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  • 1.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hadzidimitriou, Anastasia
    Inst Appl Biosci, Thessaloniki, Greece..
    Minga, Eva
    Inst Appl Biosci, Thessaloniki, Greece..
    Agathangelidis, Andreas
    Inst Appl Biosci, Thessaloniki, Greece.;Univ Vita Salute San Raffaele, Milan, Italy.;IRCCS San Raffaele Sci Inst, Div Expt Oncol, Strateg Res Program CLL, Milan, Italy..
    Sutton, Lesley Ann
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Scarfo, Lydia
    Univ Vita Salute San Raffaele, Milan, Italy.;IRCCS San Raffaele Sci Inst, Div Expt Oncol, Strateg Res Program CLL, Milan, Italy..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Yan, Xiao-Jie
    Northwell Hlth, Feinstein Inst Med Res, New York, NY USA..
    Plevova, Karla
    CEITEC Cent European Inst Technol, Masarykbrno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Sandberg, Yorick
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Vojdeman, Fie J.
    Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Tzenou, Tatiana
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Chu, Charles C.
    Northwell Hlth, Feinstein Inst Med Res, New York, NY USA..
    Veronese, Silvio
    Osped Niguarda Ca Granda, Mol Pathol Unit, Niguarda Canc Ctr, Milan, Italy.;Osped Niguarda Ca Granda, Dept Haematol, Niguarda Canc Ctr, Milan, Italy..
    Mansouri, Larry
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Giudicelli, Veronique
    Univ Montpellier, Lab ImmunoGenet Mol LIGM, IMGT, IGH,UPR CNRS 1142, Montpellier, France..
    Nguyen-Khac, Florence
    Hematol Dept, Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Panagiotidis, Panagiotis
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Juliusson, Gunnar
    Lund Univ & Hosp, Dept Hematol, Lund Stem Cell Ctr, Lund, Sweden..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Lefranc, Marie-Paule
    Univ Montpellier, Lab ImmunoGenet Mol LIGM, IMGT, IGH,UPR CNRS 1142, Montpellier, France..
    Trentin, Livio
    Padova Univ, Hematol & Clin Immunol Branch, Dept Med, Sch Med, Padua, Italy.;Venetian Inst Mol Med, Padua, Italy..
    Catherwood, Mark
    Belfast City Hosp, Dept Hematooncol, Belfast, Antrim, North Ireland..
    Montillo, Marco
    Osped Niguarda Ca Granda, Mol Pathol Unit, Niguarda Canc Ctr, Milan, Italy.;Osped Niguarda Ca Granda, Dept Haematol, Niguarda Canc Ctr, Milan, Italy..
    Niemann, Carsten U.
    Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Langerak, Anton W.
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Pospisilova, Sarka
    CEITEC Cent European Inst Technol, Masarykbrno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Stavroyianni, Niki
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Chiorazzi, Nicholas
    Northwell Hlth, Feinstein Inst Med Res, New York, NY USA..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Jelinek, Diane F.
    Mayo Clin, Dept Immunol, Rochester, MN USA..
    Shanafelt, Tait
    Mayo Clin, Dept Med, Div Hematol, Rochester, MN USA..
    Darzentas, Nikos
    CEITEC Cent European Inst Technol, Masarykbrno, Czech Republic..
    Belessi, Chrysoula
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Davi, Frederic
    Hematol Dept, Paris, France..
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Milan, Italy.;IRCCS San Raffaele Sci Inst, Div Expt Oncol, Strateg Res Program CLL, Milan, Italy..
    Rosenquist, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 4, p. E158-E161Article in journal (Refereed)
  • 2.
    Gemenetzi, Katerina
    et al.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Galigalidou, Chrysi
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Vlachonikola, Elisavet
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece..
    Stalika, Evangelia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece.; G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.; G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Xochelli, Aliki
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki , Greece.; G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karypidou, Maria
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Touloumenidou, Tasoula
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Minga, Evangelia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece..
    Douka, Vasiliki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Iskas, Michalis
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Athanasiadou, Anastasia
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Makris, Antonios
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki , Greece..
    Stavroyianni, Niki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Hadzidimitriou, Anastasia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Tp53 gene p72R polymorphism in chronic lymphocytic leukemia: incidence and clinical significance amongst cases with unmutated immunoglobulin receptors2017In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no 3, p. 726-728Article in journal (Refereed)
  • 3.
    Ghia, P.
    et al.
    Univ Vita Salute San Raffaele, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst Milan, Milan, Italy..
    Nadel, B.
    Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France..
    Sander, B.
    Karolinska Inst, Dept Lab Med, Div Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, SE-14186 Stockholm, Sweden..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Stevenson, F. K.
    Univ Southampton, Canc Res UK Ctr, Canc Sci Unit, Fac Med,Southampton Gen Hosp, Southampton, Hants, England..
    Early stages in the ontogeny of small B-cell lymphomas: genetics and microenvironment2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 282, no 5, p. 395-414Article in journal (Refereed)
    Abstract [en]

    In this review, we focus on the mechanisms underlying lymphomagenesis in chronic lymphocytic leukaemia, follicular lymphoma, mantle cell lymphoma and splenic marginal zone lymphoma. The cells of origin of these small B-cell lymphomas are distinct, as are the characteristic chromosomal lesions and clinical courses. One shared feature is retention of expression of surface immunoglobulin. Analysis of this critical receptor reveals the point of differentiation reached by the cell of origin. Additionally, the sequence patterns of the immunoglobulin-variable domains can indicate a role for stimulants of the B-cell receptor before, during and after malignant transformation. The pathways driven via the B-cell receptor are now being targeted by specific kinase inhibitors with exciting clinical effects. To consider routes to pathogenesis, potentially offering earlier intervention, or to identify causative factors, genetic tools are being used to track pretransformation events and the early phases in lymphomagenesis. These methods are revealing that chromosomal changes are only one of the many steps involved, and that the influence of surrounding cells, probably multiple and variable according to tissue location, is required, both to establish tumours and to maintain growth and survival. Similarly, the influence of the tumour microenvironment may protect malignant cells from eradication by treatment, and the resulting minimal residual disease will eventually give rise to relapse. The common and different features of the four lymphomas will be summarized to show how normal B lymphocytes can be subverted to generate tumours, how these tumours evolve and how their weaknesses can be attacked by targeted therapies.

  • 4.
    Mastrodemou, Semeli
    et al.
    Univ Crete, Sch Med, Dept Hematol, Iraklion, Greece..
    Stalika, Evangelia
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece..
    Vardi, Anna
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece..
    Gemenetzi, Katerina
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece..
    Spanoudakis, Michalis
    Univ Crete, Sch Med, Dept Hematol, Iraklion, Greece..
    Karypidou, Maria
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece..
    Mavroudi, Irene
    Univ Crete, Sch Med, Dept Hematol, Iraklion, Greece..
    Hadzidimitriou, Anastasia
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece..
    Stavropoulos-Giokas, Catherine
    Acad Athens, Fdn Biomed Res, Hellen Cord Blood Bank, Athens, Greece..
    Papadaki, Helen A.
    Univ Crete, Sch Med, Dept Hematol, Iraklion, Greece..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece.
    Cytotoxic T cells in chronic idiopathic neutropenia express restricted antigen receptors2017In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no 12, p. 2926-2933Article in journal (Refereed)
    Abstract [en]

    Chronic idiopathic neutropenia (CIN) is an acquired disorder of granulopoiesis characterized by female predominance and mostly uncomplicated course. Crucial to CIN pathophysiology is the presence of activated T lymphocytes with myelosuppressive properties in both peripheral blood (PB) and bone marrow (BM). We systematically profiled the T cell receptor beta chain (TRB) gene repertoire in CD8(+) cells of 34 CIN patients through subcloning/Sanger sequencing analysis of TRBV-TRBD-TRBJ gene rearrangements. Remarkable repertoire skewing and oligoclonality were observed, along with shared clonotypes between different patients, alluding to antigen selection. Cross-comparison of our sequence dataset with public TRB sequence databases revealed that CIN may rarely share common immunogenetic features with other entities, however, the CIN TRB repertoire is largely disease-biased. Overall, these findings suggest that CIN may be driven by long-term exposure to a restricted set of specific CIN-associated antigens.

  • 5.
    Minici, Claudia
    et al.
    IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Biocrystallog Unit, Via Olgettina 58, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, I-20132 Milan, Italy..
    Gounari, Maria
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Cell Neoplasia Unit B, I-20132 Milan, Italy..
    Uebelhart, Rudolf
    Univ Klin Ulm, D-89081 Ulm, Germany..
    Scarfo, Lydia
    Univ Vita Salute San Raffaele, I-20132 Milan, Italy.;IRCCS San Raffaele Sci Inst, Div Expt Oncol, Cell Neoplasia Unit B, I-20132 Milan, Italy.;IRCCS San Raffaele Sci Inst, Strateg Res Program CLL, I-20132 Milan, Italy..
    Duhren-von Minden, Marcus
    Univ Klin Ulm, D-89081 Ulm, Germany..
    Schneider, Dunja
    Albert Ludwigs Univ Freiburg, Fac Biol, Ctr Biol Signaling Studies, D-79104 Freiburg, Germany..
    Tasdogan, Alpaslan
    Univ Klin Ulm, D-89081 Ulm, Germany..
    Alkhatib, Alabbas
    Albert Ludwigs Univ Freiburg, Fac Biol, Ctr Biol Signaling Studies, D-79104 Freiburg, Germany..
    Agathangelidis, Andreas
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Cell Neoplasia Unit B, I-20132 Milan, Italy..
    Ntoufa, Stavroula
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki 57001, Greece..
    Chiorazzi, Nicholas
    Feinstein Inst Med Res, Manhasset, NY 11030 USA..
    Jumaa, Hassan
    Univ Klin Ulm, D-89081 Ulm, Germany..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Ctr Res & Technol, Inst Appl Biosci, Thessaloniki 57001, Greece..
    Ghia, Paolo
    Univ Vita Salute San Raffaele, I-20132 Milan, Italy.;IRCCS San Raffaele Sci Inst, Div Expt Oncol, Cell Neoplasia Unit B, I-20132 Milan, Italy.;IRCCS San Raffaele Sci Inst, Strateg Res Program CLL, I-20132 Milan, Italy..
    Degano, Massimo
    IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Biocrystallog Unit, Via Olgettina 58, I-20132 Milan, Italy..
    Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15746Article in journal (Refereed)
    Abstract [en]

    Cell-autonomous B-cell receptor (BcR)-mediated signalling is a hallmark feature of the neoplastic B lymphocytes in chronic lymphocytic leukaemia (CLL). Here we elucidate the structural basis of autonomous activation of CLL B cells, showing that BcR immunoglobulins initiate intracellular signalling through homotypic interactions between epitopes that are specific for each subgroup of patients with homogeneous clinicobiological profiles. The molecular details of the BcR-BcR interactions apparently dictate the clinical course of disease, with stronger affinities and longer half-lives in indolent cases, and weaker, short-lived contacts mediating the aggressive ones. The diversity of homotypic BcR contacts leading to cell-autonomous signalling reconciles the existence of a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL and offers opportunities for innovative treatment strategies.

  • 6.
    Pouliou, Evi
    et al.
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece.;Univ Athens, Sch Med, Dept Pathol, Athens, Greece..
    Xochelli, Aliki
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Ctr Res & Technol Hellas CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Kanellis, George
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Stalika, Evangelia
    Ctr Res & Technol Hellas CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Sutton, Lesley-Ann
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Navarro, Alba
    Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain.;Univ Barcelona, Inst Biomed Res August Pi i Sunyer, Barcelona, Spain..
    Agathangelidis, Andreas
    Ist Sci San Raffaele, IRCCS, Div Mol Oncol, Milan, Italy.;Ist Sci San Raffaele, IRCCS, Dept Oncohematol, Milan, Italy.;Univ Vita Salutte San Raffaele, Milan, Italy..
    Dimosthenous, Kypros
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, Hematopoiet Cell Transplantat Unit, Thessaloniki, Greece..
    Patsouris, Efstratios
    Univ Athens, Sch Med, Dept Pathol, Athens, Greece..
    Korkolopoulou, Penelope
    Univ Athens, Sch Med, Dept Pathol, Athens, Greece..
    Sundström, Christer
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ghia, Paolo
    Ist Sci San Raffaele, IRCCS, Div Mol Oncol, Milan, Italy.;Ist Sci San Raffaele, IRCCS, Dept Oncohematol, Milan, Italy.;Univ Vita Salutte San Raffaele, Milan, Italy..
    Ponzoni, Maurilio
    Ist Sci San Raffaele, Milan, Italy..
    Sander, Birgitta
    Karolinska Inst, Dept Lab Med, Div Pathol, Huddinge, Sweden.;Karolinska Univ Hosp, Huddinge, Sweden..
    Campo, Elias
    Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain.;Univ Barcelona, Inst Biomed Res August Pi i Sunyer, Barcelona, Spain..
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Hadzidimitriou, Anastasia
    Ctr Res & Technol Hellas CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Ctr Res & Technol Hellas CERTH, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, Hematopoiet Cell Transplantat Unit, Thessaloniki, Greece..
    Papadaki, Theodora
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Numerous Ontogenetic Roads to Mantle Cell Lymphoma: Immunogenetic and Immunohistochemical Evidence2017In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 187, no 7, p. 1454-1458Article in journal (Refereed)
    Abstract [en]

    To obtain insight into the ontogeny of mantle cell lymphoma (MCL), we assessed 206 patients from a morphological, immunohistochemical, and immunogenetic perspective. Our series included nodal (n = 151), extranodal. (n = 28), and primary splenic (n = 27) MCL cases. Skewing of the immunoglobulin heavy variable (IGHV) gene repertoire was noted, with only four IGHV genes accounting for 46% of cases and approximately 70% of cases (107/154) bearing an imprint of somatic hypermutation (SHM) ranging from minimalto pronounced. Interestingly, a distinctive immunophenotypic and immunogenetic profile was identified for primary splenic MCL, which was enriched for DBA.44-positive cases (P < 0.001) and used the IGHV1-8 gene more frequently (P = 0.02) compared to nodal or extranodal cases, alluding to distinct immunopathogenetic and antigen selection processes. Expression of CD27 (considered a marker of activated B cells) was generally dissociated from SHM and was more prevalent in cases with no or minimal/borderline SHM. These findings support the idea that antigen drive is relevant for most MCL cases, although the specific antigens and the precise location of affinity maturation remain to be elucidated. Moreover, they raise the intriguing hypothesis of multiple cellular origins for MCL.

  • 7.
    Rawstron, Andy C.
    et al.
    St James Univ Hosp, Haematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England..
    Ssemaganda, Aloysius
    Uganda Virus Res Inst, Int AIDS Vaccine Initiat, Entebbe, Uganda..
    de Tute, Ruth
    St James Univ Hosp, Haematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England..
    Doughty, Chi
    St James Univ Hosp, Haematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England..
    Newton, Darren
    Univ Leeds, Sect Expt Haematol, Leeds, W Yorkshire, England..
    Vardi, Anna
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Evans, Paul A. S.
    St James Univ Hosp, Haematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Owen, Roger G.
    St James Univ Hosp, Haematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England..
    Lightfoot, Tracy
    Univ York, Dept Hlth Sci, Epidemiol & Canc Stat Grp, York, N Yorkshire, England..
    Wakeham, Katie
    Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland..
    Karabarinde, Alex
    MRC, Uganda Virus Res Inst, Uganda Res Unit AIDS, POB 49, Entebbe, Uganda..
    Asiki, Gershim
    MRC, Uganda Virus Res Inst, Uganda Res Unit AIDS, POB 49, Entebbe, Uganda..
    Newton, Robert
    Univ York, Dept Hlth Sci, Epidemiol & Canc Stat Grp, York, N Yorkshire, England.;MRC, Uganda Virus Res Inst, Uganda Res Unit AIDS, POB 49, Entebbe, Uganda..
    Monoclonal B-cell lymphocytosis in a hospital-based UK population and a rural Ugandan population: a cross-sectional study2017In: The Lancet Haematology, E-ISSN 2352-3026, Vol. 4, no 7, p. E334-E340Article in journal (Refereed)
    Abstract [en]

    Background Reported incidence of B-cell malignancies shows substantial geographical variation, being more common in the Americas and Europe than in Africa. This variation might reflect differences in diagnostic capability, inherited susceptibility, and infectious exposures. Monoclonal B-cell lymphocytosis (MBL) is a precursor lesion that can be screened for in apparently healthy people, allowing comparison of prevalence across different populations independently of health-care provision. We aimed to compare the prevalence and phenotypic characteristics of MBL in age-and-sex-matched populations from rural Uganda and the UK. Methods In this cross-sectional study, we recruited volunteers aged at least 45 years who were seronegative for HIV-1 from the established Ugandan General Population Cohort and obtained their whole-blood samples. We also obtained blood samples from anonymised waste material of age-and-sex-matched individuals (aged >45 years, with a normal blood count and no history of cancer) in the UK. We used flow cytometry to determine the presence of MBL, defined according to standard diagnostic criteria, in the samples and compared differences in the proportion of cases with chronic lymphocytic leukaemia (CLL)-phenotype MBL and CD5-negative MBL, as well as differences in absolute monoclonal B-cell count between the two cohorts. Findings Between Jan 15 and Dec 18, 2012, we obtained samples from 302 Ugandan volunteers and 302 UK individuals who were matched by age and sex to the Ugandan population. Overall MBL prevalence was higher in the Ugandan participants (42 [14%] individuals) than in the UK cohort (25 [8%]; p=0.038). CLL-phenotype MBL was detected in three (1%) Ugandan participants and 21 (7%) UK participants (p=0.00021); all three Ugandan participants had absolute monoclonal B-cell count below one cell per mu L, whereas the 21 UK participants had a median absolute number of circulating neoplastic cells of 4.6 (IQR 2-12) cells per mu L. The prevalence of CD5-negative MBL was higher in the Ugandan cohort (41 [14%], of whom two [5%] also had CLL-phenotype MBL) than in the UK cohort (six [2%], of whom two [33%] also had CLL-phenotype MBL; p<0.0001), but the median absolute B-cell count was similar (227 [IQR 152-345] cells per mu L in the Ugandan cohort vs 135 [105-177] cells per mu L in the UK cohort; p=0.13). Interpretation MBL is common in both Uganda and the UK, but the substantial phenotypic differences might reflect fundamental differences in the pathogenesis of B-cell lymphoproliferative disorders.

  • 8.
    Rosenquist, Richard
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;UPMC Univ Paris 06, Hop Pitie Salpetriere, AP HP, Dept Hematol, Paris, France..
    Ghia, P.
    IRCCS, Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy.;UPMC Univ Paris 06, Hop Pitie Salpetriere, AP HP, Dept Hematol, Paris, France..
    Hadzidimitriou, A.
    Univ Vita Salute San Raffaele, Milan, Italy..
    Sutton, Lesley Ann
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Agathangelidis, A.
    IRCCS, Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy..
    Baliakas, Panagiotis
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Darzentas, N.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Giudicelli, V.
    Masaryk Univ, CEITEC Cent European Inst Technol, Brno, Czech Republic..
    Lefranc, M-P
    Masaryk Univ, CEITEC Cent European Inst Technol, Brno, Czech Republic..
    Langerak, A. W.
    Univ Montpellier, IGH, UMR CNRS 9002, Lab ImmunoGenet Mol LIGM,IMGT, Montpellier, France..
    Belessi, C.
    Erasmus MC, Lab Med Immunol, Dept Immunol, Rotterdam, Netherlands..
    Davi, F.
    Nikea Gen Hosp, Dept Hematol, Athens, Greece.;UPMC Univ Paris 06, Hop Pitie Salpetriere, AP HP, Dept Hematol, Paris, France..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Vita Salute San Raffaele, Milan, Italy.;UPMC Univ Paris 06, Hop Pitie Salpetriere, AP HP, Dept Hematol, Paris, France..
    Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 7, p. 1477-1481Article in journal (Other academic)
  • 9.
    Stamatopoulos, Kostas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece.
    Agathangelidis, A.
    Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece.;Univ Vita Salute San Raffaele, Div Expt Oncol, Milan, Italy.;Univ Vita Salute San Raffaele, Dept Oncohematol, Milan, Italy.;IRCCS San Raffaele Sci Inst Milano, Milan, Italy..
    Rosenquist, R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ghia, P.
    Univ Vita Salute San Raffaele, Div Expt Oncol, Milan, Italy.;Univ Vita Salute San Raffaele, Dept Oncohematol, Milan, Italy.; IRCCS San Raffaele Sci Inst Milano, Milan, Italy..
    Antigen receptor stereotypy in chronic lymphocytic leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 2, p. 282-291Article, review/survey (Refereed)
    Abstract [en]

    The discovery of almost identical or 'stereotyped' B-cell receptor immunoglobulins (BcR IG) among unrelated patients with chronic lymphocytic leukemia (CLL) cemented the idea of antigen selection in disease ontogeny and evolution. The systematic analysis of the stereotypy phenomenon in CLL revealed that around one-third of CLL patients may be grouped into subsets based on shared sequence motifs within the variable heavy complementarity determining region 3. Stereotyped subsets display a strikingly similar biology of the leukemic clones, referring to many different levels, from the immunogenetic and genetic and extending to the epigenetic and functional levels. Even more importantly, the homogeneity of stereotyped subsets has clinical consequences as patients assigned to the same stereotyped subset generally exhibit an overall similar disease course and outcome. In other words, stereotypy-based patient classification of CLL has already provided a more compartmentalized view of this otherwise heterogeneous disease and can assist in refining prognostication models. While this is relevant only for the one-third of cases expressing stereotyped BcR IG; in principle, however, the findings from further analysis of the stereotyped subsets may also contribute towards improved understanding of the remaining non-stereotyped fraction of CLL patients.

  • 10.
    Sutton, Lesley Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Institute, Dept Mol Med & Surg.
    Hadzidimitriou, Anastasia
    Baliakas, Panagiotis
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Agathangelidis, Andreas
    Langerak, Anton W.
    Stilgenbauer, Stephan
    Pospisilova, Sarka
    Davis, Zadie
    Forconi, Francesco
    Davi, Frederic
    Ghia, Paolo
    Rosenquist, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
    Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification2017In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no 6, p. 968-971Article in journal (Other academic)
  • 11.
    Vardi, A.
    et al.
    CERTH, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece.;G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;Univ Crete, Med Sch, Iraklion, Greece..
    Vlachonikola, E.
    CERTH, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece..
    Karypidou, M.
    CERTH, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece..
    Stalika, E.
    CERTH, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece..
    Bikos, V.
    Masaryk Univ, CEITEC, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Gemenetzi, K.
    CERTH, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece..
    Maramis, C.
    CERTH, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece.;Aristotle Univ Thessaloniki, Med Sch, Lab Med Informat, Thessaloniki, Greece..
    Siorenta, A.
    Gen Hosp Athens G Gennimatas, Immunol & Natl Tissue Typing Ctr, Thessaloniki, Greece..
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Pospisilova, S.
    Masaryk Univ, CEITEC, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Maglaveras, N.
    CERTH, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece.;Aristotle Univ Thessaloniki, Med Sch, Lab Med Informat, Thessaloniki, Greece..
    Chouvarda, I.
    CERTH, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece.;Aristotle Univ Thessaloniki, Med Sch, Lab Med Informat, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece..
    Hadzidimitriou, Anastasia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. CERTH, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, Thessaloniki 57001, Greece..
    Restrictions in the T-cell repertoire of chronic lymphocytic leukemia: high-throughput immunoprofiling supports selection by shared antigenic elements2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 7, p. 1555-1561Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a large-scale, next-generation sequencing (NGS) study of the T-cell repertoire, focusing on major stereotyped subsets representing CLL subgroups with undisputed antigenic drive, but also included patients carrying non-subset IG rearrangements to seek for T-cell immunogenetic signatures ubiquitous in CLL. Considering the inherent limitations of NGS, we deployed bioinformatics algorithms for qualitative curation of T-cell receptor rearrangements, and included multiple types of controls. Overall, we document the clonal architecture of the T-cell repertoire in CLL. These T-cell clones persist and further expand overtime, and can be shared by different patients, most especially patients belonging to the same stereotyped subset. Notably, these shared clonotypes appear to be disease-specific, as they are found in neither public databases nor healthy controls. Altogether, these findings indicate that antigen drive likely underlies T-cell expansions in CLL and may be acting in a CLL subset-specific context. Whether these are the same antigens interacting with the malignant clone or tumor-derived antigens remains to be elucidated.

  • 12.
    Vardi, Anna
    et al.
    Centre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, Greece.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Centre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, Greece.
    Hadzidimitriou, Anastasia
    Centre for Research and Technology Hellas, Institute of Applied Biosciences, Thessaloniki, Greece.
    T cells in chronic lymphocytic leukemia: can they fight?2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 59, p. 99209-99210Article in journal (Other academic)
  • 13.
    Vilia, Maria Giovanna
    et al.
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    Fonte, Eleonora
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    Rodriguez, Tania Veliz
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    Tocchetti, Marta
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    Ranghetti, Pamela
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    Scarfo, Lydia
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Papakonstantinou, Nikos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Ntoufa, Stavroula
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Ghia, Paolo
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Muzio, Marta
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    The inhibitory receptor toll interleukin-1R 8 (TIR8/IL-1R8/SIGIRR) is downregulated in chronic lymphocytic leukemia2017In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no 10, p. 2419-2425Article in journal (Refereed)
    Abstract [en]

    Toll interleukin-1 receptor 8 (also known as TIR8, SIGIRR, or IL1R8) is a transmembrane receptor that inhibits inflammation. Accordingly, genetic inactivation of this protein exacerbates chronic inflammation and inflammation-associated tumors in mice. In particular, lack of TIR8 triggers leukemia progression in a mouse model of chronic lymphocytic leukemia (CLL), supporting its role as a novel tumor restrainer. The aim of this study was to measure the amount of TIR8 mRNA and protein in CLL cells, and to analyze its regulation of expression. Circulating leukemic cells expressed lower levels of TIR8 compared to normal B-lymphocytes. Treatment of CLL cells with Azacytidine restored higher levels of TIR8 suggesting that DNA methylation may be involved in modulating TIR8 expression, with implications for novel therapeutic strategies.

  • 14.
    Xochelli, Aliki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Baliakas, Panagiotis
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. ..
    Kavakiotis, Ioannis
    Aristotle Univ Thessaloniki, Dept Informat, Thessaloniki, Greece..
    Agathangelidis, Andreas
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.;IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Sutton, Lesley Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Minga, Eva
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Ntoufa, Stavroula
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Tausch, Eugen
    Ulm Univ, Dept Internal Med 3, Ulm, Germany..
    Yan, Xiao-Jie
    Northwell Hlth, Feinstein Inst Med Res, Manhasset, NY USA..
    Shanafelt, Tait
    Mayo Clin, Dept Med, Dept Hematol, Rochester, MN USA..
    Plevova, Karla
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Boudjogra, Myriam
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Rossi, Davide
    Univ Piemonte Orientale, Dept Translat Med, Dept Haematol, Novara, Italy..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Navarro, Alba
    Univ Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Hosp Clin, Barcelona, Spain..
    Sandberg, Yorick
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Vojdeman, Fie Juhl
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Scarfo, Lydia
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Stavroyianni, Niki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Sudarikov, Andrey
    Natl Res Ctr Hematol, Moscow, Russia..
    Veronese, Silvio
    Osped Niguarda Ca Granda, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Dept Haematol, Milan, Italy..
    Tzenou, Tatiana
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Karan-Djurasevic, Teodora
    Univ Belgrade, Inst Mol Genet & Genet Engn, Belgrade, Serbia..
    Catherwood, Mark
    Belfast City Hosp, Dept Haematooncol, Belfast, Antrim, North Ireland..
    Kienle, Dirk
    Ulm Univ, Dept Internal Med 3, Ulm, Germany..
    Chatzouli, Maria
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Facco, Monica
    Univ Padua, Sch Med, Hematol & Clin Immunol Branch, Dept Med, Padua, Italy..
    Bahlo, Jasmin
    Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany.;Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany..
    Pott, Christiane
    Univ Hosp Schleswig Holstein, Med Dept 2, Campus Kiel, Kiel, Germany..
    Pedersen, Lone Bredo
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Mansouri, Larry
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Smedby, Karin E.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med Solna, Stockholm, Sweden..
    Chu, Charles C.
    Northwell Hlth, Feinstein Inst Med Res, Manhasset, NY USA..
    Giudicelli, Veronique
    Univ Montpellier, CNRS, UPR 1142, IMGT,LIGM,IGH, Montpellier, France..
    Lefranc, Marie-Paule
    Univ Montpellier, CNRS, UPR 1142, IMGT,LIGM,IGH, Montpellier, France..
    Panagiotidis, Panagiotis
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Juliusson, Gunnar
    Lund Univ, Lund, Sweden.;Lund Stem Cell Ctr, Hosp Dept Hematol, Lund, Sweden..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Vlahavas, Ioannis
    Aristotle Univ Thessaloniki, Dept Informat, Thessaloniki, Greece..
    Antic, Darko
    Ctr Clin, Clin Hematol, Belgrade, Serbia.;Univ Belgrade, Fac Med, Belgrade, Serbia..
    Trentin, Livio
    Univ Padua, Sch Med, Hematol & Clin Immunol Branch, Dept Med, Padua, Italy..
    Montillo, Marco
    Osped Niguarda Ca Granda, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Dept Haematol, Milan, Italy..
    Niemann, Carsten
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Doehner, Hartmut
    Ulm Univ, Dept Internal Med 3, Ulm, Germany..
    Langerak, Anton W.
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Hallek, Michael
    Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany.;Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany..
    Campo, Elias
    Univ Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Hosp Clin, Barcelona, Spain..
    Chiorazzi, Nicholas
    Northwell Hlth, Feinstein Inst Med Res, Manhasset, NY USA..
    Maglaveras, Nikos
    Aristotle Univ Thessaloniki, Lab Med Informat, Thessaloniki, Greece..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Gaidano, Gianluca
    Univ Piemonte Orientale, Dept Translat Med, Dept Haematol, Novara, Italy..
    Jelinek, Diane F.
    Mayo Clin, Dept Immunol, Rochester, MN USA..
    Stilgenbauer, Stephan
    Ulm Univ, Dept Internal Med 3, Ulm, Germany..
    Chouvarda, Ioanna
    Aristotle Univ Thessaloniki, Lab Med Informat, Thessaloniki, Greece..
    Darzentas, Nikos
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Belessi, Chrysoula
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Davi, Frederic
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Hadzidimitriou, Anastasia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Rosenquist, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Ghia, Paolo
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy.;IRCCS Ist Sci San Raffaele, Milan, Italy..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece ;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes2017In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 17, p. 5292-5301Article in journal (Refereed)
    Abstract [en]

    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 IGHV4-34expressing 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.  

  • 15.
    Xochelli, Aliki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Inst Appl Biosci, CERTH, Thessaloniki 57001, Greece..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Inst Appl Biosci, CERTH, Thessaloniki 57001, Greece..
    Clonal B-cell lymphocytosis of marginal zone origin2017In: Baillière's Best Practice & Research: Clinical Haematology, ISSN 1521-6926, E-ISSN 1532-1924, Vol. 30, no 1-2, p. 77-83Article in journal (Refereed)
    Abstract [en]

    Monoclonal B cell Lymphocytosis (MBL) is the term used to characterize individuals presenting with lymphocytosis in the absence of lymphadenopathy, organomegaly or any other features suggestive of an active disease. Based on the immunophenotypic findings, MBL cases are sub-categorized into chronic lymphocytic leukemia (CLL)-like, atypical CLL and non-CLL MBL. The latter corresponds to cases with immunophenotypic features suggestive of post germinal center derivation and still represents a diagnostic conundrum. Recent studies are starting to shed light on the true biological nature and clinical significance of this entity and have led to the introduction of the novel term clonal B lymphocytosis of marginal-zone origin (CBL-MZ); as well as the acknowledgement of CBL-MZ in the latest (2016) update of the WHO classification for lymphoid malignancies. Here we provide an overview of relevant research concerning non-CLL MBL and discuss clinicobiological implications and considerations.

  • 16.
    Young, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Noerenberg, Daniel
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frick, Mareike
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Sutton, Lesley Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Blakemore, Stuart James
    Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
    Galan-Sousa, Joel
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Plevova, Karla
    Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Baliakas, Panagiotis
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rossi, Davide
    Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy and Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland.
    Ruth, Clifford
    Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.
    Roos-Weil, Damien
    INSERM, U1170, Institut Gustave Roussy, Villejuif, France.
    Navrklova, Veronika
    European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Dörken, Bernd
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Schmitt, Clemens A
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Ekström Smedby, Karin
    Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, and Hematology Center, Karolinska University Hospital, Stockholm, Sweden.
    Juliusson, Gunnar
    Department of Laboratory Medicine, Stem Cell Center, Lund University, Lund, Sweden.
    Giacopelli, Brian
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
    Blachly, James
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
    Belessi, Chrysoula
    Hematology Department, General Hospital of Nikea, Piraeus, Greece.
    Panayiotidis, Panayiotis
    First Department of Propaedeutic Medicine, School of Medicine, University of Athens, Athens, Greece.
    Chiorazzi, Nicholas
    Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Davi, Frédéric
    Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
    Langerak, Anton W
    Department of Immunology, Laboratory for Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
    Oscier, David
    Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
    Schuh, Anna
    Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.
    Gaidano, Gianluca
    Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
    Ghia, Paolo
    Università Vita-Salute San Raffaele, Milan, Italy and Division of Experimental Oncology and Department of Onco-Hematology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
    Xu, Wei
    Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
    Fan, Lei
    Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
    Bernard, Olivier A
    INSERM, U1170, Institut Gustave Roussy, Villejuif, France.
    Nguyen-Khac, Florence
    Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
    Rassenti, Laura Z
    Division of Hematology/Oncology, Department of Medicine, University of California at San Diego/Moores Cancer Center, La Jolla, CA, USA.
    Li, Jianyonglm
    Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
    Kipps, Thomas J
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden and Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
    Pospisilova, Sarka
    Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Zenz, Thorsten
    Department of Molecular Therapy in Haematology and Oncology (G250) and Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
    Strefford, Jonathan
    Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Damm, Frederik
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany; German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany and Berlin Institute of Health (BIH), Berlin, Germany .
    EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 7, p. 1547-1554Article in journal (Refereed)
    Abstract [en]

    Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n = 1283) and two validation cohorts (UK CLL4 trial patients, n = 366; CLL Research Consortium (CRC) patients, n = 490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2- mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

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