrations in chronic lymphocytic leukemia: an overview of the clinical implications of improved diagnostics

Author: Šárka Pospíšilová, Anna Schuh, Ulrich Jäger, Richard Rosenquist, Paolo Ghia, Florence Cymbalista, Elias Campo, Stephan Stilgenbauer, Campo, Elia, Cymbalista, Florence, Ghia, Paolo, Jäger, Ulrich, Pospisilova, Sarka, Rosenquist, Richard, Schuh, Anna, Stilgenbauer, Stephan, and Universitat de Barcelona
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Diagnostic methods, Pronòstic mèdic, endocrine system diseases, Chronic lymphocytic leukemia, Review Article, Tp53 mutation, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Chemoimmunotherapy, Internal medicine, Medicine, Leucèmia limfocítica crònica, Chronic Lymphocytic Leukemia, Allele, neoplasms, Mutation, business.industry, Mutació (Biologia), Hematology, Mutation (Biology), medicine.disease, Prognosis, Cell Therapy and Immunotherapy, 3. Good health, Clinical trial, Leukemia, 030104 developmental biology, 030220 oncology & carcinogenesis, Lymphocyte, business
Abstract: Chronic lymphocytic leukemia is associated with a highly heterogeneous disease course in terms of clinical outcomes and responses to chemoimmunotherapy. This heterogeneity is partly due to genetic aberrations identified in chronic lymphocytic leukemia cells such as mutations of TP53 and/or deletions in chromosome 17p [del(17p)], resulting in loss of one TP53 allele. These aberrations are associated with markedly decreased survival and predict impaired response to chemoimmunotherapy thus being among the strongest predictive markers guiding treatment decisions in chronic lymphocytic leukemia. Clinical trials demonstrate the importance of accurately testing for TP53 aberrations [both del(17p) and TP53 mutations] before each line of treatment to allow for appropriate treatment decisions that can optimize patients’ outcomes. The current report reviews the diagnostic methods to detect TP53 disruption better, the role of TP53 aberrations in treatment decisions and current therapies available for patients with chronic lymphocytic leukemia carrying these abnormalities. The standardization in sequencing technologies for accurate identification of TP53 mutations and the importance of continued evaluation of TP53 aberrations throughout initial and subsequent lines of therapy remain unmet clinical needs as new therapeutic alternatives become available.
Published: 2018

26. Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes

Author: Véronique Giudicelli, Lesley-Ann Sutton, Panagiotis Baliakas, Anastasia Hadzidimitriou, David Oscier, Kostas Stamatopoulos, Michael Hallek, Eugen Tausch, Marco Montillo, Achilles Anagnostopoulos, Elias Campo, Yorick Sandberg, Silvio Veronese, Šárka Pospíšilová, Dirk Kienle, Karin E. Smedby, Xiao-Jie Yan, Lydia Scarfò, Andreas Agathangelidis, Nikos Darzentas, Richard Rosenquist, Stavroula Ntoufa, Larry Mansouri, Darko Antic, Niki Stavroyianni, Aliki Xochelli, Tait D. Shanafelt, Tatiana Tzenou, Andrey Sudarikov, Charles C. Chu, Anton W. Langerak, Marie-Paule Lefranc, Nicholas Chiorazzi, Eva Minga, Carsten Utoft Niemann, Ioanna Chouvarda, Nikos Maglaveras, Gianluca Gaidano, Maria Chatzouli, Karla Plevová, Mark Catherwood, Hartmut Döhner, Chrysoula Belessi, Myriam Boudjogra, Zadie Davis, Ioannis Kavakiotis, Gunnar Juliusson, Livio Trentin, Frederic Davi, Davide Rossi, Jasmin Bahlo, Diane F. Jelinek, Monica Facco, Christiane Pott, Lone Bredo Pedersen, Panagiotis Panagiotidis, Fie Juhl Vojdeman, Stephan Stilgenbauer, Teodora Karan-Djurasevic, Alba Navarro, Paolo Ghia, Ioannis Vlahavas, Immunology, Xochelli, Aliki, Baliakas, Panagioti, Kavakiotis, Ioanni, Agathangelidis, Andrea, Sutton, Lesley-Ann, Minga, Eva, Ntoufa, Stavroula, Tausch, Eugen, Yan, Xiao-Jie, Shanafelt, Tait, Plevova, Karla, Boudjogra, Myriam, Rossi, Davide, Davis, Zadie, Navarro, Alba, Sandberg, Yorick, Vojdeman, Fie Juhl, Scarfo, Lydia, Stavroyianni, Niki, Sudarikov, Andrey, Veronese, Silvio, Tzenou, Tatiana, Karan-Djurasevic, Teodora, Catherwood, Mark, Kienle, Dirk, Chatzouli, Maria, Facco, Monica, Bahlo, Jasmin, Pott, Christiane, Pedersen, Lone Bredo, Mansouri, Larry, Smedby, Karin E, Chu, Charles C, Giudicelli, Véronique, Lefranc, Marie-Paule, Panagiotidis, Panagioti, Juliusson, Gunnar, Anagnostopoulos, Achille, Vlahavas, Ioanni, Antic, Darko, Trentin, Livio, Montillo, Marco, Niemann, Carsten, Döhner, Hartmut, Langerak, Anton W, Pospisilova, Sarka, Hallek, Michael, Campo, Elia, Chiorazzi, Nichola, Maglaveras, Niko, Oscier, David, Gaidano, Gianluca, Jelinek, Diane F, Stilgenbauer, Stephan, Chouvarda, Ioanna, Darzentas, Niko, Belessi, Chrysoula, Davi, Frederic, Hadzidimitriou, Anastasia, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas
Subjects: Male, 0301 basic medicine, Cancer Research, Chronic lymphocytic leukemia, B-cell receptor, Immunoglobulin Variable Region, Somatic hypermutation, Immunogenetics, Disease, Biology, 03 medical and health sciences, hemic and lymphatic diseases, medicine, Humans, Amino Acid Sequence, breakpoint cluster region, Chronic Lymphocytic Leukemia B cell receptor BCR Immunoglobulin, medicine.disease, ADP-ribosyl Cyclase 1, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Gene Expression Regulation, Neoplastic, Leukemia, 030104 developmental biology, Oncology, Immunology, biology.protein, Female, Somatic Hypermutation, Immunoglobulin, Antibody, Immunoglobulin Heavy Chains
Abstract: Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34–expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management. Clin Cancer Res; 23(17); 5292–301. ©2017 AACR.
Published: 2017

27. Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia

Author: Frederic Davi, Davide Rossi, Sara Ek, Chrysoula Belessi, Matthias Ritgen, Andigoni Malousi, Nikos Papakonstantinou, Gianluca Gaidano, Larry Mansouri, Karla Plevová, Anastasia Hadzidimitriou, Šárka Pospíšilová, Maria Tsagiopoulou, Kostas Stamatopoulos, Martí Duran-Ferrer, Maria Gounari, Sujata Bhoi, Venera Kuci‐Emruli, Christiane Pott, Stamatia Laidou, Theodoros Moysiadis, Paolo Ghia, José I. Martín-Subero, Richard Rosenquist, Fotis Psomopoulos, Konstantinos Pasentsis, Zadie Davis, David Oscier, Stavroula Ntoufa, Niki Stavroyianni, Despoina Papazoglou, Papakonstantinou, Niko, Ntoufa, Stavroula, Tsagiopoulou, Maria, Moysiadis, Theodoro, Bhoi, Sujata, Malousi, Andigoni, Psomopoulos, Foti, Mansouri, Larry, Laidou, Stamatia, Papazoglou, Despoina, Gounari, Maria, Pasentsis, Konstantino, Plevova, Karla, Kuci-Emruli, Venera, Duran-Ferrer, Marti, Davis, Zadie, Ek, Sara, Rossi, Davide, Gaidano, Gianluca, Ritgen, Matthia, Oscier, David, Stavroyianni, Niki, Pospisilova, Sarka, Davi, Frederic, Ghia, Paolo, Hadzidimitriou, Anastasia, Belessi, Chrysoula, Martin-Subero, Jose I, Pott, Christiane, Rosenquist, Richard, and Stamatopoulos, Kostas
Subjects: Epigenomics, Male, Cancer Research, Chronic lymphocytic leukemia, B-cell receptor, Primary Cell Culture, Somatic hypermutation, Receptors, Antigen, B-Cell, Apoptosis, Biology, CLL, stereotypy, DNA methylation, gene expression, TP63, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, medicine, Tumor Cells, Cultured, Humans, RNA, Small Interfering, Promoter Regions, Genetic, Gene, Sequence Analysis, RNA, Gene Expression Profiling, Tumor Suppressor Proteins, breakpoint cluster region, DNA Methylation, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Up-Regulation, Gene Expression Regulation, Neoplastic, Real-time polymerase chain reaction, Oncology, 030220 oncology & carcinogenesis, Cancer research, Female, Transcription Factors
Abstract: Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D)-39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness. What's new? In chronic lymphocytic leukemia (CLL), cases with unmutated immunoglobulin receptors (U-CLL) are generally associated with inferior outcome, albeit still displaying considerable heterogeneity. Might such differences in CLL progression be explained by epigenetics? In this study, the authors found that an unusually aggressive subset of CLLs called subset #8 has a distinctive DNA-methylation profile. They also found that p63 is a novel pro-survival factor for CLL cells. These molecular studies may lead to new prognostic biomarkers, and possibly new therapeutic targets, for CLL.
Published: 2019

28. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia

Author: Zadie Davis, Richard Rosenquist, Chrysoula Belessi, Panagiotis Baliakas, Niki Stavroyianni, Theodoros Moysiadis, Elias Campo, Julio Delgado, Šárka Pospíšilová, Kostas Stamatopoulos, Marta Larrayoz, Davide Rossi, Jonathan C. Strefford, Larry Mansouri, Achilles Anagnostopoulos, Mattias Mattsson, Karin E. Smedby, Diego Cortese, Anastasia Hadzidimitriou, Lesley-Ann Sutton, Neus Villamor, David Oscier, Alba Navarro, Jana Kotašková, Evangelia Stalika, Gianluca Gaidano, Karla Plevová, Mark Catherwood, Gunnar Juliusson, Paolo Ghia, Sabine Jeromin, Oonagh Sheehy, Lydia Scarfò, Andreas Agathangelidis, Emma Young, Helen Parker, Eva Minga, Aliki Xochelli, Claudia Haferlach, Baliakas, Panagioti, Moysiadis, Theodoro, Hadzidimitriou, Anastasia, Xochelli, Aliki, Jeromin, Sabine, Agathangelidis, Andrea, Mattsson, Mattia, Sutton, Lesley-Ann, Minga, Eva, Scarfò, Lydia, Rossi, Davide, Davis, Zadie, Villamor, Neu, Parker, Helen, Kotaskova, Jana, Stalika, Evangelia, Plevova, Karla, Mansouri, Larry, Cortese, Diego, Navarro, Alba, Delgado, Julio, Larrayoz, Marta, Young, Emma, Anagnostopoulos, Achille, Smedby, Karin E., Juliusson, Gunnar, Sheehy, Oonagh, Catherwood, Mark, Strefford, Jonathan C., Stavroyianni, Niki, Belessi, Chrysoula, Pospisilova, Sarka, Oscier, David, Gaidano, Gianluca, Campo, Elia, Haferlach, Claudia, Ghia, Paolo, Rosenquist, Richard, Stamatopoulos, Kostas, and Universitat de Barcelona
Subjects: Male, Oncology, medicine.medical_specialty, Pronòstic mèdic, Chronic lymphocytic leukemia, Somatic hypermutation, Relative weight, Kaplan-Meier Estimate, Immunogenetics, Article, Time-to-Treatment, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, Biomarkers, Tumor, medicine, Humans, Chronic Lymphocytic Leukemia, Leucèmia limfocítica crònica, Hematologi, Aged, Neoplasm Staging, 030304 developmental biology, Aged, 80 and over, Chromosome Aberrations, 0303 health sciences, Hematology, biology, business.industry, medicine.disease, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Leukemia, 030220 oncology & carcinogenesis, Mutation, biology.protein, Female, Disease Susceptibility, Antibody, business, Trisomy
Abstract: Chronic lymphocytic leukemia patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinicobiological differences. Considering this, we assessed prognosis separately within mutated and unmutated chronic lymphocytic leukemia in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet-A mutated chronic lymphocytic leukemia 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 5- and 10-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 unmutated chronic lymphocytic leukemia patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-trearment (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 chronic lymphocytic leukemia 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 chronic lymphocytic leukemia.
Published: 2019

29. No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy

Author: Tatiana Tzenou, Richard Rosenquist, Marie-Paule Lefranc, Karla Plevová, Charles C. Chu, Yorick Sandberg, Gunnar Juliusson, Véronique Giudicelli, Livio Trentin, Mark Catherwood, Frederic Davi, Šárka Pospíšilová, Xiao-Jie Yan, Silvio Veronese, Lesley-Ann Sutton, Carsten Utoft Niemann, Nikos Darzentas, Kostas Stamatopoulos, Achilles Anagnostopoulos, Diane F. Jelinek, David Oscier, Mattias Mattsson, Nicholas Chiorazzi, Karin E. Smedby, Panagiotis Panagiotidis, Chrysoula Belessi, Florence Nguyen-Khac, Marco Montillo, Eva Minga, Paolo Ghia, Anton W. Langerak, Lydia Scarfò, Andreas Agathangelidis, Tait D. Shanafelt, Panagiotis Baliakas, Niki Stavroyianni, Larry Mansouri, Anastasia Hadzidimitriou, Zadie Davis, Fie Juhl Vojdeman, Uppsala Universitet [Uppsala], Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden, Institute of Applied Biosciences, Centre for Research and Technology-Hellas, Thessaloniki, Greece, Department of Immunology, Genetics and Pathology [Uppsala, Sueden] (IGP), Uppsala University, Department of Hematology [Uppsala], Università Vita-Salute San Raffaele, Milan, Italy., Strategic Research Program in CLL, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy, Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden, Università Vita e Salute, San Raffaele, Milano, Italy, Strategic Research Program in CLL, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK., The Feinstein Institute for Medical Research, CEITEC-Central European Institute of Technology, MasarykBrno, Czech Republic., Central European Institute of Technology [Brno] (CEITEC MU), Brno University of Technology [Brno] (BUT), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Hematology, Rigshospitalet, Copenhagen, Denmark, First Department of Propaedeutic Medicine, University of Athens, Athens, Greece, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, and Hematology Center, Karolinska University Hospital, Stockholm, Sweden, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hematology and Transplantation, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University and Hospital Department of Hematology, Lund Stem Cell Center, Lund, Sweden, Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece, Universita degli Studi di Padova, Venetian Institute Molecular Medicine (VIMM), Department of Hemato-Oncology, Belfast City Hospital, Belfast, UK, University Hospital Brno, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Immunology, Mayo Clinic, Rochester, MV, USA, Mayo Clinic [Rochester], Hematology Department, Nikea General Hospital, Piraeus, Greece, Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden., Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece., Institute of Applied Biosciences, Thessaloniki, Greece., Department of Immunology, Baliakas, Panagioti, Mattsson, Mattia, Hadzidimitriou, Anastasia, Minga, Eva, Agathangelidis, Andrea, Sutton, Lesley-Ann, Scarfo, Lydia, Davis, Zadie, Yan, Xiao-Jie, Plevova, Karla, Sandberg, Yorick, Vojdeman, Fie J, Tzenou, Tatiana, Chu, Charles C, Veronese, Silvio, Mansouri, Larry, Smedby, Karin E, Giudicelli, Véronique, Nguyen-Khac, Florence, Panagiotidis, Panagioti, Juliusson, Gunnar, Anagnostopoulos, Achille, Lefranc, Marie-Paule, Trentin, Livio, Catherwood, Mark, Montillo, Marco, Niemann, Carsten U, Langerak, Anton W, Pospisilova, Sarka, Stavroyianni, Niki, Chiorazzi, Nichola, Oscier, David, Jelinek, Diane F, Shanafelt, Tait, Darzentas, Niko, Belessi, Chrysoula, Davi, Frederic, Ghia, Paolo, Rosenquist, Richard, Stamatopoulos, Kostas, and Immunology
Subjects: Adult, Male, chemorefractorine, Oncology, medicine.medical_specialty, Cyclophosphamide, Chronic lymphocytic leukemia, [SDV]Life Sciences [q-bio], Young Adult, 03 medical and health sciences, 0302 clinical medicine, Drug Therapy, Chemoimmunotherapy, Internal medicine, medicine, Humans, Chronic Lymphocytic Leukemia, [INFO]Computer Science [cs], stereotyped subsets, Online Only Articles, Survival rate, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Aged, 80 and over, [SDV.GEN]Life Sciences [q-bio]/Genetics, Hematology, business.industry, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Fludarabine, Survival Rate, Leukemia, 030220 oncology & carcinogenesis, Female, Rituximab, Immunotherapy, business, 030215 immunology, medicine.drug
Abstract: The overall survival (OS) of patients with chronic lymphocytic leukemia (CLL) has improved over the last decades mainly due to advances in the understanding of the disease biology and the introduction of novel therapeutic approaches(1). In the present retrospective study we investigated trends in OS in subgroups of cases defined by genetic and immunogenetic features aiming at addressing the question whether advances in chemoimmunotherapy had a uniform impact across all CLL patients. We found that such advances have translated into prolonged OS in all prognostic subgroups examined except those carrying TP53 abnormalities, as expected, but also those assigned to stereotyped subsets #1 and #2, that are generally devoid of such gene aberrations. This latter finding, reported here for the first time, indicates the need for alternative treatment options for these patients.
Published: 2018

30. Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry:An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project

Author: Rawstron, AC, Kreuzer, K-A, Soosapilla, A, Spacek, M, Stehlikova, O, Gambell, P, McIver-Brown, N, Villamor, N, Psarra, K, Arroz, M, Milani, R, de la Serna, J, Cedena, MT, Jaksic, O, Nomdedeu, J, Moreno, C, Rigolin, GM, Cuneo, A, Johansen, P, Johnsen, HE, Rosenquist, R, Niemann, CU, Kern, W, Westerman, D, Trneny, M, Mulligan, S, Doubek, M, Pospisilova, S, Hillmen, P, Oscier, D, Hallek, M, Ghia, P, Montserrat, E, Rawstron, Andy C., Kreuzer, Karl-Anton, Soosapilla, Asha, Spacek, Martin, Stehlikova, Olga, Gambell, Peter, McIver-Brown, Neil, Villamor, Neu, Psarra, Katherina, Arroz, Maria, Milani, Raffaella, de la Serna, Javier, Cedena, M. Teresa, Jaksic, Ozren, Nomdedeu, Josep, Moreno, Carol, Rigolin, Gian Matteo, Cuneo, Antonio, Johansen, Preben, Johnsen, Hans E., Rosenquist, Richard, Niemann, Carsten Utoft, Kern, Wolfgang, Westerman, David, Trneny, Marek, Mulligan, Stephen, Doubek, Michael, Pospisilova, Sarka, Hillmen, Peter, Oscier, David, Hallek, Michael, Ghia, Paolo, and Montserrat, Emili
Subjects: chronic lymphocytic leukemia, diagnosis, flow cytometry, 2734, Histology, Cell Biology, Clinical Laboratory Medicine, Reproducibility of Results, Pilot Projects, Original Articles, Leukemia, Lymphocytic, Chronic, B-Cell, NO, Immunophenotyping, diagnosi, Klinisk laboratoriemedicin, immune system diseases, hemic and lymphatic diseases, Biomarkers, Tumor, Humans, Original Article, Retrospective Studies
Abstract: The diagnostic criteria for CLL rely on morphology and immunophenotype. Current approaches have limitations affecting reproducibility and there is no consensus on the role of new markers. The aim of this project was to identify reproducible criteria and consensus on markers recommended for the diagnosis of CLL. ERIC/ESCCA members classified 14 of 35 potential markers as ârequiredâ or ârecommendedâ for CLL diagnosis, consensus being defined as >75% and >50% agreement, respectively. An approach to validate ârequiredâ markers using normal peripheral blood was developed. Responses were received from 150 participants with a diagnostic workload >20 CLL cases per week in 23/150 (15%), 5â20 in 82/150 (55%), and 97% concordance with current approaches. A pilot study to validate staining quality was completed in 11 centers. Markers considered as ârequiredâ for the diagnosis of CLL by the participants in this study (CD19, CD5, CD20, CD23, Kappa, and Lambda) are consistent with current diagnostic criteria and practice. Importantly, a reproducible approach to validate and apply these markers in individual laboratories has been identified. Finally, a consensus ârecommendedâ panel of markers to refine diagnosis in borderline cases (CD43, CD79b, CD81, CD200, CD10, and ROR1) has been defined and will be prospectively evaluated. Â© 2017 International Clinical Cytometry Society.
Published: 2018

31. GLASS: assisted and standardized assessment of gene variations from Sanger sequence trace data

Author: Nikos Darzentas, Martin Demko, Adam Krejčí, Tasoula Touloumenidou, Šárka Pospíšilová, Jitka Malčíková, Boris Tichy, Karol Pál, Vojtech Bystry, Kostas Stamatopoulos, Tomáš Reigl, Paolo Ghia, Evangelia Stalika, Pal, Karol, Bystry, Vojtech, Reigl, Toma, Demko, Martin, Krejci, Adam, Touloumenidou, Tasoula, Stalika, Evangelia, Tichy, Bori, Ghia, Paolo, Stamatopoulos, Kosta, Pospisilova, Sarka, Malcikova, Jitka, and Darzentas, Nikos
Subjects: 0301 basic medicine, Statistics and Probability, Genotyping Techniques, Computer science, genetic processes, information science, Standardized test, Computational biology, 02 engineering and technology, Biology, computer.software_genre, Biochemistry, 03 medical and health sciences, symbols.namesake, Computational Theory and Mathematic, 0202 electrical engineering, electronic engineering, information engineering, Humans, natural sciences, Molecular Biology, Gene, 030304 developmental biology, TRACE (psycholinguistics), Genetics, Sanger sequencing, 0303 health sciences, Polymorphism, Genetic, Sequence Analysis, RNA, business.industry, Computer Science Applications1707 Computer Vision and Pattern Recognition, 020207 software engineering, Sequence Analysis, DNA, eye diseases, Computer Science Applications, Trace (semiology), Computational Mathematics, Alternative Splicing, 030104 developmental biology, Computational Theory and Mathematics, symbols, Human genome, Artificial intelligence, Tumor Suppressor Protein p53, Genotyping Technique, business, computer, Software, Natural language processing, Human
Abstract: MotivationSanger sequencing remains the reference method for sequence variant detection, especially in a clinical setting. However, chromatogram interpretation often requires manual inspection and in some cases considerable expertise. Additionally, variant reporting and nomenclature is typically left to the user, which can lead to inconsistencies.ResultsWe introduce GLASS, a tool built to assist with the assessment of gene variations in Sanger sequencing data. Critically, it provides a standardized variant output as recommended by the Human Genome Variation Society.AvailabilityThe program is freely available online at http://bat.infspire.org/genomepd/glass/.Contactnikos.darzentas@gmail.com, malcikova.jitka@fnbrno.czSupplementary informationSupplementary data are available at Bioinformatics online.
Published: 2016
Full Text: View/download PDF

32. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

Author: Marta Larrayoz, Panagiotis Panagiotidis, Theodoros Moysiadis, Evangelia Stalika, Kostas Stamatopoulos, Alba Navarro, Šárka Pospíšilová, Xiao-Jie Yan, Chrysoula Belessi, Jitka Malčíková, Florence Nguyen-Khac, Frederic Davi, Richard Rosenquist, Lesley-Ann Sutton, Lone Bredo Pedersen, Nicholas Chiorazzi, Karla Plevová, Gianluca Gaidano, Panagiotis Baliakas, Lydia Scarfò, Emma Young, Andreas Agathangelidis, Paolo Ghia, Anton W. Langerak, Carsten Utoft Niemann, Davide Rossi, Jonathan C. Strefford, Elias Campo, Alice F. Muggen, Myriam Boudjoghra, Larry Mansouri, Jana Kminkova, Anastasia Hadzidimitriou, Zadie Davis, David Oscier, Sutton, Lesley Ann, Young, Emma, Baliakas, Panagioti, Hadzidimitriou, Anastasia, Moysiadis, Theodoro, Plevova, Karla, Rossi, Davide, Kminkova, Jana, Stalika, Evangelia, Pedersen, Lone Bredo, Malcikova, Jitka, Agathangelidis, Andrea, Davis, Zadie, Mansouri, Larry, Scarfò, Lydia, Boudjoghra, Myriam, Navarro, Alba, Muggen, Alice F., Yan, Xiao Jie, Nguyen Khac, Florence, Larrayoz, Marta, Panagiotidis, Panagioti, Chiorazzi, Nichola, Niemann, Carsten Utoft, Belessi, Chrysoula, Campo, Elia, Strefford, Jonathan C., Langerak, Anton W., Oscier, David, Gaidano, Gianluca, Pospisilova, Sarka, Davi, Frederic, Ghia, PAOLO PROSPERO, Stamatopoulos, Kosta, Rosenquist, Richard, Immunology, Uppsala Universitet [Uppsala], Centre for Research and Technology Hellas (CERTH), Masaryk University [Brno] (MUNI), Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Università Vita e Salute, San Raffaele, Milano, Italy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), Royal Bournemouth Hospital, Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Erasmus University Medical Center [Rotterdam] (Erasmus MC), The Feinstein Institute for Medical Research, University of Southampton, National and Kapodistrian University of Athens (NKUA), Hematology Department, Nikea General Hospital, Piraeus, Greece, George Papanicolau Hospital, Universitat de Barcelona, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Chronic lymphocytic leukemia, Immunoglobulin Variable Region, Receptors, Antigen, B-Cell, Somatic hypermutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gene mutation, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Somatic evolution in cancer, 03 medical and health sciences, Genètica mèdica, 0302 clinical medicine, Gene Frequency, Biomarkers, Tumor, medicine, Humans, Leucèmia limfocítica crònica, Gene Rearrangement, B-Lymphocyte, Genetics, Mutation, Genes, Immunoglobulin, Mutació (Biologia), Medical genetics, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Articles, Gene rearrangement, Hematology, Mutation (Biology), Prognosis, medicine.disease, Complementarity Determining Regions, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Leukemia, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Immunoglobulin Joining Region, Immunoglobulin heavy chain, Female, Immunoglobulin Heavy Chains, 030215 immunology
Abstract: on behalf of ERIC, the European Research Initiative on CLL; International audience; We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobu-lins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobu-lin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P
Published: 2016

33. ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: Enrichment in subset #2 is associated with markedly short telomeres

Author: Panagiotis Baliakas, Larry Mansouri, Viktor Ljungström, Richard Rosenquist, Šárka Pospíšilová, Gunnar Juliusson, Frederic Davi, Martin Trbušek, Stavroula Ntoufa, Paolo Ghia, Karin E. Smedby, Chrysoula Belessi, Anton W. Langerak, Lesley-Ann Sutton, Jiri Mayer, Karla Plevová, Kostas Stamatopoulos, Panagiotis Panagiotidis, Tasoula Touloumenidou, Lenka Radová, Emma Young, Jonathan C. Strefford, Zadie Davis, David Oscier, Veronika Navrkalová, Navrkalova, Veronika, Young, Emma, Baliakas, Panagioti, Radova, Lenka, Sutton, Lesley Ann, Plevova, Karla, Mansouri, Larry, Ljungström, Viktor, Ntoufa, Stavroula, Davis, Zadie, Juliusson, Gunnar, Smedby, Karin E., Belessi, Chrysoula, Panagiotidis, Panagioti, Touloumenidou, Tasoula, Davi, Frederic, Langerak, Anton W., Ghia, PAOLO PROSPERO, Strefford, Jonathan C., Oscier, David, Mayer, Jiri, Stamatopoulos, Kosta, Pospisilova, Sarka, Rosenquist, Richard, Trbusek, Martin, and Immunology
Subjects: 0301 basic medicine, medicine.medical_specialty, Antigenic selection, Chronic lymphocytic leukemia, Ataxia Telangiectasia Mutated Proteins, Biology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Stereotyped subset, Online Only Articles, Telomere Shortening, Hematology, Atm mutation, Sequence Analysis, DNA, Telomere, medicine.disease, Short telomere, Leukemia, Lymphocytic, Chronic, B-Cell, Survival Analysis, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunology, Mutation
Abstract: ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset 2 is associated with markedly short telomeres, ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset 2 is associated with markedly short telomeres, ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset 2 is associated with markedly short telomeres.
Published: 2016

34. Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia

Author: Serena Barozzi, Giuseppe Loffredo, Carlo L. Balduini, Chiara Gnan, Alessandra Balduini, Caterina Marconi, Michael Doubek, Lenka Radová, Christian A. Di Buduo, Federica Melazzini, Caterina Alfano, Anna Savoia, Daniela De Rocco, Valeria Bozzi, Tommaso Pippucci, Flavia Palombo, Marco Seri, Michela Faleschini, Katerina Stano Kozubik, Patrizia Noris, Šárka Pospíšilová, Alessandro Pecci, Melazzini, Federica, Palombo, Flavia, Balduini, Alessandra, DE ROCCO, Daniela, Marconi, Caterina, Noris, Patrizia, Gnan, Chiara, Pippucci, Tommaso, Bozzi, Valeria, Faleschini, Michela, Barozzi, Serena, Doubek, Michael, Di Buduo, Christian A., Kozubik, Katerina Stano, Radova, Lenka, Loffredo, Giuseppe, Pospisilova, Sarka, Alfano, Caterina, Seri, Marco, Balduini, Carlo L., Pecci, Alessandro, Savoia, Anna, De Rocco, Daniela, Di Buduo, Christian A, Stano Kozubik, Katerina, and Balduini, Carlo L
Subjects: 0301 basic medicine, Fibrinogen, 0302 clinical medicine, hemic and lymphatic diseases, Medicine, Platelet, platelet disorders, inherited thrombocytopenia, Child, inherited thrombocytopenias, education.field_of_study, Hematology, Incidence (epidemiology), Nuclear Proteins, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Pedigree, 3. Good health, Cell Transformation, Neoplastic, Child, Preschool, Core Binding Factor Alpha 2 Subunit, Cohort, Intercellular Signaling Peptides and Proteins, medicine.drug, Adult, Platelets, medicine.medical_specialty, Adolescent, Platelet disorder, Population, Article, Young Adult, 03 medical and health sciences, Internal medicine, Humans, Family, Genetic Predisposition to Disease, education, Proto-Oncogene Proteins c-ets, business.industry, Infant, Newborn, Infant, Thrombocytopenia, Repressor Proteins, ETV6, 030104 developmental biology, Mutation, Immunology, business, 030215 immunology
Abstract: ETV6-related thrombocytopenia is an autosomal dominant thrombocytopenia that has been recently identified in a few families and has been suspected to predispose to hematologic malignancies. To gain further information on this disorder, we searched for ETV6 mutations in the 130 families with inherited thrombocytopenia of unknown origin from our cohort of 274 consecutive pedigrees with familial thrombocytopenia. We identified 20 patients with ETV6-related thrombocytopenia from seven pedigrees. They have five different ETV6 variants, including three novel mutations affecting the highly conserved E26 transformation-specific domain. The relative frequency of ETV6-related thrombocytopenia was 2.6% in the whole case series and 4.6% among the families with known forms of inherited thrombocytopenia. The degree of thrombocytopenia and bleeding tendency of the patients with ETV6-related thrombocytopenia were mild, but four subjects developed B-cell acute lymphoblastic leukemia during childhood, resulting in a significantly higher incidence of this condition compared to that in the general population. Clinical and laboratory findings did not identify any particular defects that could lead to the suspicion of this disorder from the routine diagnostic workup. However, at variance with most inherited thrombocytopenias, platelets were not enlarged. In vitro studies revealed that the maturation of the patients' megakaryocytes was defective and that the patients have impaired proplatelet formation. Moreover, platelets from patients with ETV6-related thrombocytopenia have reduced ability to spread on fibrinogen. Since the dominant thrombocytopenias due to mutations in RUNX1 and ANKRD26 are also characterized by normal platelet size and predispose to hematologic malignancies, we suggest that screening for ETV6, RUNX1 and ANKRD26 mutations should be performed in all subjects with autosomal dominant thrombocytopenia and normal platelet size.
Published: 2016

35. Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification

Author: Andreas Agathangelidis, Anton W. Langerak, Frederic Davi, Lesley-Ann Sutton, Richard Rosenquist, Zadie Davis, Paolo Ghia, Anastasia Hadzidimitriou, Šárka Pospíšilová, Panagiotis Baliakas, Francesco Forconi, Kostas Stamatopoulos, Stephan Stilgenbauer, Sutton, Lesley-Ann, Hadzidimitriou, Anastasia, Baliakas, Panagioti, Agathangelidis, Andrea, Langerak, Anton W., Stilgenbauer, Stephan, Pospisilova, Sarka, Davis, Zadie, Forconi, Francesco, Davi, Frederic, Ghia, Paolo, Rosenquist, Richard, Stamatopoulos, Kostas, and Immunology
Subjects: medicine.medical_specialty, Chronic lymphocytic leukemia, B-cell receptor, Disease, Biology, Risk Assessment, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, B cell, Hematology, Genes, Immunoglobulin, breakpoint cluster region, Prognosis, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Fludarabine, Treatment Outcome, Editorial, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Ibrutinib, Immunology, Somatic Hypermutation, Immunoglobulin, 030215 immunology, medicine.drug
Abstract: While triggering through the B-cell receptor (BcR) facilitates B-cell development and maintenance, it also carries intertwined risks for the emergence of lymphoid malignancies, since malignant B cells can exploit BcR signaling pathways in order to initiate and fuel clonal expansion. Indeed
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources

Refine your results

35 results on '"Pospisilova, Sarka"'

1. Comparative analysis of targeted next-generation sequencing panels for the detection of gene mutations in chronic lymphocytic leukemia: an ERIC multi-center study

2. Additional file 1 of Evolution of TP53 abnormalities during CLL disease course is associated with telomere length changes

3. Additional file 1 of KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

4. Additional file 2 of KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

5. Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5A promoter and undetectable expression of WNT5A gene

6. MZ lymphoproliferations: shared and unique characteristics

7. Thyroid and androgen receptor signaling are antagonized by μ-Crystallin in prostate cancer

8. Functional analysis of germline ETV6 W380R mutation causing inherited thrombocytopenia and secondary acute lymphoblastic leukemia or essential thrombocythemia

9. Transcription Factor YY1 Can Control AID-mediated Mutagenesis

10. Reappraising Immunoglobulin Repertoire Restrictions in Chronic Lymphocytic Leukemia: Focus on Major Stereotyped Subsets and Closely Related Satellites

11. Oxidative stress as a therapeutic perspective for ATM-deficient chronic lymphocytic leukemia patients

12. Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: A systematic reappraisal of classic cytogenetic data

13. Bone Marrow Stromal Cells Protect Lymphoma B-cells from Rituximab-Induced Apoptosis and Targeting Integrin alfa-4-beta-1 (VLA-4) with Natalizumab can Overcome this Resistance

14. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

15. Clustering Adult ACUTE Lymphoblastic Leukemia (ALL) Philadelphia Negative (Ph-) By Whole Exome Sequencing (WES) Analysis

16. Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations

17. Casein Kinase 1 delta/epsilon inhibition blocks CLL chemotaxis and delays leukemia onset in the E mu-TCL1 mouse model of chronic lymphocytic leukemia

18. miR-34a, miR-29c and miR-17-5p expression in chronic lymphocytic leukemia patients is dependent on p53 functionality

19. Cellular localization of epilepsy-related microRNAs in P12 and P60 rat hippocampi

20. Minor-clone TP53 mutations in CLL patients entering first-line treatment: clonal evolution and clinical impact

21. Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target

22. Higher-order connections between stereotyped subsets

23. STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma

24. HIGHER ORDER IMMUNOGLOBULIN REPERTOIRE RESTRICTIONS IN CLL: THE ILLUSTRATIVE CASE OF STEREOTYPED SUBSETS #2 AND #169

25. TP53 aberrations in chronic lymphocytic leukemia: an overview of the clinical implications of improved diagnostics

26. Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes

27. Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia

28. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia

29. No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy

30. Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry:An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project

31. GLASS: assisted and standardized assessment of gene variations from Sanger sequence trace data

32. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

33. ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: Enrichment in subset #2 is associated with markedly short telomeres

34. Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia

35. Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification

Catalog

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

35 results on '"Pospisilova, Sarka"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources