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  • 1.
    Andersson, A.
    et al.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Ritz, C.
    Department of Complex System Division, Theoretical Physics, Lund University, Lund, Sweden.
    Lindgren, D.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Eden, P.
    Edén, P., Department of Complex System Division, Theoretical Physics, Lund University, Lund, Sweden.
    Lassen, C.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Heldrup, J.
    Department of Pediatrics, Lund University Hospital, Lund, Sweden.
    Olofsson, T.
    Department of Hematology, Lund University Hospital, Lund, Sweden.
    Rade, J.
    Råde, J., Center for Mathematical Sciences, Lund University, Lund, Sweden.
    Fontes, M.
    Center for Mathematical Sciences, Lund University, Lund, Sweden.
    Porwit-MacDonald, A.
    Department of Pathology, Karolinska Hospital and Institute, Stockholm, Sweden.
    Behrendtz, Mikael
    Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Hoglund, M.
    Höglund, M., Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Johansson, B.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Fioretos, T.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Microarray-based classification of a consecutive series of 121 childhood acute leukemias: Prediction of leukemic and genetic subtype as well as of minimal residual disease status2007In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 21, no 6, p. 1198-1203Article in journal (Refereed)
    Abstract [en]

    Gene expression analyses were performed on 121 consecutive childhood leukemias (87 B-lineage acute lymphoblastic leukemias (ALLs), 11 T-cell ALLs and 23 acute myeloid leukemias (AMLs)), investigated during an 8-year period at a single center. The supervised learning algorithm k-nearest neighbor was utilized to build gene expression predictors that could classify the ALLs/AMLs according to clinically important subtypes with high accuracy. Validation experiments in an independent data set verified the high prediction accuracies of our classifiers. B-lineage ALLs with uncharacteristic cytogenetic aberrations or with a normal karyotype displayed heterogeneous gene expression profiles, resulting in low prediction accuracies. Minimal residual disease status (MRD) in T-cell ALLs with a high (>0.1) MRD at day 29 could be classified with 100% accuracy already at the time of diagnosis. In pediatric leukemias with uncharacteristic cytogenetic aberrations or with a normal karyotype, unsupervised analysis identified two novel subgroups: one consisting mainly of cases remaining in complete remission (CR) and one containing a few patients in CR and all but one of the patients who relapsed. This study of a consecutive series of childhood leukemias confirms and extends further previous reports demonstrating that global gene expression profiling provides a valuable tool for genetic and clinical classification of childhood leukemias.

  • 2.
    Baron, F
    et al.
    University of Liege, Belgium .
    Labopin, M
    Hop St Antoine, France .
    Niederwieser, D
    University of Leipzig, Germany .
    Vigouroux, S
    University Hospital, France University of Bordeaux 2, France .
    Cornelissen, J J.
    Erasmus University, Netherlands .
    Malm, Claes
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology UHL.
    Vindelov, L L.
    Rigshosp, Denmark .
    Blaise, D
    CHU Marseille, France .
    Janssen, J J W M
    Vrije University of Amsterdam, Netherlands .
    Petersen, E
    University of Medical Centre Utrecht, Netherlands .
    Socie, G
    Hop St Louis, France .
    Nagler, A
    Tel Aviv University, Israel .
    Rocha, V
    Eurocord, France EBMT ALWP, France .
    Mohty, M
    Hop St Antoine, France EBMT ALWP, France University of Nantes, France INSERM, France .
    Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation2012In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 12, p. 2462-2468Article in journal (Refereed)
    Abstract [en]

    This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of relapse (hazards ratio (HR) 0.7, P = 0.02) translating into a trend for better overall survival (OS; HR 1.3; P = 0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR 0.4, P andlt; 0.0.001) owing to high risk of nonrelapse mortality (NRM; HR 5.2, P andlt; 0.0001). In time-dependent multivariate Cox analyses, limited chronic GVHD tended to be associated with a lower risk of relapse (HR 0.72; P = 0.07) translating into a better OS (HR 1.8; P andlt; 0.001), while extensive chronic GVHD was associated with a lower risk of relapse (HR 0.65; P = 0.02) but also with higher NRM (HR 3.5; P andlt; 0.001) and thus had no net impact on OS. In-vivo T-cell depletion with antithymocyte globulin (ATG) or alemtuzumab was successful at preventing extensive chronic GVHD (P andlt; 0.001), but without improving OS for ATG and even with worsening OS for alemtuzumab (HR 0.65; P = 0.001). These results highlight the role of the immune-mediated graft-versus-leukemia effect in the RIC allo-SCT setting, but also the need for improving the prevention and treatment of severe GVHD. Leukemia (2012) 26, 2462-2468; doi: 10.1038/leu.2012.135

  • 3.
    Cahill, N
    et al.
    Uppsala University, Sweden.
    Bergh, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Kanduri, M
    Uppsala University, Sweden.
    Göransson-Kultima, H
    Uppsala University, Sweden.
    Mansouri, L
    Uppsala University, Sweden.
    Isaksson, A
    Sahlgrenska University Hospital, Sweden.
    Ryan, F
    Institute of Technology, Dublin, Ireland.
    Smedby, K E
    Karolinska Institutet, Stockholm, Sweden.
    Juliusson, G
    Institute of Technology, Dublin, Ireland.
    Sundström, C
    Uppsala University, Sweden.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Rosenquist, R
    Uppsala University, Sweden.
    450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments2013In: 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, analysing 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 (e.g. CLLU1, LPL, ZAP70, NOTCH1), epigenetic regulator (e.g. HDAC9, HDAC4, DNMT3B), B-cell signaling (e.g. IBTK) and numerous TGF-ß 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.Leukemia accepted article preview online, 27 August 2012; doi:10.1038/leu.2012.245.

  • 4.
    Carstensen, John
    et al.
    Linköping University, Faculty of Arts and Sciences. Linköping University, Department of Department of Health and Society, Tema Health and Society.
    Billström, R
    Universitetssjukhuset i Lund.
    Gruber, A
    Karolinska universitetssjukhuset.
    Hellström-Lindberg, E
    Karolinska universitetssjukhuset.
    Höglund, M
    Akademiska sjukhuset i Uppsala.
    Karlsson, Karin
    Hematologi Lunds universitet.
    Stockelberg, D
    Sahlgrenska universitetssjukhuset.
    Wahlin, A
    Norrlands universitetssjukhus.
    Åström, M
    Universitetssjukhuset i Örebro.
    Arnesson, C
    Universitetssjukhuset i Lund.
    Brunell-Abrahamsson, U
    Akademiska sjukhuset i Uppsala.
    Fredriksson, E
    Karolinska universitetssjukhuset.
    Holmberg, E
    Sahlgrenska universitetssjukhuset.
    Wiklund, F
    Norrlands universitetssjukhus.
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Nordenskjöld, Kerstin
    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%) (χ2 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. © 2006 Nature Publishing Group All rights reserved.

  • 5.
    Davidsson, Josef
    et al.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Puschmann, Andreas
    Lund Univ, Sweden.
    Tedgard, Ulf
    Skane Univ Hosp, Sweden.
    Bryder, David
    Lund Univ, Sweden.
    Nilsson, Lars
    Skane Univ Hosp, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 5, p. 1106-1115Article, review/survey (Refereed)
    Abstract [en]

    Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9Ls normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutations effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers.

  • 6.
    Frost, BM
    et al.
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden Karolinska Hosp, Karolinska Pharm, S-10401 Stockholm, Sweden Karolinska Hosp, Dept Pediat Oncol, S-10401 Stockholm, Sweden Queen Silvias Child & Adolescent Hosp, Gothenburg, Sweden Linkoping Univ Hosp, Dept Pediat, S-58185 Linkoping, Sweden Univ Lund Hosp, Dept Paediat, S-22185 Lund, Sweden Univ Umea Hosp, Dept Pediat, S-90185 Umea, Sweden.
    Eksborg, S
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden Karolinska Hosp, Karolinska Pharm, S-10401 Stockholm, Sweden Karolinska Hosp, Dept Pediat Oncol, S-10401 Stockholm, Sweden Queen Silvias Child & Adolescent Hosp, Gothenburg, Sweden Linkoping Univ Hosp, Dept Pediat, S-58185 Linkoping, Sweden Univ Lund Hosp, Dept Paediat, S-22185 Lund, Sweden Univ Umea Hosp, Dept Pediat, S-90185 Umea, Sweden.
    Bjork, O
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden Karolinska Hosp, Karolinska Pharm, S-10401 Stockholm, Sweden Karolinska Hosp, Dept Pediat Oncol, S-10401 Stockholm, Sweden Queen Silvias Child & Adolescent Hosp, Gothenburg, Sweden Linkoping Univ Hosp, Dept Pediat, S-58185 Linkoping, Sweden Univ Lund Hosp, Dept Paediat, S-22185 Lund, Sweden Univ Umea Hosp, Dept Pediat, S-90185 Umea, Sweden.
    Abrahamsson, J
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden Karolinska Hosp, Karolinska Pharm, S-10401 Stockholm, Sweden Karolinska Hosp, Dept Pediat Oncol, S-10401 Stockholm, Sweden Queen Silvias Child & Adolescent Hosp, Gothenburg, Sweden Linkoping Univ Hosp, Dept Pediat, S-58185 Linkoping, Sweden Univ Lund Hosp, Dept Paediat, S-22185 Lund, Sweden Univ Umea Hosp, Dept Pediat, S-90185 Umea, Sweden.
    Behrendtz, M
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden Karolinska Hosp, Karolinska Pharm, S-10401 Stockholm, Sweden Karolinska Hosp, Dept Pediat Oncol, S-10401 Stockholm, Sweden Queen Silvias Child & Adolescent Hosp, Gothenburg, Sweden Linkoping Univ Hosp, Dept Pediat, S-58185 Linkoping, Sweden Univ Lund Hosp, Dept Paediat, S-22185 Lund, Sweden Univ Umea Hosp, Dept Pediat, S-90185 Umea, Sweden.
    Castor, A
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden Karolinska Hosp, Karolinska Pharm, S-10401 Stockholm, Sweden Karolinska Hosp, Dept Pediat Oncol, S-10401 Stockholm, Sweden Queen Silvias Child & Adolescent Hosp, Gothenburg, Sweden Linkoping Univ Hosp, Dept Pediat, S-58185 Linkoping, Sweden Univ Lund Hosp, Dept Paediat, S-22185 Lund, Sweden Univ Umea Hosp, Dept Pediat, S-90185 Umea, Sweden.
    Forestier, E
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden Karolinska Hosp, Karolinska Pharm, S-10401 Stockholm, Sweden Karolinska Hosp, Dept Pediat Oncol, S-10401 Stockholm, Sweden Queen Silvias Child & Adolescent Hosp, Gothenburg, Sweden Linkoping Univ Hosp, Dept Pediat, S-58185 Linkoping, Sweden Univ Lund Hosp, Dept Paediat, S-22185 Lund, Sweden Univ Umea Hosp, Dept Pediat, S-90185 Umea, Sweden.
    Lonnerholm, G
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden Karolinska Hosp, Karolinska Pharm, S-10401 Stockholm, Sweden Karolinska Hosp, Dept Pediat Oncol, S-10401 Stockholm, Sweden Queen Silvias Child & Adolescent Hosp, Gothenburg, Sweden Linkoping Univ Hosp, Dept Pediat, S-58185 Linkoping, Sweden Univ Lund Hosp, Dept Paediat, S-22185 Lund, Sweden Univ Umea Hosp, Dept Pediat, S-90185 Umea, Sweden.
    Doxorubicin pharmacokinetics in children with acute lymphoblastic leukemia2001In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 15, no 3, p. P12-Conference paper (Other academic)
  • 7.
    Gunnarsson, N.
    et al.
    Umeå University, Sweden.
    Hoglund, M.
    University Hospital, Uppsala, Sweden.
    Stenke, L.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Sandin, F.
    Regional Cancer Centre, Uppsala, Sweden.
    Bjorkholm, M.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lambe, M.
    Regional Cancer Centre, Uppsala, Sweden; Karolinska Institute, Sweden.
    Markevarn, B.
    University Hospital, Umeå, Sweden.
    Olsson-Stromberg, U.
    University Hospital, Uppsala, Sweden; University Hospital, Uppsala, Sweden.
    Wadenvik, H.
    Sahlgrens University Hospital, Sweden.
    Richter, J.
    Skåne University Hospital, Sweden.
    Sjalander, A.
    Umeå University, 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)
    Abstract [en]

    n/a

  • 8.
    Gunnarsson, N.
    et al.
    Umeå University, Sweden.
    Höglund, M.
    University of Uppsala Hospital, Sweden.
    Stenke, L.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Wallberg-Jonsson, S.
    Umeå University, Sweden.
    Sandin, F.
    Regional Cancer Centre, Sweden.
    Björkholm, M.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lambe, M.
    Regional Cancer Centre, Sweden; Karolinska Institute, Sweden.
    Markevarn, B.
    University of Umeå Hospital, Sweden.
    Olsson-Stromberg, U.
    University of Uppsala Hospital, Sweden.
    Wadenvik, H.
    Sahlgrens University Hospital, Sweden.
    Richter, J.
    Skåne University Hospital, Sweden.
    Sjalander, A.
    Umeå University, 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.

  • 9. Hedenus, M
    et al.
    Birgegård, G
    Näsman, P
    Ahlberg, Lucia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    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 9-11,11 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 (P25%) 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.

  • 10.
    Hjorth-Hansen, H.
    et al.
    St Olavs Hospital, Norway; Norwegian University of Science and Technology NTNU, Norway.
    Stentoft, J.
    Aarhus University Hospital, Denmark.
    Richter, J.
    Skåne University Hospital, Sweden.
    Koskenvesa, P.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Hoeglund, M.
    University of Uppsala Hospital, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Porkka, K.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Gedde-Dahl, T.
    Oslo University Hospital, Norway.
    Gjertsen, B. T.
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Gruber, F. X.
    University Hospital North Norway, Norway.
    Stenke, L.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Eriksson, K. M.
    Sunderbysjukhuset, Sweden.
    Markevarn, B.
    Umeå University Hospital, Sweden.
    Lubking, A.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Vestergaard, H.
    Odense University Hospital, Denmark.
    Udby, L.
    Roskilde Hospital, Denmark.
    Bjerrum, O. W.
    University of Copenhagen Hospital, Denmark.
    Persson, I.
    Uppsala University, Sweden.
    Mustjoki, S.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden; University of Helsinki, Finland.
    Olsson-Stromberg, U.
    University of Uppsala Hospital, Sweden.
    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.

  • 11.
    Ilander, M.
    et al.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Olsson-Stromberg, U.
    Uppsala University Hospital, Sweden; Uppsala University, Sweden.
    Schlums, H.
    Karolinska Institute, Sweden.
    Guilhot, J.
    CHU Poitiers, France.
    Bruck, O.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Lahteenmaki, H.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Kasanen, T.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Koskenvesa, P.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Soderlund, S.
    Uppsala University Hospital, Sweden.
    Hoglund, M.
    Uppsala University Hospital, Sweden.
    Markevarn, B.
    Umeå University Hospital, Sweden.
    Sjalander, A.
    Umeå University, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Lubking, A.
    Skåne University Hospital, Sweden.
    Holm, E.
    Skåne University Hospital, Sweden.
    Bjoreman, M.
    University Hospital, Sweden.
    Lehmann, S.
    Uppsala University Hospital, Sweden; Uppsala University, Sweden; Karolinska University Hospital, Sweden.
    Stenke, L.
    Karolinska University Hospital, Sweden.
    Ohm, L.
    Karolinska University Hospital, Sweden.
    Gedde-Dahl, T.
    Oslo University Hospital, Norway.
    Majeed, W.
    Stavanger University Hospital, Norway.
    Ehrencrona, H.
    Skåne University Hospital, Sweden.
    Koskela, S.
    Finnish Red Cross Blood Serv, Finland.
    Saussele, S.
    Heidelberg University, Germany.
    Mahon, F-X
    University of Bordeaux Segalen, France.
    Porkka, K.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Hjorth-Hansen, H.
    St Olavs University Hospital, Norway.
    Bryceson, Y. T.
    Karolinska Institute, Sweden.
    Richter, J.
    Skåne University Hospital, Sweden.
    Mustjoki, S.
    University of Helsinki, Finland; Helsinki University Hospital, Finland; University of Helsinki, Finland.
    Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia2017In: 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 naive CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-alpha/IFN-gamma 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.

  • 12.
    Ingram, W.
    et al.
    Department of Haematological Medicine, Kings College Hospital, London, United Kingdom.
    Lea, N.C.
    Department of Haematological Medicine, Kings College Hospital, London, United Kingdom.
    Cervera, J.
    The Servicio de Hematologia y Hemoterapia, Hospital Universitario La Fe, Valencia, Spain.
    Germing, U.
    Department of Haematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.
    Fenaux, P.
    Hematology Department, Hopital Avicenne, Bobigny, France.
    Cassinat, B.
    Hematology Department, Hopital Avicenne, Bobigny, France.
    Kiladjian, J.J.
    Hematology Department, Hopital Avicenne, Bobigny, France.
    Varkonyi, J.
    Third Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
    Antunovic, Petar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery.
    Westwood, N.B.
    Department of Haematological Medicine, Kings College Hospital, London, United Kingdom.
    Arno, M.J.
    Genomics Center, School of Biomedical and Health Sciences, Kings College London, London, United Kingdom.
    Mohamedali, A.
    Department of Haematological Medicine, Kings College Hospital, London, United Kingdom.
    Gaken, J.
    Department of Haematological Medicine, Kings College Hospital, London, United Kingdom.
    Kontou, T.
    Department of Haematological Medicine, Kings College Hospital, London, United Kingdom.
    Czepulkowski, B.H.
    Department of Haematological Medicine, Kings College Hospital, London, United Kingdom.
    Twine, N.A.
    Department of Haematological Medicine, Kings College Hospital, London, United Kingdom.
    Tamaska, J.
    National Health Centre, Semmelweis University, Budapest, Hungary.
    Csomer, J.
    Institute of Pathology and Cancer Research, Semmelweis University, Budapest, Hungary.
    Benedek, S.
    Third Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
    Gattermann, N.
    Department of Haematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.
    Zipperer, E.
    Department of Haematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.
    Giagounidis, A.
    Department of Oncology and Clinical Immunology, St-Johannes-Hospital, Duisburg, Germany.
    Garcia-Casado, Z.
    The Servicio de Hematologia y Hemoterapia, Hospital Universitario La Fe, Valencia, Spain.
    Sanz, G.
    The Servicio de Hematologia y Hemoterapia, Hospital Universitario La Fe, Valencia, Spain.
    Mufti, G.J.
    Department of Haematological Medicine, Kings College Hospital, London, United Kingdom.
    The JAK2 V617F mutation identifies a subgroup of MDS patients with isolated deletion 5q and a proliferative bone marrow [14]2006In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 20, no 7, p. 1319-1321Other (Other academic)
    Abstract [en]

    [No abstract available]

  • 13.
    Jaako, P.
    et al.
    Lund University, Sweden.
    Ugale, A.
    Lund University, Sweden.
    Wahlestedt, M.
    Lund University, Sweden.
    Velasco-Hernandez, T.
    Lund University, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lindström, M. S.
    Karolinska Institute, Sweden.
    Bryder, D.
    Lund University, Sweden.
    Induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway delays the initiation but fails to eradicate established murine acute myeloid leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 1, p. 213-221Article in journal (Refereed)
    Abstract [en]

    Mutations resulting in constitutive activation of signaling pathways that regulate ribosome biogenesis are among the most common genetic events in acute myeloid leukemia (AML). However, whether ribosome biogenesis presents as a therapeutic target to treat AML remains unexplored. Perturbations in ribosome biogenesis trigger the 5S ribonucleoprotein particle (RNP)-Mdm2-p53 ribosomal stress pathway, and induction of this pathway has been shown to have therapeutic efficacy in Myc-driven lymphoma. In the current study we address the physiological and therapeutic role of the 5S RNP-Mdm2-p53 pathway in AML. By utilizing mice that have defective ribosome biogenesis due to downregulation of ribosomal protein S19 (Rps19), we demonstrate that induction of the 5S RNP-Mdm2-p53 pathway significantly delays the initiation of AML. However, even a severe Rps19 deficiency that normally results in acute bone marrow failure has no consistent efficacy on already established disease. Finally, by using mice that harbor a mutation in the Mdm2 gene disrupting its binding to 5S RNP, we show that loss of the 5S RNP-Mdm2-p53 pathway is dispensable for development of AML. Our study suggests that induction of the 5S RNP-Mdm2-p53 ribosomal stress pathway holds limited potential as a single-agent therapy in the treatment of AML.

  • 14.
    Juliusson, G.
    et al.
    Skåne University Hospital, Sweden; Lund University, Sweden.
    Abrahamsson, J.
    Queen Silvia Childrens Hospital, Sweden.
    Lazarevic, V.
    Skåne University Hospital, Sweden; Lund University, Sweden.
    Antunovic, Petar
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology.
    Derolf, A.
    Karolinska University Hospital, Sweden.
    Garelius, H.
    Sahlgrenska University Hospital Gothenburg, Sweden.
    Lehmann, S.
    Academic Hospital, Sweden.
    Myhr-Eriksson, K.
    Sunderby Hospital, Sweden.
    Mollgard, L.
    Sahlgrenska University Hospital Gothenburg, Sweden.
    Uggla, B.
    Örebro University Hospital, Sweden.
    Wahlin, A.
    Umeå University, Sweden.
    Wennstrom, L.
    Queen Silvia Childrens Hospital, Sweden; Sahlgrenska University Hospital Gothenburg, Sweden.
    Hoglund, M.
    Academic Hospital, Sweden.
    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 (Other academic)
    Abstract [en]

    n/a

  • 15.
    Lehmann, S.
    et al.
    Uppsala University, Sweden; Karolinska Institute, Sweden.
    Deneberg, S.
    Karolinska Institute, Sweden.
    Antunovic, Petar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Rangert-Derolf, A.
    Karolinska University Hospital, Sweden.
    Garelius, H.
    Sahlgrens University Hospital, Sweden.
    Lazarevic, V.
    Skåne University Hospital, Sweden.
    Myhr-Eriksson, K.
    Örebro University Hospital, Sweden.
    Mollgard, L.
    Sahlgrens University Hospital, Sweden.
    Uggla, B.
    Örebro University Hospital, Sweden.
    Wahlin, A.
    Örebro University Hospital, Sweden.
    Wennstrom, L.
    Sahlgrens University Hospital, Sweden.
    Hoglund, M.
    Uppsala University, Sweden.
    Juliusson, G.
    Skåne University Hospital, Sweden.
    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 (Other academic)
    Abstract [en]

    n/a

  • 16.
    Lehmann, S.
    et al.
    Karolinska University Hospital.
    Ravn, A.
    Karolinska University Hospital.
    Carlsson, L.
    Karolinska University Hospital.
    Antunovic, Petar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery.
    Deneberg, S.
    Karolinska University Hospital.
    Mollgard, L.
    Karolinska University Hospital.
    Rangert Derolf, A.
    Karolinska University Hospital.
    Stockelberg, D.
    Sahlgrens University Hospital.
    Tidefelt, U.
    Orebro University Hospital.
    Wahlin, A.
    Umea University.
    Wennstrom, L.
    Sahlgrens University Hospital.
    Hoglund, M.
    Acad Hospital, Uppsala.
    Juliusson, G.
    Skane University Hospital.
    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 less than 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 dehydro-genase, 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.

  • 17.
    Lilljebjorn, H.
    et al.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Heidenblad, M.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Nilsson, B.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Lassen, C.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Horvat, A.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Heldrup, J.
    Department of Pediatrics, Lund University Hospital, Lund, Sweden.
    Behrendtz, M.
    Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Johansson, B.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Andersson, A.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Fioretos, T.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Combined high-resolution array-based comparative genomic hybridization and expression profiling of ETV6/RUNX1-positive acute lymphoblastic leukemias reveal a high incidence of cryptic Xq duplications and identify several putative target genes within the commonly gained region2007In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 21, no 10, p. 2137-2144Article in journal (Refereed)
    Abstract [en]

    Seventeen ETV6/RUNX1-positive pediatric acute lymphoblastic leukemias were investigated by high-resolution array-based comparative genomic hybridization (array CGH), gene expression profiling and fluorescence in situ hybridization. Comparing the array CGH and gene expression patterns revealed that genomic imbalances conferred a great impact on the expression of genes in the affected regions. The array CGH analyses identified a high frequency of cytogenetically cryptic genetic changes, for example, del(9p) and del(12p). Interestingly, a duplication of Xq material, varying between 30 and 60-201,Mb in size, was found in 6 of 11 males (55%), but not in females. Genes on Xq were found to have a high expression level in cases with dup(Xq), a similar overexpression was confirmed in t(12,21)-positive cases in an external gene expression data set. By studying the expression profile and the proposed function of genes in the minimally gained region, several candidate target genes (SPANXB, HMGB3, FAM50A, HTATSF1 and RAP2C) were identified. Among them, the testis-specific SPANXB gene was the only one showing a high and uniform overexpression, irrespective of gender and presence of Xq duplication, suggesting that this gene plays an important pathogenetic role in t(12,21)-positive leukemia.

  • 18.
    Lilljebjörn, H.
    et al.
    Lund University, Sweden .
    Rissler, M.
    Lund University, Sweden .
    Lassen, C.
    Lund University, Sweden .
    Heldrup, J.
    Lund University, Sweden .
    Behrendtz, M.
    Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Mitelman, F.
    Lund University, Sweden .
    Johansson, B.
    Lund University, Sweden .
    Fioretos, T.
    Lund University, Sweden .
    Whole-exome sequencing of pediatric acute lymphoblastic leukemia2012In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 7, p. 1602-1607Article in journal (Refereed)
    Abstract [en]

    Acute lymphoblastic leukemia (ALL), the most common malignant disorder in childhood, is typically associated with numerical chromosomal aberrations, fusion genes or small focal deletions, thought to represent important pathogenetic events in the development of the leukemia. Mutations, such as single nucleotide changes, have also been reported in childhood ALL, but these have only been studied by sequencing a small number of candidate genes. Herein, we report the first unbiased sequencing of the whole exome of two cases of pediatric ALL carrying the ETV6/RUNX1 (TEL/AML1) fusion gene (the most common genetic subtype) and corresponding normal samples. A total of 14 somatic mutations were identified, including four and seven protein-altering nucleotide substitutions in each ALL. Twelve mutations (86%) occurred in genes previously described to be mutated in other types of cancer, but none was found to be recurrent in an extended series of 29 ETV6/RUNX1-positive ALLs. The number of single nucleotide mutations was similar to the number of copy number alterations as detected by single nucleotide polymorphism arrays. Although the true pathogenetic significance of the mutations must await future functional evaluations, this study provides a first estimate of the mutational burden at the genetic level of t(12;21)-positive childhood ALL.

  • 19.
    Nordlund, J.
    et al.
    Uppsala University, Sweden .
    Kiialainen, A.
    Uppsala University, Sweden .
    Karlberg, O.
    Uppsala University, Sweden .
    Berglund, E. C.
    Uppsala University, Sweden .
    Göransson-Kultima, H.
    Uppsala University, Sweden .
    Sonderkaer, M.
    Aalborg University, Denmark .
    Nielsen, K. L.
    Aalborg University, Denmark .
    Gustafsson, M. G.
    Uppsala University, Sweden .
    Behrendtz, M.
    Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Forestier, E.
    Umeå University, Sweden .
    Perkkio, M.
    Kuopio University Hospital, Finland .
    Söderhäll, S.
    Karolinska University Hospital, Sweden .
    Lönnerholm, G.
    Uppsala University, Sweden .
    Syvänen, A-C
    Uppsala University, Sweden .
    Digital gene expression profiling of primary acute lymphoblastic leukemia cells2012In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 6, p. 1218-1227Article in journal (Refereed)
    Abstract [en]

    We determined the genome-wide digital gene expression (DGE) profiles of primary acute lymphoblastic leukemia (ALL) cells from 21 patients taking advantage of `second-generation sequencing technology. Patients included in this study represent four cytogenetically distinct subtypes of B-cell precursor (BCP) ALL and T-cell lineage ALL (T-ALL). The robustness of DGE combined with supervised classification by nearest shrunken centroids (NSC) was validated experimentally and by comparison with published expression data for large sets of ALL samples. Genes that were differentially expressed between BCP ALL subtypes were enriched to distinct signaling pathways with dic(9;20) enriched to TP53 signaling, t(9;22) to interferon signaling, as well as high hyperdiploidy and t(12;21) to apoptosis signaling. We also observed antisense tags expressed from the non-coding strand of similar to 50% of annotated genes, many of which were expressed in a subtype-specific pattern. Antisense tags from 17 gene regions unambiguously discriminated between the BCP ALL and T-ALL subtypes, and antisense tags from 76 gene regions discriminated between the 4 BCP subtypes. We observed a significant overlap of gene regions with alternative polyadenylation and antisense transcription (Pless than1 x 10(-15)). Our study using DGE profiling provided new insights into the RNA expression patterns in ALL cells.

  • 20.
    Olsson, L.
    et al.
    Lund University, Sweden .
    Castor, A.
    Skåne University Hospital, Lund, Sweden .
    Behrendtz, M.
    Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Biloglav, A.
    Lund University, Sweden .
    Forestier, E.
    Umeå University, Sweden .
    Paulsson, K.
    Lund University, Sweden .
    Johansson, B.
    Lund University, Sweden / University and Regional Laboratories Region Skåne, Lund, Sweden.
    Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 20112014In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 28, no 2, p. 302-310Article in journal (Refereed)
    Abstract [en]

    Despite the favorable prognosis of childhood acute lymphoblastic leukemia (ALL), a substantial subset of patients relapses. As this occurs not only in the high risk but also in the standard/intermediate groups, the presently used risk stratification is suboptimal. The underlying mechanisms for treatment failure include the presence of genetic changes causing insensitivity to the therapy administered. To identify relapse-associated aberrations, we performed single-nucleotide polymorphism array analyses of 307 uniformly treated, consecutive pediatric ALL cases accrued during 1992-2011. Recurrent aberrations of 14 genes in patients who subsequently relapsed or had induction failure were detected. Of these, deletions/uniparental isodisomies of ADD3, ATP10A, EBF1, IKZF1, PAN3, RAG1, SPRED1 and TBL1XR1 were significantly more common in B-cell precursor ALL patients who relapsed compared with those remaining in complete remission. In univariate analyses, age (greater than= 10 years), white blood cell counts (greater than100 x 10(9)/l), t(9; 22)(q34; q11), MLL rearrangements, near-haploidy and deletions of ATP10A, IKZF1, SPRED1 and the pseudoautosomal 1 regions on Xp/Yp were significantly associated with decreased 10-year event-free survival, with IKZF1 abnormalities being an independent risk factor in multivariate analysis irrespective of the risk group. Older age and deletions of IKZF1 and SPRED1 were also associated with poor overall survival. Thus, analyses of these genes provide clinically important information.

  • 21.
    Skogsberg, A.
    et al.
    Department of Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
    Tobin, G.
    Department of Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
    Krober, A.
    Kröber, A., Department of Internal Medicine III, University of Ulm, Ulm, Germany.
    Kienle, D.
    Department of Internal Medicine III, University of Ulm, Ulm, Germany.
    Thunberg, U.
    Department of Oncology, Radiology and Clinical Immunology, Uppsala University, SE-751 85 Uppsala, Sweden.
    Aleskog, A.
    Åleskog, A., Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
    Karlsson, K.
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Laurell, A.
    Department of Oncology, Radiology and Clinical Immunology, Uppsala University, SE-751 85 Uppsala, Sweden.
    Merup, M.
    Department of Medicine, Karolinska University Hospital, Huddinge, Sweden.
    Vilpo, J.
    Department of Clinical Chemistry, Tampere University Hospital, Tampere, Finland.
    Sundstrom, C.
    Sundström, C., Department of Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
    Roos, G.
    Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
    Jernberg-Wiklund, H.
    Department of Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
    Dohner, H.
    Döhner, H., Department of Internal Medicine III, University of Ulm, Ulm, Germany.
    Nilsson, K.
    Department of Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
    Stilgenbauer, S.
    Department of Internal Medicine III, University of Ulm, Ulm, Germany.
    Rosenquist, R.
    Department of Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
    The G(-248)A polymorphism in the promoter region of the Bax gene does not correlate with prognostic markers or overall survival in chronic lymphocytic leukemia2006In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 20, no 1, p. 77-81Article in journal (Refereed)
    Abstract [en]

    The G(-248)A polymorphism in the promoter region of the Bax gene was recently associated with low Bax expression, more advanced stage, treatment resistance and short overall survival in B-cell chronic lymphocytic leukemia (CLL), the latter particularly in treated patients. To investigate this further, we analyzed 463 CLL patients regarding the presence or absence of the G(-248)A polymorphism and correlated with overall survival, treatment status and known prognostic factors, for example, Binet stage, VH mutation status and genomic aberrations. In this material, similar allele and genotype frequencies of the Bax polymorphism were demonstrated in CLL patients and controls (n=207), where 19 and 21% carried this polymorphism, respectively, and no skewed distribution of the polymorphism was evident between different Binet stages and VH mutated and unmutated CLLs. Furthermore, no difference in overall survival was shown between patients displaying the G(-248)A polymorphism or not (median survival 85 and 102 months, respectively, P=0.21), and the polymorphism did not influence outcome specifically in treated CLL. Neither did the polymorphism affect outcome in prognostic subsets defined by VH mutation status or genomic aberrations. In conclusion, the pathogenic role and clinical impact of the Bax polymorphism is limited in CLL. © 2006 Nature Publishing Group All rights reserved.

  • 22.
    Velasco-Hernandez, T.
    et al.
    Lund University, Sweden.
    Tornero, D.
    Skånes University Hospital, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Lund University, Sweden; Skånes University Hospital, Sweden.
    Loss of HIF-1 alpha accelerates murine FLT-3(ITD)-induced myeloproliferative neoplasia2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, no 12, p. 2366-2374Article in journal (Refereed)
    Abstract [en]

    Hypoxia-induced signaling is important for normal and malignant hematopoiesis. The transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) has a crucial role in quiescence and self-renewal of hematopoietic stem cells (HSCs), as well as leukemia-initiating cells (LICs) of acute myeloid leukemia and chronic myeloid leukemia. We have investigated the effect of HIF-1 alpha loss on the phenotype and biology of FLT-3(ITD)-induced myeloproliferative neoplasm (MPN). Using transgenic mouse models, we show that deletion of HIF-1 alpha leads to an enhanced MPN phenotype reflected by an increased number of white blood cells, more severe splenomegaly and decreased survival. The proliferative effect of HIF-1 alpha loss is cell intrinsic as shown by transplantation into recipient mice. HSC loss and organ-specific changes in the number and percentage of long-term HSCs were the most pronounced effects on a cellular level after HIF-1 alpha deletion. Furthermore, we found a metabolic hyperactivation of malignant cells in the spleen upon loss of HIF-1 alpha. Some of our findings are in contrary to what has been previously described for the role of HIF-1 alpha in other myeloid hematologic malignancies and question the potential of HIF-1 alpha as a therapeutic target.

  • 23.
    Wong, W. M.
    et al.
    Lund University, Sweden.
    Dolinska, M.
    Karolinska Institute, Sweden.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ekblom, M.
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Qian, H.
    Karolinska Institute, Sweden.
    Letter: A novel Lin-CD34+CD38-integrin alpha 2-bipotential megakaryocyte-erythrocyte progenitor population in the human bone marrow in LEUKEMIA, vol 30, issue 6, pp 1399-14022016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 6, p. 1399-1402Article in journal (Other academic)
    Abstract [en]

    n/a

  • 24. Zwaan, CM
    et al.
    Reinhardt, D
    Corbacioglu, S
    Jurgens, H
    Samuelsson, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Biondi, A
    Smith, OP
    Bokkerink, JPM
    Tissing, WJE
    Creutzig, U
    Kaspers, GJL
    First clinical experiences with Gemtuzumab ozogamicin (GO, Mylotarg (c)) in CD33 positive relapsed/refractory leukemia in children2003In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 17, no 3, p. P51a-Conference paper (Other academic)
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