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  • 1. Abelsson, Johanna
    et al.
    Andreasson, Bjorn
    Samuelsson, Jan
    Hultcrantz, Malin
    Ejerblad, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Johansson, Berit
    Emanuel, Robyn
    Mesa, Ruben
    Johansson, Peter
    Patients with polycythemia vera have worst impairment of quality of life among patients with newly diagnosed myeloproliferative neoplasms2013In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, no 10, 2226-2230 p.Article in journal (Refereed)
    Abstract [en]

    The quality of life (QoL) at the time of diagnosis of myeloproliferative neoplasm (MPN) has, to date, not been studied. One hundred and seventy-nine patients with MPN: 80 with essential thrombocythemia (ET), 73 with polycythemia vera (PV), 22 with primary myelofibrosis (PMF) and four with MPN undifferentiated, were included in this study. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQC30) and the MPN-Symptom Assessment Form (MPN-SAF) were used to evaluate QoL. Fatigue was the most reported symptom in these patients. Patients with PV reported significantly higher mean scores for inactivity, dizziness, cough, itching, depression and lower total QoL compared to patients with ET. Patients with PV had significantly more headache and itching compared to patients with PMF. When the newly diagnosed patients with MPN were compared with a cohort of patients with MPN with mean disease duration of 7.8 years, the differences were most striking for patients with PMF, with significantly more fatigue, abdominal discomfort, concentration problems, insomnia, fever, weight loss and lower overall QoL developed over time.

  • 2. Agathangelidis, Andreas
    et al.
    Vardi, Anna
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stereotyped B-cell receptors in chronic lymphocytic leukemia2014In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, no 10, 2252-2261 p.Article, review/survey (Refereed)
    Abstract [en]

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

  • 3.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    von Heideman, Anne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lagercrantz, Svetlana
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bergh, Jonas
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma2002In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 43, no 11, 2179-2189 p.Article in journal (Refereed)
    Abstract [en]

    Little is known about mechanisms leading to secondary non-Hodgkin lymphomas (NHL) in patients treated for Hodgkin lymphoma (HL). Our aim was to characterise in detail a cell line derived from a diffuse large B-cell lymphoma (DLBCL) that had developed in a patient with relapsing HL. The cell line U-2932 was established from ascites in a patient suffering from DLBCL previously treated for HL with multiple chemotherapy regimens. Characterisation was based on morphology, immunophenotype, Epstein-Barr virus (EBV)-status, IgH gene rearrangement status, tumourigenicity, p53 sequencing, and immunohistochemical expression of p53, BCL-2 and BCL-6. The karyotype was investigated using G-banding, comparative genomic hybridisation (CGH) and spectral karyotype (SKY) analysis. This cell line shows typical morphological features of a DLBCL and grows as colonies in nude mice. It expresses a B-cell phenotype with a somatically hypermutated V(H)4-39 gene and is negative for EBV. The origin of U-2932 was confirmed by demonstrating an identical V(H)4 rearrangement in ascites from the patient. A point mutation of the tumour-suppressor gene p53 was detected in amino acid position 176 and immunohistochemical over-expression of the p53 protein was also demonstrated. U-2932 carries a complex karyotype including high-level amplifications of the chromosomal bands 18q21 and 3q27 and expresses aberrant BCL-2 and BCL-6 immunohistochemically. We were unable to investigate the clonal relationship between the original HL and U-2932. In conclusion, U-2932 is a unique B cell line established from a patient suffering from HL followed by NHL. Overexpression of BCL-2, BCL-6 and p53 may play a role in the tumourigenesis and drug resistance. This cell line may become a useful tool to better understand the mechanisms responsible for development of secondary NHL in patients treated for HL.

  • 4.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Engström, Peter
    Christensson, Birger
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Relapsed Hodgkin's lymphoma: immunostaining patterns in relation to survival2002In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 43, no 6, 1253-1260 p.Article in journal (Refereed)
    Abstract [en]

    Patients with relapsing Hodgkin's lymphoma (HL) have a rather poor prognosis and mechanisms that lead to resistance to therapy are poorly understood. Our aims were to investigate the immunohistochemical staining patterns of Rb (retinoblastoma protein) and the p53 tumour suppressor protein in HL at initial presentation and at relapse in order to elucidate a possible role in disease progression and resistance to therapy. Further to evaluate the presence and prognostic importance of Epstein-Barr virus (EBV) and anaplastic lymphoma kinase (ALK). Eighty-one cases of relapsing HL were reexamined histopathologically and immunostained for the expression of p53, Rb, ALK and CD30. EBV was detected with LMP-1 stainings and in situ hybridisation for EBER. Clinical data were extracted from the Swedish National Health Care Programme for HL. Median follow-up time was six years (range 0-12) from the date of relapse. The majority of cases were positive for p53 and Rb both at presentation and at relapse, though to a different extent. Both an increase and a decrease in the proportion of stained tumour cells were observed. None of our cases was ALK-positive and 44% were EBV-positive. No specific staining pattern was directly correlated to survival. In 12 patients a switch in HL subtype from diagnosis to relapse was observed and the five-year Hodgkin-specific survival (HLS) was statistically significantly inferior, 37 vs 81% (p = 0.002), in those patients. We found a significant relation between the expression of p53 and EBV at diagnosis and relapse, indicating a clonal relationship. We were unable to find any specific staining pattern of p53 or Rb, affecting survival.

  • 5.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Mansouri, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Klareskog, Lars
    Askling, Johan
    Iliadou, Anastasia Nyman
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lossos, Izidore S.
    Natkunam, Yasodha
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    LMO2 protein expression predicts survival in patients with rheumatoid arthritis and diffuse large B-cell lymphoma2011In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 52, no 6, 1146-1149 p.Article in journal (Refereed)
  • 6.
    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.
    Strefford, Jonathan C.
    Bikos, Vasilis
    Parry, Marina
    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.
    Oscier, David
    Splenic marginal-zone lymphoma: ontogeny and genetics2015In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, no 2, 301-310 p.Article, review/survey (Refereed)
    Abstract [en]

    Splenic marginal-zone lymphoma (SMZL) is a rare tumor that has recently emerged as a prototype for how the interplay between genetics and environment shapes the natural history of lymphomas. Indeed, the recent identification of molecular immunogenetic subgroups within SMZL may prove to be relevant not only for the sub-classification of the disease but also for improved understanding of the underlying biology. In contrast to other B-cell lymphomas, SMZL lacks a characteristic genetic lesion, although the majority of cases harbor genomic aberrations, as recently revealed by high-throughput studies that identified recurrent genetic aberrations, several in pathways related to marginal-zone differentiation and B-cell signaling. Here we provide an overview of recent research into the molecular and cellular biology of SMZL and related disorders, with special emphasis on immunogenetics and genomic aberrations, and discuss the value of molecular and cellular markers for the diagnosis and differential diagnosis of these entities.

  • 7. Barbany, Gisela
    et al.
    Gauffin, Fredrika
    Ofverholm, Ingegerd
    Karlsson, Hakan
    Thörn, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Arvidson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Heyman, Mats
    Gustafsson, Britt
    Nordgren, Ann
    The ETV6/RUNX1 fusion transcript is not detected in RNA isolated from neonatal dried blood spots from children later diagnosed with the corresponding leukemia2013In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, no 12, 2742-2744 p.Article in journal (Refereed)
  • 8. Berenjian, Saideh
    et al.
    Hu, Kefei
    Abedi-Valugerdi, Manuchehr
    Hassan, Moustapha
    Hassan, Sadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Morein, Bror
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    The nanoparticulate Quillaja saponin KGI exerts anti-proliferative eff ects by down-regulation of cell cycle molecules in U937 and HL-60 human leukemia cells2014In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, no 7, 1618-1624 p.Article in journal (Refereed)
    Abstract [en]

    Cancer cells are characterized by uncontrolled replication involving loss of control of cyclin dependent kinases (CDKs) and cyclins, and by abolished differentiation. In this study we introduce KGI, which is a nanoparticle with a Quillaja saponin as an active molecule. By the use of RNA array analysis and confirmation at the protein level, we show that KGI affects myeloid leukemia cells (in particular, the U937 monoblast cancer cell) by the following mechanisms: (A) ceasing cell replication via proteasome degradation, (B) down-regulation of key molecules at check points between G1/S and G2/M phases, (C) reduction of thymidine kinase activity, followed by (D) exit to differentiation and production of interleukin-8 (IL-8), eventually leading to apoptosis. Leukemia cell lines (U937 and HL-60 cells) were exposed to KGI for 8 h, after which the drug was removed. The cancer cells did not revert to replication over the following 10 days. Thus our findings suggest that the nanoparticle KGI inhibits proliferation and promotes differentiation in leukemic cells by interfering with the cell cycle process.

  • 9.
    Berglund, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Roos, Göran
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Thymidylate synthase polymorphism relevant for survival in patients with diffuse large B-cell lymphoma?2009In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 10, 1723-1725 p.Article in journal (Refereed)
  • 10.
    Berglund, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Fridberg, Marie
    Wingren, Anette Gjörloff
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Leuchowius, Karl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lagercrantz, Svetlana
    Horvat, Andrea
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Establishment of a cell line from a chemotherapy resistant diffuse large B-cell lymphoma2007In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 48, no 5, 1038-1041 p.Article in journal (Refereed)
  • 11. Buckley, Patrick G.
    et al.
    Walsh, Sarah H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Roos, Göran
    Langford, Cordelia F.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Genome-wide microarray-based comparative genomic hybridization analysis of lymphoplasmacytic lymphomas reveals heterogeneous aberrations2009In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 9, 1528-34 p.Article in journal (Refereed)
    Abstract [en]

    Lymphoplasmacytic lymphoma (LPL) is not a sharply delineated lymphoma entity, either morphologically, phenotypically, or clinically. The diagnosis is often made by excluding other small cell lymphomas with plasmacytic differentiation, thus a genetic diagnostic marker would be of great benefit. Conventional cytogenetic techniques have previously demonstrated a deletion of 6q in a proportion of cases, varying from 7 to 55%. In this report, we apply array-based comparative genomic hybridization on 11 LPL samples. Genomic aberrations were detected in 9 of 11 cases, and included gains and losses. In general, the number of genetic aberrations was relatively low (two to three abnormalities per case). Recurrent aberrations detected were deletion of 6q (two cases), deletion of chromosome 17 (two cases), gain of 3q (two cases), and gain of chromosome 7 (two cases). This report not only confirms the reported loss of 6q in a proportion of cases but also highlights the genetic heterogeneity of LPL, in accordance with the known immunophenotypical, morphological, and clinical diversity of the disease.

  • 12.
    Christiansen, Ilse
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kälkner, Karl-Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gidlöf, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Soluble ICAM-1 in Hodgkin´s disease: a promising independent predictive marker for survival1995In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 19, no 3-4, 243-51 p.Article in journal (Refereed)
    Abstract [en]

    The serum levels of soluble ICAM-1 (sICAM-1, sCD54) were significantly elevated (p = .0006) in patients with Hodgkin's disease (HD) (n = 101) compared to healthy controls (n = 31). Serum levels of sICAM-1 in HD correlated significantly with the presence of B-symptoms, histology and tumour burden as reflected in the Ann Arbor staging system, but not to bulky disease. sICAM-1 was compared to other serum factors claimed to be of prognostic significance in HD, including erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), deoxythymidine kinase (TK), soluble interleukin-2 receptor (sIL-2R, sCD25) and soluble CD30 (sCD30, sKi-1-antigen). Serum levels of sICAM-1 correlated positively with all of these markers. In univariate regression analyses, all but ESR correlated with disease-free survival but only sICAM-1, sIL-2R and sCD30 correlated with overall survival. In multivariate analyses only sIL-2R (as a continuous variable) added independent prognostic information in addition to age, stage and B-symptoms. sICAM-1 and sCD30 approached significance (p = 0.07 and p = 0.08, respectively) for disease-free survival. sCD30 correlated with overall survival (p = 0.03) while sICAM-1 did not. When dichotomised at optimal cut-off levels, sICAM-1 as well as sIL-2R and sCD30 added independent prognostic information for both disease-free and overall survival. Based on the present observations, it appears that sICAM-1 may be a predictor for relapse and survival in HD. Determination of serum levels of sICAM-1 (in addition to sIL-2R and sCD30) may thus be of potential value when selecting HD patients eligible for intensive therapy in clinical trials.

  • 13. Fridberg, Marie
    et al.
    Servin, Anna
    Anagnostaki, Lola
    Linderoth, Johan
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rosén, Anders
    Mustelin, Tomas
    Jerkeman, Mats
    Persson, Jenny L.
    Wingren, Anette Gjörloff
    Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma: higher expression of ZAP70 and PKC-beta II in the non-germinal center group and poor survival in patients deficient in nuclear PTEN2007In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 48, no 11, 2221-2232 p.Article in journal (Refereed)
    Abstract [en]

    Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) show varying responses to conventional therapy, and this might be contributed to the differentiation stage of the tumor B-cells. The aim of the current study was to evaluate a panel of kinases (ZAP70, PKC-β I and II and phosphorylated PKB/Akt) and phosphatases (PTEN, SHP1 and SHP2) known to be frequently deregulated in lymphoid malignancies. De novo DLBCL cases were divided into two subgroups, the germinal center (GC) group (14/28) and the non-germinal center (non-GC) or activated B-cell (ABC) group (14/28). ZAP70 and PKC-β II were expressed in a significantly higher percentage of tumor cells in the clinically more aggressive non-GC group compared with the prognostically favourable GC group. Also, the subcellular localization of PKC-β I and II differed in DLBCL cells, with the PKC-β I isoform being expressed in both the cytoplasm and nucleus, while PKC-β II was found exclusively in the cytoplasm. Loss of nuclear PTEN correlated with poor survival in cases from both subgroups. In addition, five cell lines of DLBCL origin were analyzed for protein expression and for mRNA levels of PTEN and SHP1. For the first time, we show that ZAP70 is expressed in a higher percentage of tumor cells in the aggressive non-GC subgroup of DLBCL and that PKC-β I and II are differently distributed in the two prognostic subgroups of de novo DLBCL.

  • 14. Geisler, Christian
    et al.
    Kolstad, Arne
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Raty, Riikka
    Mantle cell lymphoma: does primary intensive immunochemotherapy improve overall survival for younger patients?2009In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 8, 1249-1256 p.Article, review/survey (Refereed)
    Abstract [en]

    MCL is a rare entity of non-Hodgkin lymphoma, hitherto considered incurable. There is no standard therapy, but the current treatment results do seem to have led to a prolongation of the median survival from 3 to 5 years. Following CHOP-like induction, high-dose radiochemotherapy, and autologous stem cell transplantation (ASCT) chemotherapy has been shown in a controlled trial to be superior in younger patients, but does not, however, lead to long-term freedom from disease. Results of recent prospective but uncontrolled trials of more intensive frontline immunochemotherapy containing cytarabine and rituximab followed by ASCT, however, now for the first time indicate plateaus of the curves of event-free, progression-free and overall survival, suggesting cure, but more studies and longer follow-up is needed. Following relapse, autologous stem-cell transplantation does not seem to be of value, but graft-versus-lymphoma effect has been documented, and allogeneic stem cell transplantation with reduced-intensity conditioning is emerging as the treatment of choice in this setting.

  • 15.
    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, 726-728 p.Article in journal (Refereed)
  • 16. Ghia, Paolo
    et al.
    Gounari, Maria
    Minici, Claudia
    Duehren-von Minden, Marcus
    Schneider, Dunja
    Alkhatib, Alabbas
    Belhart, Rudolf
    Agathangelidis, Andreas
    Ntoufa, Stavroula
    Chiorazzi, Nicholas
    Jumaa, Hassan
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Degano, Massimo
    Crystallographic evidence of autologous recognition by a clonotypic B cell receptor in chronic lymphocytic leukemia2015In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, no S1, 110-111 p.Article in journal (Other academic)
  • 17.
    Gunnarsson, Rebeqa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Exploring the Genetic Landscape in Chronic Lymphocytic Leukemia Using High-Resolution Technologies2013In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, no 8, 1583-1590 p.Article, review/survey (Refereed)
    Abstract [en]

    During recent years, microarray-based technologies and next-generation sequencing (NGS) has have been applied in chronic lymphocytic leukemia (CLL) in order to identify novel genomic aberrations that may contribute to the pathogenesis of the disease. Even though high-resolution microarray studies have confirmed the importance of the known recurrent aberrations, i.e. del(11q), trisomy 12, del(13q) and del(17p), and have more precisely delineated the genomic borders of these aberrations, only a few novel aberrations, found at a low frequency, have been detected with these techniques. Contrary to this, the application of NGS technology of the coding genome (exome sequencing) or the entire genome (whole-genome sequencing) has unveiled a number of novel recurrent mutations in e.g. the NOTCH1, SF3B1 and BIRC3 genes. Importantly, mutations in these latter genes were reported to be associated with particularly poor outcome, similar to TP53 aberrations, and may play key roles in tumor development, treatment resistance and prognosis. In this review, we will not only summarize the latest achievements using array-based or NGS technologies, but also point to new directions for research aiming to unravel the complex genetic 'map' in CLL and its prognostic subsets.

  • 18.
    Hallböök, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björkholm, Magnus
    Hägglund, Hans
    Smedmyr, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Does granulocyte colony-stimulating factor improve long-term outcome in adult acute lymphoblastic leukemia?2009In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 11, 1872-1874 p.Article in journal (Refereed)
  • 19.
    Hasni, Muhammad Sharif
    et al.
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Berglund, Mattias
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Yakimchuk, Konstantin
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Guan, Jiyu
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Linderoth, Johan
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Okret, Sam
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Estrogen receptor beta 1 in diffuse large B-cell lymphoma growth and as a prognostic biomarker2017In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no 2, 418-427 p.Article in journal (Refereed)
    Abstract [en]

    Diffuse large B-cell lymphoma (DLBCL) shows a higher incidence in males versus females. Epidemiological studies have shown that female gender is a favorable prognostic factor, which may be explained by estrogens. Here we show that when grafting human DLBCL cells to immunocompromised mice, tumor growth in males is faster. When treating mice grafted with either germinal center or activated B-cell like DLBCL cells with the selective estrogen receptor beta (ER beta) agonist diarylpropionitrile, tumor growth was significantly inhibited. Furthermore, nuclear ER beta 1 expression analysis in primary DLBCL's by immunohistochemistry revealed expression in 89% of the cases. Nuclear ERb1 expression was in a univariate and multivariate analysis, an independent prognostic factor for adverse progression-free survival in Rituximab-chemotherapy treated DLBCL (p = 0.02 and p = 0.04, respectively). These results suggest that estrogen signaling through ERb1 is an interesting future therapeutic target for treatment of DLBCL, and that ERb1 expression can be used as a prognostic marker.

  • 20. Johansson, Ann-Sofie
    et al.
    Norén-Nyström, Ulrika
    Larefalk, Åsa
    Holmberg, Dan
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Fish oil delays lymphoma progression in the TLL mouse2010In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 51, no 11, 2092-2097 p.Article in journal (Refereed)
    Abstract [en]

    The objective was to investigate the effects of omega-3 fatty acids, known for their anti-inflammatory effects, on time to lymphoma progression and survival in the TLL mouse, a strain genetically prone to developing aggressive T-cell lymphoma. Compared to mice fed a standard diet, TLL mice fed omega-3 (menhaden fish oil) experienced a significant delay in disease progression and were more likely to remain alive and symptom free during the first 8 months of the study. In contrast, omega-6 supplementation (corn oil) did not significantly affect lymphoma progression. Irrespective of diet, all mice eventually progressed, and 1-year survival was not different between the groups. Immunological analysis demonstrated a significantly altered B-cell compartment and fewer NK cells in healthy C57Black6 mice fed omega-3, compared to controls. In conclusion, a diet rich in omega-3 fatty acids delays lymphoma development in the TLL mouse possibly by mechanisms that include complex effects on immune function.

  • 21. Johansson, Ann-Sofie
    et al.
    Pawelzik, Sven-Christian
    Larefalk, Åsa
    Jakobsson, Per-Johan
    Holmberg, Dan
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Lymphoblastic T-cell lymphoma in mice is unaffected by Celecoxib as single agent or in combination with cyclophosphamide2009In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 7, 1198-1203 p.Article in journal (Refereed)
    Abstract [en]

    Celecoxib, an inhibitor of cyclooxygenase-2, is a promising novel antitumor agent with pleitropic mechanisms of action. Whereas this drug induces growth arrest and apoptosis of B-lymphoma cells, its effect against aggressive T-cell neoplasms remains to be studied. We therefore evaluated Celecoxib therapy of immunocompetent mice transplanted with lymphoblastic T-cell lymphomas. Oral Celecoxib in clinically relevant and non-toxic doses did not affect the degree of hypersplenism or the number of viable lymphoma cells. The clinical deterioration of Celecoxib-treated mice was not different from untreated controls. The impact of adding Celecoxib (60 mg/kg) to cyclophosphamide (200 mg/kg x 1, i.p.) was assessed but showed no benefit compared to cyclophosphamide alone. Thus, Celecoxib lacks effect against lymphoblastic T-cell lymphoma in mice.

  • 22. Johansson, Peter
    et al.
    Mesa, Ruben
    Scherber, Robyn
    Abelsson, Johanna
    Samuelsson, Jan
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Andréasson, Björn
    Association between quality of life and clinical parameters in patients with myeloproliferative neoplasms2012In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 53, no 3, 441-444 p.Article in journal (Refereed)
    Abstract [en]

    The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a validated quality of life (QoL) instrument. In our Swedish cohort of 114 patients the symptomatic burden was found to be severe, with fatigue reported in 88% of the patients and reduced QoL in the majority of patients. Patients with primary myelofibrosis had the highest scores, low QoL, for most MPN-SAF items, compared to patients with polycythemia vera and essential thrombocythemia. Higher age showed significant associations with the BFI (Brief Fatigue Inventory) score, early satiety, concentration problems, dizziness, insomnia, cough and weight loss. Blood values, disease duration and myelosuppressive treatment did not significantly associate with any of the MPN-SAF items, with the exception of higher hemoglobin, which correlated with sad mood. Male patients with MPN scored significantly higher as regards sexual problems and weight loss compared to female patients. Overall, the MPN-SAF was found to be a valid instrument for assessing symptomatic burden among this population.

  • 23.
    Kimby, Eva
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Abrahamsson, Marie
    Reg Canc Ctr, Stockholm, Sweden..
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    First report from the Swedish CLL-registry: a nationwide registry with high coverage2015In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, no S1, 42-42 p.Article in journal (Other academic)
  • 24. Kimby, Eva
    et al.
    Jurlander, Jesper
    Geisler, Christian
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Holte, Harald
    Lehtinen, Tuula
    Östenstad, Björn
    Hansen, Mads
    Uppsala University.
    Österborg, Anders
    Lindén, Ola
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: a randomized phase II study from the Nordic Lymphoma Group2008In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 49, no 1, 102-112 p.Article in journal (Refereed)
    Abstract [en]

    The purpose of this phase II randomized trial was to evaluate the effect and safety of interferon-alpha2a (IFN) in combination with extended dosing rituximab in patients with symptomatic, advanced indolent lymphoma responding to a standard single course of rituximab. Totally 123 patients were treated with rituximab 375 mg/m2 once weekly for 4 weeks leading to 14 complete response (CR; 11%), 56 partial response (PR; 46%), and 13 minor responses (MR; 11%). Patients achieving either PR or MR were randomized to four more infusions of rituximab alone (n = 36) or in combination with five weeks of IFN (n = 33), with an overall response rate (CR + PR) of 78% and 94%, respectively. Significantly more patients in the combination arm improved their response from PR/MR to CR (P < 0.05) and more maintained their responses for > or = 24 months (72% versus 50%), respectively. Overall, 26 out of the 52 patients who achieved CR underwent minimal residual disease (MRD) evaluation. Totally 17 of these (65%) achieved MRD negativity, 14 of whom remain in CR after 4.8 years' follow-up. The addition of IFN to rituximab was generally safe, but reversible thrombocytopenia and neutropenia were noted in one and six patients, respectively, requiring a reduction in the IFN dose. Extended rituximab is effective and well tolerated and combination with IFN seems to improve both the quality and duration of the responses, providing the opportunity to achieve long-term molecular CRs and prolonged failure-free survival without chemotherapy.

  • 25. Kimby, Eva
    et al.
    Östenstad, Björn
    Brown, Peter
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Erlanson, Martin
    Holte, Harald
    Linden, Ola
    Johansson, Ann-Sofie
    Ahlgren, Tomas
    Wader, Karin
    Wahlin, Björn Engelbrekt
    Delabie, Jan
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Two courses of four weekly infusions of rituximab with or without interferon-α2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas2015In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, no 9, 2598-2607 p.Article in journal (Refereed)
    Abstract [en]

    Patients with advanced CD20 + indolent lymphoma, requiring therapy, were randomized to rituximab (four weekly infusions of 375 mg/m(2)) or to rituximab combined with 5 weeks of interferon-α2a (IFN-α2a) (3-4.5 MIU daily) as priming. Responding patients were eligible for a second cycle with the same allocated treatment. In total, 156 patients were randomized to rituximab and 157 to rituximab + IFN-α2a. In the intention-to treat (ITT) population, 244 patients (78%) responded to cycle 1. After a second cycle the complete remission/complete remission unconfirmed (CR/CRu) rate was 41% with the combination versus 24% with monotherapy (p = 0.005). The median time to treatment failure (primary endpoint) in ITT patients was 28 vs. 21.5 months, respectively (p = 0.302). After a long median follow-up (61 months), 33% (42% of patients responding to cycle 1) were still failure-free with an overall survival rate of 88% and with no difference between the treatment groups. The trial was registered at ClinicalTrials.gov Identifier: NCT01609010.

  • 26.
    Kinch, Amelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Association between HLA-A1 and -A2 types and Epstein-Barr virus status of post-transplant lymphoproliferative disorder2016In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 57, no 10, 2351-2358 p.Article in journal (Refereed)
    Abstract [en]

    The susceptibility to Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) may be affected by the human leukocyte antigen (HLA) type. We investigated HLA-A and HLA-B allele frequencies, focusing on HLA-A1 and -A2, in a population-based case series of EBV + (n = 60) and EBV- (n = 44) PTLD after solid organ transplantation. The proportion of EBV + PTLD was highest in HLA-A1 homozygotes (100%), lower in carriers of HLA-A1/AX (79%), HLA-A1/A2 (55%), HLA-A2/AX (54%), and lowest in HLA-A2 homozygotes (37%). HLA-A1 type was overrepresented (22% versus 7%, p = 0.05) and HLA-A2 type underrepresented (57% versus 80%, p = 0.01) in patients with EBV + compared with EBV - PTLD. EBV + PTLD in HLA-A1 carriers developed almost exclusively in already EBV-seropositive individuals. EBV status of PTLD was not related to any other HLA-A or HLA-B type. Our findings suggest that HLA-A1 carriers may have an increased risk of EBV + PTLD due to a decreased ability to control the latent EBV infection.

  • 27.
    Laurell, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Kolstad, Arne
    Jerkeman, Mats
    Raty, Riikka
    Geisler, Christian H.
    High dose cytarabine with rituximab is not enough in first-line treatment of mantle cell lymphoma with high proliferation: early closure of the Nordic Lymphoma Group Mantle Cell Lymphoma 5 trial2014In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, no 5, 1206-1208 p.Article in journal (Refereed)
  • 28. Lazarevic, Vladimir
    et al.
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Remberger, Mats
    Wahlin, Anders
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Juliusson, Gunnar
    Kimby, Eva
    Malm, Claes
    Omar, Hamdy
    Johansson, Jan-Erik
    Long-term survival following allogeneic or syngeneic stem cell transplant for follicular lymphoma in Sweden2011In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 52, no 1, 69-71 p.Article in journal (Refereed)
  • 29. Lazarevic, Vladimir
    et al.
    Remberger, Mats
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Juliusson, Gunnar
    Omar, Hamdy
    Halböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kimby, Eva
    Malm, Claes
    Wahlin, Anders
    Johansson, Jan-Erik
    Long-term survival after allogeneic stem cell transplant for relapsed large B cell lymphomas: a retrospective study2012In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 53, no 3, 503-505 p.Article in journal (Refereed)
  • 30. Lehmann, Sören
    et al.
    Paul, Crister
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The expression of cellular retinoid binding proteins in non-APL leukemic cells and its association with retinoid sensitivity2002In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 43, no 4, 851-8 p.Article in journal (Other academic)
    Abstract [en]

    Retinoic acid (RA) has important effects on cell differentiation and cell growth and on normal embryonic development. Intracellular retinoid signaling induced by endogenous or exogenous RA is regulated by retinoid binding proteins such as CRBPI, CRABPI and CRABPII and there are data suggesting that the expression of these proteins can influence the sensitivity to the growth inhibitory effects of ATRA. In this study, we investigated the basal and ATRA-induced expression of CRBPI and CRABPI and II in leukemic cell lines and in cells from patients with acute myeloid leukemia (AML). CRBPI as well as CRABPI and II were expressed in all tested cell lines and in leukemic cells from all 18 AML-patients. CRABPII mRNA expression was more abundant than CRBPI and CRABPI in both the cell lines and the patient cells but the levels compared the house keeping gene was lower in the patient cells. In all cell lines and in 69% of the patient samples, ATRA did upregulate CRABPII whereas CRBPI exhibited a varying response and CRABPI was more commonly downregulated. The sensitivity to the growth inhibitory effects of ATRA did not correlate with the basal expression of any of these proteins. However, ATRA-induced upregulation of CRABPII did significantly correlate with the ATRA sensitivity (p < 0.005) as well as with ATRA-induced upregulation of the retinoid receptor RARbeta (p < 0.05). We conclude that the retinoid binding proteins CRBPI and CRABPI and II are expressed in myeloid leukemic cells of non-M3 type but that the level of expression does not affect ATRA sensitivity.

  • 31. Linderoth, Johan
    et al.
    Ehinger, Mats
    Jerkeman, Mats
    Bendahl, Pär-Ola
    Åkerman, Måns
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Erlanson, Martin
    Roos, Göran
    Cavallin-Ståhl, Eva
    CD40 expression identifies a prognostically favourable subgroup of diffuse large B-cell lymphoma2007In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 48, no 9, 1774-1779 p.Article in journal (Refereed)
    Abstract [en]

    In order to confirm our earlier findings of the prognostic effects of CD23 and CD40 expression in diffuse large B-cell lymphoma (DLBCL), possibly due to association with the germinal center (GC) phenotype and/or an increased autologous tumour response, tumour specimens from 125 patients with de novo DLBCL were investigated for immunohistochemical expression of CD23, CD40, BCL6, CD10, MUM1, CD4 and CD8. CD40 was positive in 64% and was associated with improved overall survival (p = 0.03). A GC phenotype was present in 47%, and was also associated with a better overall survival (p = 0.006) but did not correlate with CD40-expression. There was no correlation between amount of tumour infiltrating T-cells and CD40-positivity. CD23 was positive in 10% and expression did not correlate with prognosis. In conclusion, the prognostic effect of CD40 expression was confirmed, but did not correlate with GC-phenotype or T-cell infiltration.

  • 32. Machaczka, Maciej
    et al.
    Johansson, Jan-Erik
    Remberger, Mats
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Malm, Claes
    Lazarevic, Vladimir Lj
    Wahlin, Anders
    Omar, Hamdy
    Juliusson, Gunnar
    Kimby, Eva
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Allogeneic hematopoietic stem cell transplant with reduced-intensity conditioning for chronic lymphocytic leukemia in Sweden: does donor T-cell engraftment 3 months after transplant predict survival?2012In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 53, no 9, 1699-1705 p.Article in journal (Refereed)
    Abstract [en]

    Thirty-eight adult patients with chronic lymphocytic leukemia (CLL) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allo-SCT) in Sweden between 1999 and 2007. The cumulative incidences of acute graft-versus-host disease (GVHD) grades II-IV and chronic GVHD were 29% and 47%, respectively. Rates of non-relapse mortality, progression-free survival (PFS) and overall survival (OS) were 18%, 47% and 74% at 1 year, and 21%, 25% and 45% at 5 years, respectively. T-cell chimerism after transplant was measured in 31 out of 34 patients (91%) surviving beyond day + 100. Seventeen patients achieved > 90% donor T-cell engraftment at 3 months after allo-SCT and, compared with the 12 patients with <= 90% donor T-cell engraftment, they showed favorable PFS at 1 year (82% vs. 33%, p = 0.002) and better long-term PFS and OS (p = 0.002 and 0.046, respectively). Donor T-cell engraftment of > 90% at 3 months after RIC allo-SCT for CLL seems to predict favorable short-term and long-term outcome.

  • 33. Machaczka, Maciej
    et al.
    Vaktnäs, Johan
    Klimkowska, Monika
    Hägglund, Hans
    Hematology Center Karolinska, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Malignancy-associated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center2011In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 52, no 4, 613-619 p.Article in journal (Refereed)
    Abstract [en]

    A retrospective, population-based study was conducted to evaluate the incidence, clinical features, and outcome of malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) in adults. Between January 1996 and December 2009, eight out of 887 (0.9%) patients diagnosed with hematological malignancies developed aggressive M-HLH in an area inhabited by approximately 160,000 people. Thus the estimated annual incidence of M-HLH in adulthood was 0.36/100,000 individuals/year. The clinical course of M-HLH was aggressive in all patients. Six patients were treated with a modified HLH-94 protocol; three achieved remission (durable in one case) while the others did not respond and died within an average of 2.4 months (range 1.5-3.5) after M-HLH diagnosis. Infection complicating the course of M-HLH occurred in four (50%) patients, all of whom developed fulminant M-HLH and died. Although the small study population limits the results, the long observation period strengthens its value.

  • 34.
    Marincevic, Millaray
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Tobin, Gerard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Infrequent occurrence of PIK3CA mutations in chronic lymphocytic leukemia2009In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 5, 829-830 p.Article in journal (Refereed)
  • 35.
    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, 2926-2933 p.Article 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.

  • 36. Myhrinder, Anna Lanemo
    et al.
    Hellqvist, Eva
    Bergh, Ann-Charlotte
    Jansson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Hultman, Per
    Jonasson, Jon
    Buhl, Anne Mette
    Pedersen, Lone Bredo
    Jurlander, Jesper
    Klein, Eva
    Weit, Nicole
    Herling, Marco
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Rosen, Anders
    Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia2013In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, no 8, 1769-1779 p.Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.

  • 37. Ohm, Lotta
    et al.
    Lundqvist, Adam
    Dickman, Paul
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Persson, Ulf
    Stenke, Leif
    Carlsson, Katarina Steen
    Björkholm, Magnus
    Real-world cost-effectiveness in chronic myeloid leukemia: the price of success during four decades of development from non-targeted treatment to imatinib2015In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, no 5, 1385-1391 p.Article in journal (Refereed)
    Abstract [en]

    Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML). We evaluated clinical outcome and cost-effectiveness, using Swedish registry data based on patients with CML diagnosed 1973-2008. Outcome from three time periods (I: 1973-1979; II: 1991-1997; III: 2002-2008) associated with symptomatic treatment, interferon-α/stem cell transplant and implementation of imatinib, respectively, were compared and a lifetime cost-effectiveness model developed. Survival data from population registries, estimated resource use from clinical practice and quality of life estimates were employed. Substantial health gains were noted over time, paralleled by increased treatment costs. Median survival was 1.9, 4.0 and 13 years during the respective time periods. The incremental cost-effectiveness ratio (ICER) between periods III and II was €52 700 per quality-adjusted life year (QALY) gained. An estimated 80% price reduction of imatinib, related to patent expiry, would reduce this ICER to €22 700. Our data from four decades reveal dramatically improved survival in CML, paralleled by ICER levels generally accepted by health authorities.

  • 38.
    Olsson-Strömberg, Ulla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björkholm, Magnus
    Braide, Inger
    Carlson, Karin
    Gahrton, Gösta
    Grimfors, Gunnar
    Hast, Robert
    Ljungman, Per
    Löfvenberg, Eva
    Stenke, Leif
    Wahlin, Anders
    Winqvist, Gunnar
    Öberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Successful mobilization of Ph-negative blood stem cells with intensive chemotherapy + G-CSF in patients with chronic myelogenous leukemia in first chronic phase2006In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 47, no 9, 1768-1773 p.Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate the feasibility of mobilizing Philadelphia chromosome negative (Ph-) blood stem cells (BSC) with intensive chemotherapy and lenograstim (G-CSF) in patients with CML in first chronic phase (CP1). During 1994-1999 12 centers included 37 patients <56 years. All patients received 6 months' IFN, stopping at median 36 (1-290) days prior to the mobilization chemotherapy. All received one cycle of daunorubicin 50 mg/m2 and 1 hour infusion on days 1-3, and cytarabine (ara-C) 200 mg/m2 24 hours' i.v. infusion on days 1-7 (DA) followed by G-CSF 526 microg s.c. once daily from day 8 after the start of chemotherapy. Leukaphereses were initiated when the number of CD 34+ cells was >5/microl blood. Patients mobilizing poorly could receive a 4-day cycle of chemotherapy with mitoxantrone 12 mg/m2/day and 1 hour i.v infusion, etoposide 100 mg/m2/day and 1 hour i.v. infusion and ara-C 1 g/m2/twice a day with 2 hours' i.v infusion (MEA) or a second DA, followed by G-CSF 526 microg s.c once daily from day 8 after the start of chemotherapy. Twenty-seven patients received one cycle of chemotherapy and G-CSF, whereas 10 were mobilized twice. Twenty-three patients (62%) were successfully (MNC >3.5 x 10(8)/kg, CFU-GM >1.0 x 10(4)/kg, CD34+ cells >2.0 x 10(6)/kg and no Ph+ cells in the apheresis product) [n = 16] or partially successfully (as defined above but 1-34% Ph+ cells in the apheresis product) [n = 7] mobilized. There was no mortality during the mobilization procedure. Twenty-one/23 patients subsequently underwent auto-SCT. The time with PMN <0.5 x 10(9)/l was 10 (range 7-49) and with platelets <20 x 10(9)/l was also 10 (2-173) days. There was no transplant related mortality. The estimated 5-year overall survival after auto-SCT was 68% (95% CI 47 - 90%), with a median follow-up time of 5.2 years.We conclude that in a significant proportion of patients with CML in CP 1, intensive chemotherapy combined with G-CSF mobilizes Ph- BSC sufficient for use in auto-SCT.

  • 39. Paul, Esbjörn
    et al.
    Uggla, Bertil
    Deneberg, Stefan
    Bengtzen, Sofia
    Hermansson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahlman, Ingrid
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wiman, Klas G
    Nahi, Hareth
    Low p14ARF expression in de novo acute myeloid leukemia with normal karyotype is associated with poor survival2009In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 50, no 9, 1512-1518 p.Article in journal (Refereed)
    Abstract [en]

    The p14ARF protein activates the p53 tumor suppressor by binding to and inhibiting its negative regulator HDM-2. We have studied the prognostic impact of p14ARF in acute myeloid leukemia (AML). Leukemic cells from 57 adult patients with normal karyotype de novo AML were analyzed for p14ARF mRNA expression level using real-time polymerase chain reaction (RT-PCR). We also tested the effect of conventional anti-leukemic drugs and the mutant p53-targeting small molecule PRIMA-1 in vitro. Patients whose cells expressed more p14ARF mRNA than the 75th percentile (0.26) had significantly better survival compared with those expressing lower levels, 61 vs. 30% 3-year survival (p = 0.046). The difference remained significant also when NPM1/FLT3 status was considered. The mean effects of all the tested conventional anti-leukemic drugs were greater in leukemic cell samples expressing p14ARF mRNA >or= 0.26, but the differences were not statistically significant. In contrast, PRIMA-1 had a significantly greater effect on leukemic cell samples with low levels of p14ARF mRNA. We conclude that low levels of p14ARF mRNA in leukemic cells from patients with normal karyotype AML is associated with poor prognosis. Treatment with drugs targeting p53 may be a future possibility to improve outcome for these patients.

  • 40.
    Rosenquist Brandell, Richard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Bhoi, Sujata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Prognostic markers and their clinical applicability in chronic lymphocytic leukemia: where do we stand?2013In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, no 11, 2351-2364 p.Article, review/survey (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is a clinically and biologically heterogeneous disease where the majority of patients have an indolent disease course, while others may experience a far more aggressive disease, treatment failure and poor overall survival. During the last two decades, there has been an intense search to find novel biomarkers that can predict prognosis as well as guide treatment decisions. Two of the most reliable molecular prognostic markers, both of which are offered in routine diagnostics, are the immunoglobulin heavy chain variable (IGHV) gene mutational status and fluorescence in situ hybridization (FISH) detection of prognostically relevant genomic aberrations (e.g. 11q-, 13q-, +12 and 17p-). In addition to these markers, a myriad of additional biomarkers have been postulated as potential prognosticators in CLL, on the protein (e.g. CD38, ZAP70, TCL1), the RNA (e.g. LPL, CLLU1, micro-RNAs) and the genomic (e.g. TP53, NOTCH1, SF3B1 and BIRC3 mutations) level. Efforts are now being made to test these novel markers in larger patient cohorts as well as in prospective trials, with the ultimate goal to combine the "best" markers in a "CLL prognostic index" applicable for the individual patient. Although it is clear that these studies have significantly improved our knowledge regarding both prognostication and the biology of the disease, there is still an immediate need for recognizing biomarkers that can predict therapy response, and efforts should now focus on addressing this pertinent issue. In the present article, we review the extensive literature in the field of prognostic markers in CLL, focus on the most clinically relevant markers and discuss future directions regarding biomarkers in CLL.

  • 41.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    A new piece to the stereotypy "puzzle" in chronic lymphocytic leukemia2015In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, no 11, 3008-3009 p.Article in journal (Other academic)
  • 42. Seelig, Davis M
    et al.
    Ito, Daisuke
    Forster, Colleen L
    Yoon, Una A
    Breen, Matthew
    Burns, Linda J
    Bachanova, Veronika
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
    O'Brien, Timothy D
    Schmechel, Stephen C
    Rizzardi, Anthony E
    Modiano, Jaime F
    Linden, Michael A
    Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies2017In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no 7, 1702-1710 p.Article in journal (Refereed)
    Abstract [en]

    Activation of the classical nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway is a common molecular event observed in both human and canine diffuse large B-cell lymphoma (DLBCL). Although the oncogenic potential of the alternative NFκB pathway (ANFκBP) has also been recently identified in DLBCL, its precise role in tumor pathogenesis and potential as a treatment target is understudied. We hypothesized that up-regulation of the ANFκBP plays an important role in the proliferation and survival of canine DLBCL cells, and we demonstrate that the ANFκBP is constitutively active in primary canine DLBCL samples and a cell line (CLBL1). We further demonstrate that a small interfering RNA inhibits the activation of the NFκB pathway and induces apoptosis in canine DLBCL cells. In conclusion, the ANFκBP facilitates survival of canine DLBCL cells, and thus, dogs with spontaneous DLBCL can provide a useful large animal model to study therapies targeting the ANFκBP.

  • 43. Stalika, Evangelia
    et al.
    Papalexandri, Apostolia
    Iskas, Michalis
    Stavroyianni, Niki
    Kanellis, George
    Kotta, Konstantina
    Pontikoglou, Charalambos
    Siorenta, Alexandra
    Anagnostopoulos, Achilles
    Papadaki, Helen
    Papadaki, Theodora
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Familial CD3(+) T large granular lymphocyte leukemia: evidence that genetic predisposition and antigen selection promote clonal cytotoxic T-cell responses2014In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, no 8, 1781-1787 p.Article in journal (Refereed)
    Abstract [en]

    CD3(+)T-large granular lymphocyte (T-LGL) proliferations often present with cytopenias and splenomegaly and are linked to autoimmunity, especially rheumatoid arthritis and Felty's syndrome. We report here the intra-family occurrence of T-LGL leukemia in a father and son, both presenting with cytopenias and splenomegaly. Both patients carried the HLA-DRB1*04 allele, strongly associated with rheumatoid arthritis and Felty's syndrome, exhibited distinctive histopathological features suggestive of immune-mediated suppression of hematopoiesis and expressed a remarkably skewed T-cell receptor beta chain gene repertoire with overtime evolution (clonal drift). Immunoinformatics analysis and comparisons with clonotype sequences from various entities revealed (quasi)identities between (i) father and son, and (ii) father or son and patients with autoimmune disorders,T-LGL leukemia or chronic idiopathic neutropenia. Altogether, our results further corroborate antigen selection in the ontogeny of T-LGL leukemia and point to the interplay between genetics and the (micro)environment in shaping the outcome of cytotoxic T cell responses.

  • 44. Thelander, Emma Flordal
    et al.
    Ichimura, Koichi
    Corcoran, Martin
    Barbany, Gisela
    Nordgren, Ann
    Heyman, Mats
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Mungall, Andy
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Collins, V Peter
    Grandér, Dan
    Larsson, Catharina
    Lagercrantz, Svetlana
    Characterization of 6q deletions in mature B cell lymphomas and childhood acute lymphoblastic leukemia2008In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 49, no 3, 477-487 p.Article in journal (Refereed)
    Abstract [en]

    The study was undertaken with the aim to outline deletion patterns involving the long arm of chromosome 6, a common abnormality in lymphoproliferative disorders. Using a chromosome 6 specific tile path array, 60 samples from in total 49 cases with mantle cell lymphoma (MCL), de novo diffuse large B-cell lymphoma (DLBCL), transformed DLBCL as well as preceding follicular lymphoma (FL), and childhood acute lymphoblastic leukemia (ALL), were characterized. Twenty-six of the studied cases, representing all diagnoses, showed a 6q deletion among which 85% involved a 3Mb region in 6q21. The minimal deleted interval in 6q21 encompasses the FOXO3A, PRDM1 and HACE1 candidate genes. The PRDM1 gene was found homozygously deleted in a case of DLBCL. Moreover, in two DLBCL cases, an overlapping homozygous deletion was identified in 6q23.3-24.1, encompassing the TNFAIP3 gene among others. Taken together, we refined the deletion pattern within the long arm of chromosome 6 in four different types of hematological malignances, suggesting the location of tumor suppressor genes involved in the tumor progression.

  • 45. Thelander, Emma Flordal
    et al.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Molecular genetic characterization reveals new subsets of mantle cell lymphoma2008In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 49, no 6, 1042-1049 p.Article, review/survey (Refereed)
    Abstract [en]

    Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, which is believed to originate from naive B-cells in the mantle zone of lymph nodes. Recently, a more diverse cellular origin has been implicated in MCL, since the disease was shown to consist of two subsets based on immunoglobulin heavy-chain variable (IGHV) gene analysis; a major subset with unmutated IGHV genes and a smaller subset (similar to 20 to 30%) displaying mutated IGHV genes. Presence of somatic hypermutation in the 'mutated' subset suggests either exposure to a germinal centre ( GC) environment or that somatic hypermutation has been acquired in a non-GC context. Furthermore, a preferential IGHV gene utilization has been revealed in MCL, where IGHV3-21 and IGHV4-34 are the most predominant. MCLs with an IGHV3-21 usage almost exclusively share the same light chain (IGLV3-19) use and this subset is also related to a better prognosis. MCL cases utilising the IGHV3-21 gene display less chromosomal alterations than MCLs using other IGHV genes and in addition, gains in 15q and losses in 9p were not observed in any of these cases. These latter findings are in favour of the hypothesis that IGHV3-21(+) tumours may represent a distinct MCL subentity and that there is a possible role for antigens in MCL development. In this review, we will summarise these recent studies of IG gene rearrangements in MCL as well as molecular cytogenetic characteristics of this malignancy.

  • 46. Thomas, Rachael
    et al.
    Seiser, Eric L.
    Motsinger-Reif, Alison
    Borst, Luke
    Valli, Victor E.
    Kelley, Kathryn
    Suter, Steven E.
    Argyle, David
    Burgess, Kristine
    Bell, Jerold
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Modiano, Jaime F.
    Breen, Matthew
    Refining tumor-associated aneuploidy through 'genomic recoding' of recurrent DNA copy number aberrations in 150 canine non-Hodgkin lymphomas2011In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 52, no 7, 1321-1335 p.Article in journal (Refereed)
    Abstract [en]

    Identification of the genomic regions most intimately associated with non-Hodgkin lymphoma (NHL) pathogenesis is confounded by the genetic heterogeneity of human populations. We hypothesize that the restricted genetic variation of purebred dogs, combined with the contrasting architecture of the human and canine karyotypes, will increase the penetrance of fundamental NHL-associated chromosomal aberrations in both species. We surveyed non-random aneuploidy in 150 canine NHL cases, revealing limited genomic instability compared to their human counterparts and no evidence for CDKN2A/B deletion in canine B-cell NHL. 'Genomic recoding' of canine NHL data into a 'virtual human' chromosome format showed remarkably few regions of copy number aberration (CNA) shared between both species, restricted to regions of dog chromosomes 13 and 31, and human chromosomes 8 and 21. Our data suggest that gene discovery in NHL may be enhanced through comparative studies exploiting the less complex association between CNAs and tumor pathogenesis in canine patients.

  • 47.
    Thunberg, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Turesson, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Genetic variation in tumor necrosis factor and risk of diffuse large B-cell lymphoma and follicular lymphoma: differences between subgroups in Swedish patients2010In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 51, no 8, 1563-1566 p.Article in journal (Refereed)
  • 48.
    Tobin, Gerard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The immunoglobulin genes: Structure and specificity in chronic lymphocytic leukemia2007In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 48, no 6, 1081-1086 p.Article, review/survey (Refereed)
    Abstract [en]

    The rearrangement of the immunoglobulin genes (IG) provides a large diversity of B-cell receptors conformations and allows the immune system to respond differently to foreign antigens. In chronic lymphocytic leukemia (CLL), there are a restricted number of stereotyped B-cell receptors rearranged by the tumor B-cells between CLL patients. These subsets with stereotyped receptors appear to have clinical implications, for example cases that rearrange the IGHV3-21 gene display poor clinical prognosis. The number of subsets with stereotyped receptors has been reported at a frequency of over 20% of CLL cases; however, the specificities of these receptors are still not clearly defined. Reactivity to epitopes from bacterial antigen, cytoskeleton components such as vimentin, and antigens on viable and apoptotic T-cell have been proposed. The role of antigen in CLL development is currently being more clearly defined with identification of stereotyped receptors, and their antigen specificity and the continued role antigen stimulation plays in CLL disease will be an important question in the future.

  • 49.
    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, 2419-2425 p.Article 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.

  • 50. Wahlin, Bjorn Engelbrekt
    et al.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Sander, Birgitta
    Christensson, Birger
    Jeppsson-Ahlberg, Asa
    Hjalmarsson, Eric
    Holte, Harald
    Ostenstad, Bjorn
    Brown, Peter D.
    Smeland, Erlend Bremertun
    Kimby, Eva
    Higher World Health Organization grades of follicular lymphoma correlate with better outcome in two Nordic Lymphoma Group trials of rituximab without chemotherapy2014In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, no 2, 288-295 p.Article in journal (Refereed)
    Abstract [en]

    A common treatment for follicular lymphoma is rituximab monotherapy. To identify patients for whom this regimen is adequate as first-line therapy, we applied the World Health Organization (WHO) classification for grading follicular lymphoma in a prospective central pathology review of the biopsies of previously untreated patients in two randomized trials of rituximab without chemotherapy. In the first trial (n(1) = 53), higher WHO grades correlated with longer time to next treatment, independently of clinical prognostic factors (p = 0.030); the finding was replicated in the second trial (n(2) = 221; p = 0.019). Higher grades were associated with better treatment responses (p = 0.018). Furthermore, also grades externally confirmed by independent local pathologists correlated with time to next treatment (p = 0.048). Flow cytometry in a separate patient series showed that the intensity of CD20 increased with the malignant cell size (p < 0.00005). In conclusion, WHO grade 1 follicular lymphoma correlates with inferior outcome after rituximab monotherapy. WHO grading might provide a clinically useful tool for personalized therapy.

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