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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.
    Hadzidimitriou, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Rossi, D
    Minga, E
    Villamor, N
    Larrayoz, M
    Kminkova, J
    Agathangelidis, A
    Davis, Z
    Tausch, E
    Stalika, E
    Kantorova, B
    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.
    Scarfò, L
    Cortese, Diego
    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.
    Navrkalova, V
    Rose-Zerilli, M J J
    Smedby, K E
    Juliusson, G
    Anagnostopoulos, A
    Makris, A M
    Navarro, A
    Delgado, J
    Oscier, D
    Belessi, C
    Stilgenbauer, S
    Ghia, P
    Pospisilova, S
    Gaidano, G
    Campo, E
    Strefford, J C
    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.
    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.
    Recurrent mutations refine prognosis in chronic lymphocytic leukemia2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, p. 329-336Article in journal (Refereed)
    Abstract [en]

    Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

  • 2.
    Barbuil, Tiziano
    et al.
    Osped Giovanni 23, Div Hematol, Bergamo, Italy.
    Tefferi, Ayalew
    Mayo Clin, Dept Med, Div Hematol, Rochester, MN USA.
    Vannucchi, Alessandro M.
    Univ Florence, AOU Careggi, Ctr Res & Innovat Myeloproliferat Neoplasms, CRIMM, Florence, Italy.
    Passamonti, Francesco
    Univ Insubria, Osped Circolo, Dept Med & Surg, Div Hematol,ASST Sette Laghi, Varese, Italy.
    Silvers, Richard T.
    Weill Cornell Med, Div Hematol Oncol, New York, NY USA.
    Hoffman, Ronald
    Mt Sinai Sch Med, Dept Med, Tisch Canc Inst, New York, NY USA.
    Verstovsek, Srdan
    Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA.
    Mesa, Ruben
    UT Hlth San Antonio Canc Ctr, San Antonio, TX USA.
    Kiladjian, Jean-Jacques
    Univ Paris 07, Hop St Louis, AP HP, INSERM,Ctr Invest Clin CIC 1427, Paris, France.
    Hehlmann, Rudiger
    Heidelberg Univ, Univ Hosp Mannheim, Dept Hematol & Oncol, Mannheim, Germany.
    Reiter, Andreas
    Heidelberg Univ, Univ Hosp Mannheim, Dept Hematol & Oncol, Mannheim, Germany.
    Cervantes, Francisco
    Univ Barcelona, IDIBAPS, Hosp Clin, Barcelona, Spain.
    Harrison, Claire
    Guys & St Thomas NHS Fdn Trust, Dept Hematol, London, England.
    Mc Mullin, Mary Frances
    Queens Univ, Ctr Med Educ, Belfast, Antrim, North Ireland.
    Hasselbalch, Hans Carl
    Zealand Univ Hosp, Dept Hematol, Roskilde, Denmark.
    Koschmieder, Steffen
    Rhein Westfal TH Aachen, Fac Med, Dept Hematol Oncol Hemostaseol & Stem Cell Transp, Aachen, Germany.
    Marchetti, Monia
    Hosp Cardinal Massaia, Oncol SOC, Hematol Day Serv, Asti, Italy.
    Bacigalupo, Andrea
    Univ Cattolica Sacro Cuore, Fdn Policlin Univ Gemelli, Ist Ematol, Rome, Italy.
    Finazzil, Guido
    Osped Giovanni 23, Div Hematol, Bergamo, Italy.
    Kroeger, Nicolaus
    Univ Hosp Hamburg Eppendorf, Dept Stem Cell Transplantat, Hamburg, Germany.
    Griesshammer, Martin
    Univ Hannover, Acad Hosp, Johannes Wesling Med Ctr Minden, Dept Hematol & Oncol, Minden, Germany.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Barosi, Giovanni
    IRCCS Policlin S Matteo Fdn, Ctr Study Myelofibrosis, Pavia, Italy.
    Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 5, p. 1057-1069Article, review/survey (Refereed)
    Abstract [en]

    This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.

  • 3. Barosi, G.
    et al.
    Besses, C.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Briere, J.
    Cervantes, F.
    Finazzi, G.
    Gisslinger, H.
    Griesshammer, M.
    Gugliotta, L.
    Harrison, C.
    Hasselbalch, H.
    Lengfelder, E.
    Reilly, J. T.
    Michiels, J. J.
    Barbui, T.
    A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group2007In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 21, no 2, p. 277-280Article in journal (Refereed)
    Abstract [en]

    A widely accepted definition of resistance or intolerance to hydroxyurea (HU) in patients with essential thrombocythemia (ET) is lacking. An international working group (WG) was convened to develop a consensus formulation of clinically significant criteria for defining resistance/intolerance to HU in ET. To this aim, an analytic hierarchy process (AHP), a multiple-attribute decision-making technique, was used. The steps consisted of selecting the candidate criteria for defining resistance/intolerance; identifying the motivations that could influence the preference of the WG for any individual criterion; comparing the candidate criteria in a pair-wise manner; and grading them according their ability to fulfill the motivations. Every step in the model was derived by questionnaires or group discussion. The WG proposed that the definition of resistance/intolerance should require the fulfillment of at least one of the following criteria: platelet count greater than 600,000/micro l after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight over 80 kg); platelet count greater than 400,000/micro l and WBC less than 2500/micro l or Hb less than 10 g/dl at any dose of HU; presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any dose of HU; HU-related fever.

  • 4. Barosi, G
    et al.
    Tefferi, A
    Besses, C
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cervantes, F
    Finazzi, G
    Gisslinger, H
    Griesshammer, M
    Harrison, C
    Hehlmann, R
    Hermouet, S
    Kiladjian, J-J
    Kröger, N
    Mesa, R
    Mc Mullin, M F
    Pardanani, A
    Passamonti, F
    Samuelsson, J
    Vannucchi, A M
    Reiter, A
    Silver, R T
    Verstovsek, S
    Tognoni, G
    Barbui, T
    Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 1, p. 20-26Article in journal (Refereed)
    Abstract [en]

    The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.

  • 5.
    Botling, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    CD49f (alpha 6 integrin) and CD66a (BGP) are specifically induced by retinoids during human monocytic differentiation1995In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 9, no 12, p. 2034-41Article in journal (Refereed)
    Abstract [en]

    Retinoic acid (RA) and 1,25(OH)2-cholecalciferol (VitD3) are potent regulators of normal and malignant myeloid cells. In the human monoblast cell line U-937 they induce terminal differentiation, and the resulting phenotypes display both common and distinct, inducer-specific, properties. This paper shows that in U-937 cells the two retinoids, all-trans and 9-cis RA, induced the expression of CD49f (alpha 6 integrin subunit) and CD66a (biliary glycoprotein, BGP) mRNA and protein. In contrast, expression of CD49f and CD66a was not found in untreated or VitD3-induced cells. Cytokine-induced modulation of CD49f and CD66a expression was restricted to the retinoid-induced U-937 cells. The retinoid specific induction of CD49f and CD66a was confirmed in the related monoblastic cell line THP-1. Human blood monocytes and the monocytic cell line Mono Mac 6 responded poorly to RA, with respect to the regulation of CD49f and CD66a expression, indicating that early monocytic precursors were targets for the retinoid-specific regulation. Thus, the expression of CD49f and CD66a is developmentally regulated and specifically induced by all-trans and 9-cis Ra in human monocytic cells.

  • 6.
    Cahill, Nicola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Bergh, A-C
    Kanduri, M
    Göransson-Kultima, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ryan, F
    Smedby, K E
    Juliusson, G
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Rosén, A
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments.2013In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, no 1, p. 150-158Article in journal (Refereed)
    Abstract [en]

    In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-β and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.

  • 7. Carlsson, G.
    et al.
    Boxhammer, S.
    Garwicz, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Henter, J. I.
    Palmblad, J.
    Nordenskjöld, M.
    Porwit, A.
    Fadeel, Bengt
    Survivin expression in the bone marrow of patients with severe congenital neutropenia2009In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 23, no 3, p. 622-625Article in journal (Refereed)
  • 8.
    Chase, A.
    et al.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Leung, W.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Tapper, W.
    Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Jones, A. V.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Knoops, L.
    Clin Univ St Luc, Hematol Unit, B-1200 Brussels, Belgium.;Catholic Univ Louvain, de Duve Inst, B-1200 Brussels, Belgium..
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Forsberg, Lars A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Guglielmelli, P.
    Univ Florence, Dept Expt & Clin Med, Lab Congiunto MMPC, Florence, Italy..
    Zoi, K.
    Acad Athens, Biomed Res Fdn, Haematol Res Lab, Athens, Greece..
    Hall, V.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Chiecchio, L.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England..
    Eder-Azanza, L.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England..
    Bryant, C.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Docherty, L.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    White, H. E.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Score, J.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Mackay, D. J. G.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Vannucchi, A. M.
    Univ Florence, Dept Expt & Clin Med, Lab Congiunto MMPC, Florence, Italy..
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cross, N. C. P.
    Salisbury Dist Hosp, Salisbury NHS Fdn Trust, Wessex Reg Genet Lab, Salisbury SP2 8BJ, Wilts, England.;Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England..
    Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 10, p. 2069-2074Article in journal (Refereed)
    Abstract [en]

    Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2 Mb running from 14q32.12 to the telomere. Exome sequencing (n = 7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P < 0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r = 0.76; P = 0.0001). The absence of driver gene mutations in the exomes of three individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal haemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n = 11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal haemopoiesis either as an initiating event or as a secondary change.

  • 9.
    Chase, Andrew
    et al.
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    Pellagatti, Andrea
    Univ Oxford, Oxford BRC Haematol Theme, Bloodwise Mol Haematol Unit, Nuffield Div Clin Lab Sci,Radcliffe Dept Med, Oxford, England.
    Singh, Shalini
    Univ Oxford, Oxford BRC Haematol Theme, Bloodwise Mol Haematol Unit, Nuffield Div Clin Lab Sci,Radcliffe Dept Med, Oxford, England.
    Score, Joannah
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    Tapper, William J.
    Univ Southampton, Fac Med, Southampton, Hants, England.
    Lin, Feng
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    Hoade, Yvette
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    Bryant, Catherine
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    Trim, Nicola
    Birmingham Womens NHS Fdn Trust, West Midlands Reg Genet Lab, Birmingham, W Midlands, England.
    Yip, Bon Ham
    Univ Oxford, Oxford BRC Haematol Theme, Bloodwise Mol Haematol Unit, Nuffield Div Clin Lab Sci,Radcliffe Dept Med, Oxford, England.
    Zoi, Katerina
    Acad Athens, Biomed Res Fdn, Haematol Res Lab, Athens, Greece.
    Rasi, Chiara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Beijer Laboratory of Genome Research, Uppsala University,Uppsala, Sweden.
    Dumanski, Jan P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Boultwood, Jacqueline
    Univ Oxford, Oxford BRC Haematol Theme, Bloodwise Mol Haematol Unit, Nuffield Div Clin Lab Sci,Radcliffe Dept Med, Oxford, England.
    Cross, Nicholas C. P.
    Univ Southampton, Fac Med, Southampton, Hants, England;Salisbury NHS Fdn Trust, Salisbury Dist Hosp, Wessex Reg Genet Lab, Salisbury, Wilts, England.
    PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age-related clonal hematopoiesis and myeloid neoplasia2019In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 5, p. 1184-1194Article in journal (Refereed)
    Abstract [en]

    Acquired uniparental disomy (aUPD, also known as copy-neutral loss of heterozygosity) is a common feature of cancer cells and characterized by extended tracts of somatically-acquired homozygosity without any concurrent loss or gain of genetic material. The presumed genetic targets of many regions of aUPD remain unknown. Here we describe the association of chromosome 22 aUPD with mutations that delete the C-terminus of PRR14L in patients with chronic myelomonocytic leukemia (CMML), related myeloid neoplasms and age-related clonal hematopoiesis (ARCH). Myeloid panel analysis identified a median of three additional mutated genes (range 1-6) in cases with a myeloid neoplasm (n = 8), but no additional mutations in cases with ARCH (n = 2) suggesting that mutated PRR14L alone may be sufficient to drive clonality. PRR14L has very limited homology to other proteins and its function is unknown. ShRNA knockdown of PRR14L in human CD34+ cells followed by in vitro growth and differentiation assays showed an increase in monocytes and decrease in neutrophils, consistent with a CMML-like phenotype. RNA-Seq and cellular localization studies suggest a role for PRR14L in cell division. PRR14L is thus a novel, biallelically mutated gene and potential founding abnormality in myeloid neoplasms.

  • 10.
    Cortese, Diego
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sutton, Lesley Ann
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Smedby, K E
    Geisler, C
    Gunnarsson, R
    Juliusson, G
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    On the way towards a 'CLL prognostic index': focus on TP53, BIRC3, SF3B1, NOTCH1 and MYD88 in a population-based cohort.2014In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 28, no 3, p. 710-713Article in journal (Refereed)
  • 11.
    Dahlin, J. S.
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    Ungerstedt, J. S.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Grootens, J.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    Sander, B.
    Karolinska Inst, Karolinska Univ Hosp, Div Pathol, Dept Lab Med, Stockholm, Sweden..
    Guelen, T.
    Karolinska Univ, Huddinge Hosp, Dept Resp Dis & Allergy, Stockholm, Sweden..
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Uppsala Hosp, Sect Hematol, Uppsala, Sweden..
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    Detection of circulating mast cells in advanced systemic mastocytosis2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 9, p. 1954-+Article in journal (Refereed)
  • 12. Darzentas, N.
    et al.
    Hadzidimitriou, A.
    Murray, Fiona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hatzi, K.
    Josefsson, P.
    Laoutaris, N.
    Moreno, C.
    Anagnostopoulos, A.
    Jurlander, J.
    Tsaftaris, A.
    Chiorazzi, N.
    Belessi, C.
    Ghia, Paolo
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Davi, F.
    Stamatopoulos, K.
    A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence2010In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 24, no 1, p. 125-132Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is uniquely characterized by the existence of subsets of cases with quasi-identical, 'stereotyped' B-cell receptors (BCRs). Herein we investigate this stereotypy in 2662 patients with CLL, the largest series yet, using purpose-built bioinformatics methods based on sequence pattern discovery. Besides improving the identification of 'stereotyped' cases, we demonstrate that CLL actually consists of two different categories, based on the BCR repertoire, with important biological and ontogenetic differences. The first ( approximately 30% of cases) shows a very restricted repertoire and is characterized by BCR stereotypy (clustered cases), whereas the second includes cases with heterogeneous BCRs (nonclustered cases). Eleven major CLL clusters were identified with antigen-binding sites defined by just a few critically positioned residues, regardless of the actual immunoglobulin (IG) variable gene used. This situation is closely reminiscent of the receptors expressed by cells participating in innate immune responses. On these grounds, we argue that whereas CLL cases with heterogeneous BCRs likely derive from the conventional B-cell pool, cases with stereotyped BCRs could derive from progenitor cells evolutionarily adapted to particular antigenic challenges, perhaps intermediate between a true innate immune system and the conventional adaptive B-cell immune system, functionally similar to what has been suggested previously for mouse B1 cells.

  • 13. Davi, F.
    et al.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ghia, P.
    Belessi, C.
    Stamatopoulos, K.
    Determination of IGHV gene mutational status in chronic lymphocytic leukemia: bioinformatics advances meet clinical needs2008In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 22, no 1, p. 212-214Article in journal (Refereed)
  • 14. Davidsson, J.
    et al.
    Paulsson, K.
    Lindgren, D.
    Lilljebjörn, H.
    Chaplin, T.
    Forestier, E.
    Andersen, M. K.
    Nordgren, A.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fioretos, T.
    Young, B. D.
    Johansson, B.
    Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations2010In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 24, no 5, p. 924-931Article in journal (Refereed)
    Abstract [en]

    Although childhood high hyperdiploid acute lymphoblastic leukemia is associated with a favorable outcome, 20% of patients still relapse. It is important to identify these patients already at diagnosis to ensure proper risk stratification. We have investigated 11 paired diagnostic and relapse samples with single nucleotide polymorphism array and mutation analyses of FLT3, KRAS, NRAS and PTPN11 in order to identify changes associated with relapse and to ascertain the genetic evolution patterns. Structural changes, mainly cryptic hemizygous deletions, were significantly more common at relapse (P<0.05). No single aberration was linked to relapse, but four deletions, involving IKZF1, PAX5, CDKN2A/B or AK3, were recurrent. On the basis of the genetic relationship between the paired samples, three groups were delineated: (1) identical genetic changes at diagnosis and relapse (2 of 11 cases), (2) clonal evolution with all changes at diagnosis being present at relapse (2 of 11) and (3) clonal evolution with some changes conserved, lost or gained (7 of 11), suggesting the presence of a preleukemic clone. This ancestral clone was characterized by numerical changes only, with structural changes and RTK-RAS mutations being secondary to the high hyperdiploid pattern.

  • 15. Eckerle, S.
    et al.
    Brune, V.
    Döring, C.
    Tiacci, E.
    Bohle, V.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kodet, R.
    Paulli, M.
    Falini, B.
    Klapper, W.
    Chaubert, A. B.
    Willenbrock, K.
    Metzler, D.
    Bräuninger, A.
    Küppers, Ralf
    Hansmann, M-L.
    Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma2009In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 23, no 11, p. 2129-2138Article in journal (Refereed)
    Abstract [en]

    Anaplastic large cell lymphoma (ALCL) is a main type of T-cell lymphomas and comprises three distinct entities: systemic anaplastic lymphoma kinase (ALK) positive, systemic ALK(-) and cutaneous ALK(-) ALCL (cALCL). Little is known about their pathogenesis and their cellular origin, and morphological and immunophenotypical overlap exists between ALK(-) ALCL and classical Hodgkin lymphoma (cHL). We conducted gene expression profiling of microdissected lymphoma cells of five ALK(+) and four ALK(-) systemic ALCL, seven cALCL and sixteen cHL, and of eight subsets of normal T and NK cells. The analysis supports a derivation of ALCL from activated T cells, but the lymphoma cells acquired a gene expression pattern hampering an assignment to a CD4(+), CD8(+) or CD30(+) T-cell origin. Indeed, ALCL display a down-modulation of many T-cell characteristic molecules. All ALCL types show significant expression of NFkappaB target genes and upregulation of genes involved in oncogenesis (e.g. EZH2). Surprisingly, few genes are differentially expressed between systemic and cALCL despite their different clinical behaviour, and between ALK(-) ALCL and cHL despite their different cellular origin. ALK(+) ALCL are characterized by expression of genes regulated by pathways constitutively activated by ALK. This study provides multiple novel insights into the molecular biology and pathogenesis of ALCL.

  • 16. Feldman, E. J.
    et al.
    Cortes, J.
    DeAngelo, D. J.
    Holyoake, T.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    O'Brien, S. G.
    Reiffers, J.
    Turner, A. R.
    Roboz, G. J.
    Lipton, J. H.
    Maloisel, F.
    Colombat, P.
    Martinelli, G.
    Nielsen, J. L.
    Petersdorf, S.
    Guilhot, F.
    Barker, J.
    Kirschmeier, P.
    Frank, E.
    Statkevich, P.
    Zhu, Y.
    Loechner, S.
    List, A.
    On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia2008In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 22, no 9, p. 1707-1711Article in journal (Refereed)
    Abstract [en]

    Lonafarnib is an orally bio-available farnesyltransferase inhibitor that prevents farnesylation of specific target proteins including Ras. In a multicenter study, 67 patients with advanced myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) were treated with a continuous oral dose of 200-300 mg of lonafarnib and were evaluated for hematologic, pathologic and pharmacodynamic response. The median age of patients was 70 years (range 44-86). There were 32 patients with MDS (RAEB-20 and RAEB-t-12) and 35 with CMML. Overall 16 (24%) of the patients responded with two patients achieving a complete remission and one a partial response. Responses were seen in 6/32 and 10/35 patients with MDS and CMML, respectively. Of the 19 patients who were platelet transfusion-dependent prior to treatment, 5 (26%) became transfusion-free for a median duration of 185 days. A decrease in the farnesylation of the HDJ-2 protein measured in patient-derived cells was observed in the majority of patients during treatment with lonafarnib, but no clear correlation between changes in farnesylation and clinical effect could be made. Gastrointestinal toxicity was significant with 19% of patients discontinuing therapy due to diarrhea, nausea and/or anorexia. Lonafarnib has demonstrable activity in patients with advanced MDS and CMML.

  • 17.
    Fredriksson, Mona
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Barbany, Gisela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Kataja, Matti
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Assessing hematopoietic chimerism after stem cell transplantation by multiplexed SNP genotyping using microarrays and quantitative analysis of SNP alleles2004In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 18, no 2, p. 255-266Article in journal (Refereed)
    Abstract [en]

    Single-nucleotide polymorphisms (SNPs) have the potential to be particularly useful as markers for monitoring of chimerism after stem cell transplantation (SCT) because they can be analyzed by accurate and robust methods. We used a two-phased minisequencing strategy for monitoring chimerism after SCT. First, informative SNPs with alleles differing between donor and recipient were identified using a multiplex microarray-based minisequencing system screening 51 SNPs to ensure that multiple informative SNPs were detected in each donor-recipient pair. Secondly, the development of chimerism was followed up after SCT by sensitive, quantitative analysis of individual informative SNPs by applying the minisequencing method in a microtiter plate format. Using this panel of SNPs, we identified multiple informative SNPs in nine unrelated and in 16 related donor-recipient pairs. Samples from nine of the donor-recipient pairs taken at time points ranging from 1 month to 8 years after transplantation were available for analysis. In these samples, we monitored the allelic ratios of two or three informative SNPs in individual minisequencing reactions. The results agreed well with the data obtained by microsatellite analysis. Thus, we conclude that the two-phased minisequencing strategy is a useful approach in the following up of patients after SCT.

  • 18.
    Fredriksson, Mona
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Barbany, Gisela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hermanson, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kataja, Matti
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Assessing hematopoietic chimerism after allogeneic stem cell transplantation by multiplexed SNP genotyping using microarrays and quantitative analysis of SNP alleles2004In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 18, no 2, p. 255-266Article in journal (Refereed)
    Abstract [en]

    Single-nucleotide polymorphisms (SNPs) have the potential to be particularly useful as markers for monitoring of chimerism after stem cell transplantation (SCT) because they can be analyzed by accurate and robust methods. We used a two-phased minisequencing strategy for monitoring chimerism after SCT. First, informative SNPs with alleles differing between donor and recipient were identified using a multiplex microarray-based minisequencing system screening 51 SNPs to ensure that multiple informative SNPs were detected in each donor–recipient pair. Secondly, the development of chimerism was followed up after SCT by sensitive, quantitative analysis of individual informative SNPs by applying the minisequencing method in a microtiter plate format. Using this panel of SNPs, we identified multiple informative SNPs in nine unrelated and in 16 related donor–recipient pairs. Samples from nine of the donor–recipient pairs taken at time points ranging from 1 month to 8 years after transplantation were available for analysis. In these samples, we monitored the allelic ratios of two or three informative SNPs in individual minisequencing reactions. The results agreed well with the data obtained by microsatellite analysis. Thus, we conclude that the two-phased minisequencing strategy is a useful approach in the following up of patients after SCT.

  • 19.
    Frost, B M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Forestier, E
    Gustafsson, G
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hellebostad, M
    Jonmundsson, G
    Kanerva, J
    Schmiegelow, K
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lönnerholm, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Translocation t(1;19) is related to low cellular drug resistance in childhood acute lymphoblastic leukaemia2005In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 19, no 1, p. 165-169Article in journal (Refereed)
  • 20.
    Geelen, Inge G. P.
    et al.
    Albert Schweitzer Hosp, Dept Internal Med Hematol, Dordrecht, Netherlands.
    Sandin, Fredrik
    Reg Canc Ctr, Uppsala, Sweden.
    Thielen, Noortje
    Diakonessen Hosp, Dept Internal Med, Utrecht, Netherlands;Vrije Univ Amsterdam, Dept Hematol, Med Ctr, Amsterdam, Netherlands.
    Janssen, Jeroen J. W. M.
    Vrije Univ Amsterdam, Dept Hematol, Med Ctr, Amsterdam, Netherlands.
    Hoogendoorn, Mels
    Med Ctr Leeuwarden, Dept Hematol, Leeuwarden, Netherlands.
    Visser, Otto
    Netherlands Comprehens Canc Org IKNL, Utrecht, Netherlands.
    Cornelissen, Jan J.
    Erasmus MC, Dept Hematol, Rotterdam, Netherlands.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Westerweel, Peter E.
    Albert Schweitzer Hosp, Dept Internal Med Hematol, Dordrecht, Netherlands.
    Validation of the EUTOS long-term survival score in a recent independent cohort of "real world" CML patients2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 10, p. 2299-2303Article in journal (Refereed)
  • 21. Ghia, P
    et al.
    Stamatopoulos, K
    Belessi, C
    Moreno, C
    Stilgenbauer, S
    Stevenson, F
    Davi, F
    Rosenquist, R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia2007In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 21, no 1, p. 1-3Article in journal (Refereed)
  • 22. Ghia, Paolo
    et al.
    Belessi, C.
    Daví, F.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stamatopoulos, K.
    Reply to 'Male preponderance in chronic lymphocytic leukemia utilizing IGHV1-69.' When size of the sample matters2007In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 21, no 12, p. 2539-2540Article in journal (Refereed)
  • 23.
    Gidlöf, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Dohlsten, Mikael
    Kalland, Terje
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Antibodies can direct superantigen-mediated T cell killing of chronic B-lymphocytic leukemia cells1995In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 9, no 9, p. 1534-1542Article in journal (Refereed)
    Abstract [en]

    The bacterial superantigen staphylococcal enterotoxin A (SEA) is a highly potent activator of cytotoxic T cells when presented on MHC class II molecules of target cells. Our earlier studies showed that such SEA-directed T cells efficiently killed chronic B lymphocytic leukemia (B-CLL) cells. With the ultimate goal to replace the natural specificity of SEA for MHC class II molecules with the specificity of a monoclonal antibody (mAb), we initially made a mutated protein A-SEA (PA-SEAm) fusion protein with > 100-fold reduced binding affinity for MHC class II compared to native SEA. The fusion protein was successfully used to direct T cells to B-CLL cells coated with different B lineage specific (CD19, CD20) or associated (CD37, CD40) mAbs. The PA-SEAm protein was 10-100-fold more potent against mAb coated compared to uncoated HLA class II+ B-CLL cells. No correlation was seen between the amount of mAb bound to the cell surface and sensitivity to lysis. Preactivation of B-CLL cells by phorbol ester increased their sensitivity, and lysis was dependent on ICAM-1 molecules. However, no preactivation of the target cells was needed when a cocktail of two or four mAbs was used. Circulating leukemia and spleen cells were equally well killed. We conclude that the natural target specificity of SEA, MHC class II, can be reduced by mutagenesis and novel binding specificity can be introduced by linkage to tumor reactive mAbs. Our findings encourage the construction of recombinant SEA mutant fusion proteins for specific T cell therapy of hematopoietic tumors such as B-CLL.

  • 24.
    Glimelius, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Edström, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Fischer, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Amini, Rose-Marie
    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, Oncology.
    Angiogenesis and mast cells in Hodgkin lymphoma2005In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 19, no 12, p. 2360-2362Article in journal (Refereed)
  • 25.
    Gounari, Maria
    et al.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece;IRCCS Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Ntoufa, Stavroula
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Gerousi, Marina
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Vilia, Maria Giovanna
    IRCCS Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Moysiadis, Theodoros
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Kotta, Konstantia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Papakonstantinou, Nikos
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Scarfo, Lydia
    IRCCS Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Agathangelidis, Andreas
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Fonte, Eleonora
    IRCCS Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Ranghetti, Pamela
    IRCCS Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Nenou, Athanasia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Xochelli, Aliki
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Coscia, Marta
    Univ Torino, Div Ematol, Azienda Osped Univ S Giovanni Battista Torino, Turin, Italy.
    Tedeschi, Alessandra
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Oncol Haematol, Milan, Italy.
    Stavroyianni, Niki
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
    Muzio, Marta
    IRCCS Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Ghia, Paolo
    IRCCS Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Dichotomous Toll-like receptor responses in chronic lymphocytic leukemia patients under ibrutinib treatment2019In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 4, p. 1030-1034Article in journal (Refereed)
  • 26.
    Gunnarsson, N.
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, L.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Sandin, F.
    Reg Canc Ctr, Uppsala, Sweden..
    Bjorkholm, M.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Dreimane, A.
    Univ Hosp, Dept Hematol, Linkoping, Sweden..
    Lambe, M.
    Reg Canc Ctr, Uppsala, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Markevarn, B.
    Univ Hosp, Dept Hematol, Umea, Sweden..
    Olsson-Stromberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Hosp, Dept Med Sci, Uppsala, Sweden.;Univ Hosp, Div Hematol, Uppsala, Sweden..
    Wadenvik, H.
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden..
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Sjalander, A.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    No increased prevalence of malignancies among first-degree relatives of 800 patients with chronic myeloid leukemia: a population-based study in Sweden2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 8, p. 1825-1827Article in journal (Other academic)
  • 27.
    Gunnarsson, N.
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, L.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Wallberg-Jonsson, S.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Sandin, F.
    Reg Canc Ctr, Uppsala, Sweden..
    Björkholm, M.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Dreimane, A.
    Linkoping Univ Hosp, Dept Hematol, Linkoping, Sweden..
    Lambe, M.
    Reg Canc Ctr, Uppsala, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Markevarn, B.
    Univ Umea Hosp, Dept Hematol, Umea, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wadenvik, H.
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden..
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Själander, A.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Increased prevalence of prior malignancies and autoimmune diseases in patients diagnosed with chronic myeloid leukemia2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 7, p. 1562-1567Article in journal (Refereed)
    Abstract [en]

    We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune disease (AD) and chronic inflammatory disease (CID) in CML patients prior to their CML diagnosis. Nationwide population-based registers were used to identify patients diagnosed with CML in Sweden 2002-2012 and to estimate the prevalence of other malignancies, AD and CID prior to their CML diagnosis. For each patient with CML, five matched controls were selected from the general population. Conditional logistic regression was used to calculate odds ratios (OR). Nine hundred and eighty-four CML patients were assessed, representing more than 45 000 person-years of follow-up. Compared with matched controls, the prevalence of prior malignancies and AD was elevated in CML patients: OR 1.47 (95% confidence interval (CI) 1.20-1.82) and 1.55 (95% CI 1.21-1.98), respectively. No associations were detected between CML and previous CID. An increased prevalence of other malignancies and AD prior to the diagnosis of CML suggest that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.

  • 28. Gunnarsson, R.
    et al.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mansouri, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Göransson, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jansson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rasmussen, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Staaf, J.
    Lundin, J.
    Norin, S.
    Buhl, A. M.
    Smedby, K. E.
    Hjalgrim, H.
    Karlsson, K.
    Jurlander, J.
    Juliusson, G.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Large but not small copy-number alterations correlate to high-risk genomic aberrations and survival in chronic lymphocytic leukemia: a high-resolution genomic screening of newly diagnosed patients2010In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 24, no 1, p. 211-215Article in journal (Refereed)
  • 29.
    Gunnarsson, Rebeqa
    et al.
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    DiLorenzo, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundin-Ström, Kristina B.
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    Olsson, Linda
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden;Dept Clin Genet & Pathol, Div Lab Med, Lund, Sweden.
    Biloglav, Andrea
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    Lilljebjörn, Henrik
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    Rissler, Marianne
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    Wahlberg, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Castor, Anders
    Skane Univ Hosp, Dept Pediat, Lund, Sweden.
    Behrendtz, Mikael
    Linkoping Univ Hosp, Dept Pediat, Linkoping, Sweden.
    Fioretos, Thoas
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden;Dept Clin Genet & Pathol, Div Lab Med, Lund, Sweden.
    Paulsson, Kajsa
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Bertil
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden;Dept Clin Genet & Pathol, Div Lab Med, Lund, Sweden.
    Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 10, p. 2117-2125Article in journal (Refereed)
    Abstract [en]

    High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of these encode nucleic acid/protein binding factors or proteins with catalytic activity. We conclude that the pathogenetically important consequence of dup(1q) in BCP ALL is a gene-dosage effect, with the deregulated genes differing between genetic subtypes, but involving similar molecular functions, biological processes, and protein classes.

  • 30.
    Halldórsdóttir, Anna Margret
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Lundin, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Murray, Fiona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Knuutila, S
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ehrencrona, H
    Sander, B
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Impact of TP53 mutation and 17p deletion in mantle cell lymphoma2011In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551Article in journal (Refereed)
  • 31. Hedenus, M.
    et al.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Näsman, P.
    Ahlberg, L.
    Karlsson, T.
    Lauri, B.
    Lundin, J.
    Lärfars, G.
    Österborg, A.
    Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study2007In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 21, no 4, p. 627-632Article in journal (Refereed)
    Abstract [en]

    This randomized study assessed if intravenous iron improves hemoglobin (Hb) response and permits decreased epoetin dose in anemic (Hb 9-11 g/dl), transfusion-independent patients with stainable iron in the bone marrow and lymphoproliferative malignancies not receiving chemotherapy. Patients (n=67) were randomized to subcutaneous epoetin beta 30 000 IU once weekly for 16 weeks with or without concomitant intravenous iron supplementation. There was a significantly (P<0.05) greater increase in mean Hb from week 8 onwards in the iron group and the percentage of patients with Hb increase >or=2 g/dl was significantly higher in the iron group (93%) than in the no-iron group (53%) (per-protocol population; P=0.001). Higher serum ferritin and transferrin saturation in the iron group indicated that iron availability accounted for the Hb response difference. The mean weekly patient epoetin dose was significantly lower after 13 weeks of therapy (P=0.029) and after 15 weeks approximately 10 000 IU (>25%) lower in the iron group, as was the total epoetin dose (P=0.051). In conclusion, the Hb increase and response rate were significantly greater with the addition of intravenous iron to epoetin treatment in iron-replete patients and a lower dose of epoetin was required.

  • 32.
    Hjorth-Hansen, H.
    et al.
    St Olavs Hosp, Dept Hematol, PB 8250 Sluppen, NO-7006 Trondheim, Norway.;Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway..
    Stentoft, J.
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Koskenvesa, P.
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dreimane, A.
    Linkoping Univ, Dept Med & Hlth Sci, Dept Hematol, Cty Council Ostergotland, Linkoping, Sweden..
    Porkka, K.
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Sweden..
    Gedde-Dahl, T.
    Oslo Univ Hosp, Rikshosp, Dept Hematol, Oslo, Norway..
    Gjertsen, B. T.
    Haukeland Hosp, Hematol Sect, Dept Internal Med, Bergen, Norway.;Univ Bergen, Dept Clin Sci, Bergen, Norway..
    Gruber, F. X.
    Univ Hosp North Norway, Dept Hematol, Tromso, Norway..
    Stenke, L.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Eriksson, K. M.
    Sunderbysjukhuset, Dept Internal Med, Lulea, Sweden..
    Markevarn, B.
    Umea Univ Hosp, Dept Hematol, Umea, Sweden..
    Lubking, A.
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Sweden..
    Vestergaard, H.
    Odense Univ Hosp, Dept Hematol, Odense, Denmark..
    Udby, L.
    Roskilde Hosp, Dept Hematol, Roskilde, Denmark..
    Bjerrum, O. W.
    Univ Copenhagen Hosp, Dept Hematol, Rigshosp, Copenhagen, Denmark..
    Persson, Inger
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Mustjoki, S.
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Sweden.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Safety and efficacy of the combination of pegylated interferon-alpha 2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 9, p. 1853-1860Article in journal (Refereed)
    Abstract [en]

    Dasatinib (DAS) and interferon-a have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-alpha 2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 mu g/week and it increased to 25 mu g/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR4 was achieved by 46% and MR4.5 by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS +/- PegIFN is warranted.

  • 33. Hoffmann, V S
    et al.
    Baccarani, M
    Hasford, J
    Castagnetti, F
    Di Raimondo, F
    Casado, L F
    Turkina, A
    Zackova, D
    Ossenkoppele, G
    Zaritskey, A
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Indrak, K
    Sninska, Z
    Sacha, T
    Clark, R
    Bogdanovic, A
    Hellmann, A
    Griskevicius, L
    Schubert-Fritschle, G
    Sertic, D
    Guilhot, J
    Lejniece, S
    Zupan, I
    Burgstaller, S
    Koskenvesa, P
    Everaus, H
    Costeas, P
    Lindoerfer, D
    Rosti, G
    Saussele, S
    Hochhaus, A
    Hehlmann, R
    Treatment and outcome of 2904 CML patients from the EUTOS population-based registry2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 3, p. 593-601Article in journal (Refereed)
    Abstract [en]

    The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.Leukemia advance online publication, 23 September 2016; doi:10.1038/leu.2016.246.

  • 34. Hoffmann, V. S.
    et al.
    Baccarani, M.
    Hasford, J.
    Lindoerfer, D.
    Burgstaller, S.
    Sertic, D.
    Costeas, P.
    Mayer, J.
    Indrak, K.
    Everaus, H.
    Koskenvesa, P.
    Guilhot, J.
    Schubert-Fritschle, G.
    Castagnetti, F.
    Di Raimondo, F.
    Lejniece, S.
    Griskevicius, L.
    Thielen, N.
    Sacha, T.
    Hellmann, A.
    Turkina, A. G.
    Zaritskey, A.
    Bogdanovic, A.
    Sninska, Z.
    Zupan, I.
    Steegmann, J-L
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Clark, R. E.
    Covelli, A.
    Guidi, G.
    Hehlmann, R.
    The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 6, p. 1336-1343Article in journal (Refereed)
    Abstract [en]

    This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100 000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.

  • 35.
    Hoster, E.
    et al.
    Univ Hosp Munich, Dept Internal Med 3, Munich, Germany.;Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany..
    Geisler, C. H.
    Rigshosp, Hematol Dept, DK-2100 Copenhagen, Denmark..
    Doorduijn, J.
    Erasmus MC Canc Inst, Dept Hematol, Rotterdam, Netherlands..
    van der Holt, B.
    Erasmus MC Canc Inst, Clin Trial Ctr, HOVON Data Ctr, Rotterdam, Netherlands..
    Walewski, J.
    Maria Sklodowska Curie Mem Inst & Oncol Ctr, Dept Lymphoid Malignancies, Warsaw, Poland..
    Bloehdorn, J.
    Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany..
    Ribrag, V.
    Inst Gustave Roussy, Villejuif, France..
    Salles, G.
    Univ Lyon 1, Hosp Civils Lyon, Pierre Benite, France..
    Hallek, M.
    Univ Cologne, Dept Internal Med 1, D-50931 Cologne, Germany..
    Pott, C.
    Univ Hosp Schleswig Holstein, Med Dept 2, Campus Kiel, Kiel, Germany..
    Szymczyk, M.
    Maria Sklodowska Curie Mem Inst & Oncol Ctr, Dept Lymphoid Malignancies, Warsaw, Poland..
    Kolstad, A.
    Norwegian Radium Hosp, Oncol Dept, Oslo, Norway..
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Raty, R.
    Univ Helsinki, Cent Hosp, Dept Hematol, Helsinki, Finland..
    Jerkeman, M.
    Skane Univ Hosp, Dept Oncol, Lund, Sweden..
    van't Veer, M.
    Erasmus MC Canc Inst, Dept Hematol, Rotterdam, Netherlands..
    Kluin-Nelemans, J. C.
    Univ Groningen, Univ Med Ctr Groningen, Dept Hematol, Groningen, Netherlands..
    Klapper, W.
    Univ Kiel, Dept Pathol, Hematopathol Sect, Kiel, Germany.;Univ Kiel, Lymph Node Registry, Kiel, Germany..
    Unterhalt, M.
    Univ Hosp Munich, Dept Internal Med 3, Munich, Germany..
    Dreyling, M.
    Univ Hosp Munich, Dept Internal Med 3, Munich, Germany..
    Hermine, O.
    Univ Paris 05, Hop Necker, AP HP, Dept Hematol, Paris, France.;Univ Sorbonne Paris Cite, INSERM U1163, Paris, France.;Univ Sorbonne Paris Cite, CNRS 8254, Imagine Inst, Paris, France..
    Total body irradiation after high-dose cytarabine in mantle cell lymphoma: a comparison of Nordic MCL2, HOVON-45, and European MCL Younger trials2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 6, p. 1428-1430Article in journal (Refereed)
  • 36. Ibbotson, R.
    et al.
    Athanasiadou, A.
    Sutton, Lesley Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Davis, Z.
    Gardiner, A.
    Baliakas, P.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Anagnostopoulos, A.
    Juliusson, G.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Oscier, D.
    Stamatopoulos, K.
    Coexistence of trisomies of chromosomes 12 and 19 in chronic lymphocytic leukemia occurs exclusively in the rare IgG-positive variant2012In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 1, p. 170-172Article in journal (Refereed)
  • 37. Ilander, M
    et al.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Schlums, H
    Guilhot, J
    Brück, O
    Lähteenmäki, H
    Kasanen, T
    Koskenvesa, P
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Markevärn, B
    Själander, A
    Lotfi, K
    Dreimane, A
    Lübking, A
    Holm, E
    Björeman, M
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden.
    Stenke, L
    Ohm, L
    Gedde-Dahl, T
    Majeed, W
    Ehrencrona, H
    Koskela, S
    Saussele, S
    Mahon, F-X
    Porkka, K
    Hjorth-Hansen, H
    Bryceson, Y T
    Richter, J
    Mustjoki, S
    Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia.2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 5, p. 1108-1116Article in journal (Refereed)
    Abstract [en]

    Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.Leukemia advance online publication, 16 December 2016; doi:10.1038/leu.2016.360.

  • 38.
    Juliusson, Gunnar
    et al.
    Skane Univ Hosp, Dept Hematol & Oncol, Lund, Sweden; Lund Univ, Dept Lab Med, Lund, Sweden.
    Abrahamsson, J
    Lazarevic, V
    Antunovic, P
    Derolf, Å
    Garelius, H
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Myhr-Eriksson, K
    Möllgård, L
    Uggla, B
    Wahlin, A
    Wennström, L
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Prevalence and characteristics of survivors from acute myeloid leukemia in Sweden2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 3, p. 728-731Article in journal (Refereed)
  • 39. Juliusson, Gunnar
    et al.
    Billström, R.
    Gruber, A.
    Hellström-Lindberg, E.
    Höglund, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, K.
    Stockelberg, D.
    Wahlin, A.
    Åström, M.
    Arnesson, C.
    Brunell-Abrahamsson, U.
    Carstensen, J.
    Fredriksson, E.
    Holmberg, E.
    Nordenskjöld, K.
    Wiklund, F.
    Attitude towards remission induction for elderly patients with acute myeloid leukemia influences survival2006In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 20, no 1, p. 42-47Article in journal (Refereed)
    Abstract [en]

    Combination chemotherapy may induce remission from acute myeloid leukemia (AML), but validated criteria for treatment of elderly are lacking. The remission intention (RI) rate for elderly patients, as reported to the Swedish Leukemia Registry, was known to be different when comparing the six health care regions, but the consequences of different management are unknown. The Leukemia Registry, containing 1672 AML patients diagnosed between 1997 and 2001, with 98% coverage and a median follow-up of 4 years, was completed with data from the compulsory cancer and population registries. Among 506 treated and untreated patients aged 70-79 years with AML (non-APL), there was a direct correlation between the RI rate in each health region (range 36-76%) and the two-year overall survival, with no censored observations (6-21%) (chi-squared for trend=11.3, P<0.001; r2=0.86, P<0.02, nonparametric). A 1-month landmark analysis showed significantly better survival in regions with higher RI rates (P=0.003). Differences could not be explained by demographics, and was found in both de novo and secondary leukemias. The 5-year survival of the overall population aged 70-79 years was similar between the regions. Survival of 70-79-year-old AML patients is better in regions where more elderly patients are judged eligible for remission induction.

  • 40. Junlen, H. R.
    et al.
    Peterson, S.
    Kimby, E.
    Lockmer, S.
    Linden, O.
    Nilsson-Ehle, H.
    Erlanson, M.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Radlund, A.
    Hagberg, O.
    Wahlin, B. E.
    Follicular lymphoma in Sweden: nationwide improved survival in the rituximab era, particularly in elderly women: a Swedish Lymphoma Registry Study2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 3, p. 668-676Article in journal (Refereed)
    Abstract [en]

    Treatment for follicular lymphoma (FL) improved with rituximab. In Sweden, first-line rituximab was gradually introduced between 2003 and 2007, with regional differences. The first national guidelines for FL were published in November 2007, recommending rituximab in first-line therapy. Using the population-based Swedish Lymphoma Registry, 2641 patients diagnosed with FL from 2000 to 2010 were identified and characterized by year and region of diagnosis, age (median, 65 years), gender (50% men), first-line therapy and clinical risk factors. Overall and relative survivals were estimated by calendar periods (2000-2002, 2003-2007 and 2008-2010) and region of diagnosis. With each period, first-line rituximab use and survival increased. Survival was superior in regions where rituximab was quickly adopted and inferior where slowly adopted. These differences were independent in multivariable analyses. Ten-year relative survival for patients diagnosed 2003-2010 was 92%, 83%, 78% and 64% in the age groups 18-49, 50-59, 60-69 and. 70, respectively. With increasing rituximab use, male sex emerged as an adverse factor. Survival improved in all patient categories, particularly in elderly women. The introduction and the establishment of rituximab have led to a nationwide improvement in FL survival. However, rituximab might be inadequately dosed in younger women and men of all ages.

  • 41.
    Kaderi, Mohd Arifin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Norberg, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Murray, Fiona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Merup, M.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Roos, G.
    Åleskog, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Karlsson, K.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tobin, G.
    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.
    The BCL-2 promoter (-938C>A) polymorphism does not predict clinical outcome in chronic lymphocytic leukemia2008In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 22, no 2, p. 339-343Article in journal (Refereed)
    Abstract [en]

    The (-938C>A) polymorphism in the promoter region of the BCL-2 gene was recently associated with inferior time to treatment and overall survival in B-cell chronic lymphocytic leukemia (CLL) patients displaying the -938A/A genotype and may thus serve as an unfavorable genetic marker in CLL. Furthermore, the -938A/A genotype was associated with increased expression of Bcl-2. To investigate this further, we analyzed the -938 genotypes of the BCL-2 gene in 268 CLL patients and correlated data with treatment status, overall survival and known prognostic factors, for example, Binet stage, immunoglobulin heavy-chain variable (IGHV) mutational status and CD38 expression. In contrast to the recent report, the current cohort of CLL patients showed no differences either in time to treatment or overall survival in relation to usage of a particular genotype. In addition, no correlation was evident between the (-938C>A) genotypes and IGHV mutational status, Binet stage or CD38. Furthermore, the polymorphism did not appear to affect the Bcl-2 expression at the RNA level. Taken together, our data do not support the use of the (-938C>A) BCL-2 polymorphism as a prognostic marker in CLL and argue against its postulated role in modulating Bcl-2 levels.

  • 42. Kontro, M
    et al.
    Kumar, A
    Majumder, M M
    Eldfors, S
    Parsons, A
    Pemovska, T
    Saarela, J
    Yadav, B
    Malani, D
    Fløisand, Y
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Remes, K
    Gjertsen, B T
    Kallioniemi, O
    Wennerberg, K
    Heckman, C A
    Porkka, K
    HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 2, p. 301-309Article in journal (Refereed)
    Abstract [en]

    Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to β2-microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.Leukemia advance online publication, 2 September 2016; doi:10.1038/leu.2016.222.

  • 43. Kostareli, E
    et al.
    Gounari, M
    Janus, A
    Murray, Fiona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Brochet, X
    Giudicelli, V
    Pospisilova, S
    Oscier, D
    Foroni, L
    di Celle, P F
    Tichy, B
    Pedersen, L B
    Jurlander, J
    Ponzoni, M
    Kouvatsi, A
    Anagnostopoulos, A
    Thompson, K
    Darzentas, N
    Lefranc, M-P
    Belessi, C
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Davi, F
    Ghia, P
    Stamatopoulos, K
    Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity2012In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 5, p. 1127-1131Article in journal (Refereed)
  • 44. Kostareli, E.
    et al.
    Sutton, Lesley Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hadzidimitriou, A.
    Darzentas, N.
    Kouvatsi, A.
    Tsaftaris, A.
    Anagnostopoulos, A.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stamatopoulos, K.
    Intraclonal diversification of immunoglobulin light chains in a subset of chronic lymphocytic leukemia alludes to antigen-driven clonal evolution2010In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 24, no 7, p. 1317-1324Article in journal (Refereed)
    Abstract [en]

    The study of intraclonal diversification (ID) in immunoglobulin (IG) genes offers valuable insight into the role of ongoing interactions with antigen in lymphomagenesis. We recently showed that ID in the IG heavy chain genes of patients with chronic lymphocytic leukemia (CLL) was generally limited; however, intense ID was evident in selected cases, especially those expressing stereotyped IGHV4-34 rearrangements and assigned to subset 4. Here, we report results from a large-scale subcloning study of IG light variable genes, in a total of 1008 subcloned sequences from 56 CLL cases. Multiple analogies were noted between heavy and light chains regarding the occurrence and molecular features of ID. More specifically, the impact of ID on the clonotypic light chains was generally low, with the significant exception of subset 4. Similar to the IGHV4-34 heavy chains of this subset, their partner IGKV2-30 light chains were affected by an active and precisely targeted ID process. Altogether, these findings strengthen the argument that stereotypy in subset 4 extends to stereotyped ID patterns for both heavy and light chains through persistent antigenic stimulation. Furthermore, they strongly suggest that light chains have an active role in the antigen selection process, at least for certain subsets of CLL cases.

  • 45. Langerak, A. W.
    et al.
    Davi, F.
    Ghia, P.
    Hadzidimitriou, A.
    Murray, Fiona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Potter, K. N.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stamatopoulos, K.
    Belessi, C.
    Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases2011In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 25, no 6, p. 979-984Article in journal (Refereed)
    Abstract [en]

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

  • 46. Langerak, A. W.
    et al.
    Groenen, P. J. T. A.
    Brueggemann, M.
    Beldjord, K.
    Bellan, C.
    Bonello, L.
    Boone, E.
    Carter, G. I.
    Catherwood, M.
    Davi, F.
    Delfau-Larue, M-H
    Diss, T.
    Evans, P. A. S.
    Gameiro, P.
    Garcia Sanz, R.
    Gonzalez, D.
    Grand, D.
    Håkansson, Å.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hummel, M.
    Liu, H.
    Lombardia, L.
    Macintyre, E. A.
    Milner, B. J.
    Montes-Moreno, S.
    Schuuring, E.
    Spaargaren, M.
    Hodges, E.
    van Dongen, J. J. M.
    EuroClonality/BIOMED-2 guidelines for interpretation and reporting of Ig/TCR clonality testing in suspected lymphoproliferations2012In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 10, p. 2159-2171Article, review/survey (Refereed)
    Abstract [en]

    PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.

  • 47.
    Larsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Venables, P.
    Andersson, A-C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fan, W.
    Rigby, S.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Cohen, M.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Tissue and differentiation specific expression of the endogenous retrovirus ERV3 (HERV-R) in normal human tissues and during induced monocytic differentiation in the U-937 cell line1997In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 11, no Suppl. 3, p. 142-4Article in journal (Refereed)
    Abstract [en]

    ERV3 (HERV-R) is a complete, single copy human endogenous retrovirus located on the long arm of chromosome 7. The open reading frame in its envelope gene has been conserved during evolution but the gag and pol genes contain in-frame termination codons. To find a suitable experimental model system for analysis of the functions of the ERV3 genome, an extensive screening study of different normal and neoplastic human tissues was performed. Most tissues express low levels of the ERV3 env mRNA although high expression levels are observed in placenta, sebaceous glands, adrenals, testis, bronchial, epithelium and the monocytic cell line U-937. In U-937 cells the ERV3 env expression varied in a manner related to the differentiation status of the cells; being highest in the terminally differentiated non proliferating cells. U-937 cells can be induced to differentiate from the monoblastic to the mature monocyte/macrophage stage upon stimulation by several substances such as phorbolesters (TPA), Vitamin D3, Retinoic Acid (RA) and combinations of some cytokines. We conclude that the ERV3 locus is expressed in a tissue and differentiation specific way and that the U-937 cell line is a suitable model system to further analyze the proposed functions of ERVs such as immunomodulation, cell fusion and protection against exogenous retroviral infections.

  • 48. Le Blanc, K.
    et al.
    Samuelsson, H.
    Gustafsson, B.
    Remberger, M.
    Sundberg, B.
    Arvidson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ljungman, P.
    Lönnies, H.
    Nava, S.
    Ringdén, O.
    Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells2007In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 21, no 8, p. 1733-1738Article in journal (Refereed)
    Abstract [en]

    Seven patients underwent treatment with mesenchymal stem cells (MSCs), together with allogeneic hematopoietic stem cell transplantation (HSCT). MSCs were given to three patients for graft failure and four patients were included in a pilot study. HSCT donors were three human leukocyte antigen (HLA)-identical siblings, three unrelated donors and one cord blood unit. The conditioning was myeloablative in four patients and reduced in three patients. MSC donors were HLA-identical siblings in three cases and haploidentical in four cases. Neutrophil counts >0.5 ×109/l was reached at a median of 12 (range 10-28) days. Platelet counts >30 x 109/l was achieved at a median of 12 (8-36) days. Acute graft-versus-host disease (GVHD) grade 0-l was seen in five patients. Two patients developed grade II, which in one patient evolved into chronic GVHD. One severe combined immunodeficiency (SCID) patient died of aspergillosis, the others are alive and well. One patient, diagnosed with aplastic anemia had graft failure after her first transplantation and severe Henoch-Schönlein Purpura (HSP). After retransplantation of MSCs and HSCs, she recovered from both the HSP and aplasia. Thus, co-transplantation of MSC resulted in fast engraftment of absolute neutrophil count (ANC) and platelets and 100% donor chimerism, even in three patients regrafted for graft failure/rejection.

  • 49. Lehmann, S
    et al.
    Ravn, A
    Carlsson, L
    Antunovic, P
    Deneberg, S
    Möllgård, L
    Derolf, A Rangert
    Stockelberg, D
    Tidefelt, U
    Wahlin, A
    Wennström, L
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Juliusson, G
    Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry2011In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 25, no 7, p. 1128-1134Article in journal (Refereed)
    Abstract [en]

    Our knowledge about acute promyelocytic leukemia (APL) patients is mainly based on data from clinical trials, whereas population-based information is scarce. We studied APL patients diagnosed between 1997 and 2006 in the population-based Swedish Adult Acute Leukemia Registry. Of a total of 3897 acute leukemia cases, 3205 (82%) had non-APL acute myeloid leukemia (AML) and 105 (2.7%) had APL. The incidence of APL was 0.145 per 100,000 inhabitants per year. The median age at the time of diagnosis was 54 years; 62% were female and 38% male. Among younger APL patients, female sex predominated (89% of patients <40 years). Of the 105 APL patients, 30 (29%) died within 30 days (that is, early death (ED)) (median 4 days) and 28 (26%) within 14 days from diagnosis. In all, 41% of the EDs were due to hemorrhage; 35% of ED patients never received all-trans-retinoic acid treatment. ED rates increased with age but more clearly with poor performance status. ED was also associated with high white blood cells, lactate dehydrogenase, creatinine, C-reactive protein and low platelet count. Of non-ED patients, 97% achieved complete remission of which 16% subsequently relapsed. In total, 62% are still alive at 6.4 years median follow-up. We conclude that ED rates remain very high in an unselected APL population.

  • 50.
    Lehmann, Sören
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Institute .
    Deneberg, S.
    Karolinska Institute.
    Antunovic, P.
    Linköping Univ Hosp.
    Rangert-Derolf, A.
    Karolinska Univ Hosp.
    Garelius, H.
    Sahlgrens Univ Hosp.
    Lazarevic, V.
    Skåne Univ Hosp.
    Myhr-Eriksson, K.
    Örebro Univ Hosp.
    Möllgård, L.
    Sahlgrens Univ Hosp.
    Uggla, B.
    Örebro Univ Hosp.
    Wahlin, A.
    Örebro Univ Hosp.
    Wennstrom, L.
    Sahlgrens Univ Hosp.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Juliusson, G.
    Skåne Univ Hosp.
    Early death rates remain high in high-risk APL: update from the Swedish Acute Leukemia Registry 1997-20132017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 6, p. 1457-1459Article in journal (Refereed)
12 1 - 50 of 87
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