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  • 1. Aguilo, Francesca
    et al.
    Avagyan, Serine
    Labar, Amy
    Sevilla, Ana
    Lee, Dung-Fang
    Kumar, Parameet
    Lemischka, Ihor R
    Zhou, Betty Y
    Snoeck, Hans-Willem
    Prdm16 is a physiologic regulator of hematopoietic stem cells.2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, no 19Article in journal (Refereed)
    Abstract [en]

    Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation.

  • 2. Armstrong, Scott A
    et al.
    Mabon, Meghann E
    Silverman, Lewis B
    Li, Aihong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Gribben, John G
    Fox, Edward A
    Sallan, Stephen E
    Korsmeyer, Stanley J
    FLT3 mutations in childhood acute lymphoblastic leukemia.2004In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 103, no 9, p. 3544-3546Article in journal (Refereed)
    Abstract [en]

    Activating mutations of the FLT3 receptor tyrosine kinase are common in acute myelogenous leukemia (AML) but are rare in adult acute lymphoblastic leukemia (ALL). We have recently shown that FLT3 is highly expressed and often mutated in ALLs with rearrangement of the mixed lineage leukemia (MLL) gene on chromosome 11q23. Because hyperdiploid ALL samples also show high-level expression of FLT3, we searched for the presence of FLT3 mutations in leukemic blasts from 71 patients with ALL. The data show that approximately 25% (6 of 25) of hyperdiploid ALL samples possess FLT3 mutations, whereas only 1 of 29 TEL/AML1-rearranged samples harbored mutations (P =.04, Fisher exact test). Three mutations are novel in-frame deletions within a 7-amino acid region of the receptor juxtamembrane domain. Finally, 3 samples from patients whose disease would relapse harbored FLT3 mutations. These data suggest that patients with hyperdiploid or relapsed ALL might be considered candidates for therapy with newly described small-molecule FLT3 inhibitors.

  • 3. Avagyan, Serine
    et al.
    Aguilo, Francesca
    Kamezaki, Kenjiro
    Snoeck, Hans-Willem
    Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis.2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 23Article in journal (Refereed)
    Abstract [en]

    Hematopoiesis is the process whereby BM HSCs renew to maintain their number or to differentiate into committed progenitors to generate all blood cells. One approach to gain mechanistic insight into this complex process is the investigation of quantitative genetic variation in hematopoietic function among inbred mouse strains. We previously showed that TGF-β2 is a genetically determined positive regulator of hematopoiesis. In the presence of unknown nonprotein serum factors TGF-β2, but not TGF-β1 or -β3, enhances progenitor proliferation in vitro, an effect that is subject to mouse strain-dependent variation mapping to a locus on chr.4, Tb2r1. TGF-β2-deficient mice show hematopoietic defects, demonstrating the physiologic role of this cytokine. Here, we show that TGF-β2 specifically and predominantly cell autonomously enhances signaling by FLT3 in vitro and in vivo. A coding polymorphism in Prdm16 (PR-domain-containing 16) underlies Tb2r1 and differentially regulates transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ), identifying lipid PPAR ligands as the serum factors required for regulation of FLT3 signaling by TGF-β2. We furthermore show that PPARγ agonists play a FLT3-dependent role in stress responses of progenitor cells. These observations identify a novel regulatory axis that includes PPARs, Prdm16, and TGF-β2 in hematopoiesis.

  • 4. Balgobind, Brian V
    et al.
    Raimondi, Susana C
    Harbott, Jochen
    Zimmermann, Martin
    Alonzo, Todd A
    Auvrignon, Anne
    Beverloo, H Berna
    Chang, Myron
    Creutzig, Ursula
    Dworzak, Michael N
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Gibson, Brenda
    Hasle, Henrik
    Harrison, Christine J
    Heerema, Nyla A
    Kaspers, Gertjan J L
    Leszl, Anna
    Litvinko, Nathalia
    Nigro, Luca Lo
    Morimoto, Akira
    Perot, Christine
    Pieters, Rob
    Reinhardt, Dirk
    Rubnitz, Jeffrey E
    Smith, Franklin O
    Stary, Jan
    Stasevich, Irina
    Strehl, Sabine
    Taga, Takashi
    Tomizawa, Daisuke
    Webb, David
    Zemanova, Zuzana
    Zwaan, C Michel
    van den Heuvel-Eibrink, Marry M
    Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study.2009In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 114, no 12, p. 2489-2496Article in journal (Refereed)
    Abstract [en]

    Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (+/- 5%), with large differences across subgroups (11% +/- 5% to 92% +/- 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.

  • 5. Bruce, Lesley J
    et al.
    Ghosh, Sandip
    King, May Jean
    Layton, D Mark
    Mawby, William J
    Stewart, Gordon W
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Delaunay, Jean
    Tanner, Michael J A
    Absence of CD47 in protein 4.2-deficient hereditary spherocytosis in man: an interaction between the Rh complex and the band 3 complex.2002In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 100, no 5, p. 1878-1885Article in journal (Refereed)
    Abstract [en]

    We present data on a patient of South Asian origin with recessive hereditary spherocytosis (HS) due to absence of protein 4.2 [4.2 (-) HS]. Protein 4.2 cDNA sequence analysis showed the presence of a novel 41-bp frameshift deletion that predicts a truncated peptide designated protein 4.2 Hammersmith. Quantitative reverse transcription-polymerase chain reaction indicated that the mutant mRNA was unstable. Sequencing of protein 4.2 genomic DNA revealed that the deletion stems from aberrant splicing. The proband was homozygous for a G>T substitution at position 1747 (cDNA numbering) that activates a cryptic acceptor splice site within exon 11 of the protein 4.2 gene (EPB42). The proband's mother was found to be heterozygous for this substitution. Unlike protein 4.2 null mice, the proband's red cells showed no evidence for abnormal cation permeability. Quantitation of red cell membrane proteins was carried out by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blotting, and flow cytometric measurement. CD47, a protein associated with the Rh complex, was markedly reduced to about 1% (in the proband) and 65% (in the mother) that found in healthy controls. The Rh-associated glycoprotein migrated with a higher than normal apparent molecular weight on SDS-PAGE. There was no obvious reduction in Rh polypeptides. These observations indicate that protein 4.2 and CD47 interact in the human red cell membrane. They provide further evidence for an association between the band 3 complex (band 3, ankyrin, protein 4.2, glycophorin A) and the Rh complex (Rh-associated glycoprotein, Rh polypeptides, glycophorin B, CD47, LW) and define a point of attachment between the Rh complex and the red cell cytoskeleton.

  • 6. Buitenkamp, Trudy D.
    et al.
    Izraeli, Shai
    Zimmermann, Martin
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Heerema, Nyla A.
    van den Heuvel-Eibrink, Marry M.
    Pieters, Rob
    Korbijn, Carin M.
    Silverman, Lewis B.
    Schmiegelow, Kjeld
    Liang, Der-Cheng
    Horibe, Keizo
    Arico, Maurizio
    Biondi, Andrea
    Basso, Giuseppe
    Rabin, Karin R.
    Schrappe, Martin
    Cario, Gunnar
    Mann, Georg
    Morak, Maria
    Panzer-Grumayer, Renate
    Mondelaers, Veerle
    Lammens, Tim
    Cave, Helene
    Stark, Batia
    Ganmore, Ithamar
    Moorman, Anthony V.
    Vora, Ajay
    Hunger, Stephen P.
    Pui, Ching-Hon
    Mullighan, Charles G.
    Manabe, Atsushi
    Escherich, Gabriele
    Kowalczyk, Jerzy R.
    Whitlock, James A.
    Zwaan, C. Michel
    Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 123, no 1, p. 70-77Article in journal (Refereed)
    Abstract [en]

    Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Munster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% +/- 2% vs 15% +/- 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% +/- 1% vs 2.0% +/- < 1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% +/- 2% vs 81% +/- 2%, P < .0001) and overall survival (74% +/- 2% vs 89% +/- 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 x 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.

  • 7. Caruso, Christina
    et al.
    Guruprasad, Puneeth
    Mannino, Robert G.
    Zhang, Hanqing
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Josephson, Cassandra D.
    Roback, John D.
    Lam, Wilbur A.
    Integrated Microfluidic Automated Particle Tracking Enables High-Throughput Cell Deformability Cytometry for Red Cell Disorders2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Article in journal (Other academic)
  • 8. Coenen, Eva A
    et al.
    Raimondi, Susana C
    Harbott, Jochen
    Zimmermann, Martin
    Alonzo, Todd A
    Auvrignon, Anne
    Beverloo, H Berna
    Chang, Myron
    Creutzig, Ursula
    Dworzak, Michael N
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Gibson, Brenda
    Hasle, Henrik
    Harrison, Christine J
    Heerema, Nyla A
    Kaspers, Gertjan J L
    Leszl, Anna
    Litvinko, Nathalia
    Lo Nigro, Luca
    Morimoto, Akira
    Perot, Christine
    Reinhardt, Dirk
    Rubnitz, Jeffrey E
    Smith, Franklin O
    Stary, Jan
    Stasevich, Irina
    Strehl, Sabine
    Taga, Takashi
    Tomizawa, Daisuke
    Webb, David
    Zemanova, Zuzana
    Pieters, Rob
    Zwaan, C Michel
    van den Heuvel-Eibrink, Marry M
    Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: results of an international study2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, no 26, p. 7102-7111Article in journal (Refereed)
    Abstract [en]

    We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as ≥ 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied.

  • 9. Dahlen, Torsten
    et al.
    Edgren, Gustaf
    Höglund, Martin
    Lambe, Mats
    Björkholm, Magnus
    Sandin, Fredrik
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Richter, Johan
    Ohm, Lotta
    Back, Magnus
    Stenke, Leif
    Increased Risk of Cardiovascular Events Associated with TKI Treatment in Chronic Phase Chronic Myeloid Leukemia: Data from Swedish Population-Based Registries2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 10. den Hollander, J
    et al.
    Rimpi, Sara
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Doherty, JR
    Rudelius, M
    Buck, A
    Hoellein, A
    Kremer, M
    Graf, N
    Scheerer, M
    Hall, MA
    Goga, A
    von Bubnoff, N
    Duyster, J
    Peschel, C
    Cleveland, JL
    Nilsson, Jonas A
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Keller, U
    Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state2010In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 116, no 9, p. 1498-1505Article in journal (Refereed)
    Abstract [en]

    Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant-Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function. (Blood. 2010;116(9):1498-1505)

  • 11. Frost, Britt-Marie
    et al.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Gustafsson, Göran
    Nygren, Peter
    Hellebostad, Marit
    Jonsson, Olafur G
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Larsson, Rolf
    Lönnerholm, Gudmar
    Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia2004In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 104, no 8, p. 2452-2457Article in journal (Refereed)
    Abstract [en]

    The t(12;21) (p13;q22) translocation resulting in ETV6/RUNX1 (previously named TEL/AML1) gene fusion is present in about 25% of children with precursor B-lineage acute lymphoblastic leukemia (B-ALL). We successfully tested 275 precursor BALL samples from children aged 1 to 17 years to determine the relation between t(12;21) and in vitro cellular drug resistance, measured by the fluorometric microculture cytotoxicity assay (FMCA). Samples from 83 patients (30%) were positive for t(12;21). The ETV6/RUNX1(+) samples were significantly more sensitive than ETV6/RUNX1(-) samples to doxorubicin, etoposide, amsacrine, and dexamethasone, whereas the opposite was true for cytarabine. After matching for unevenly distributed patient characteristics, that is, excluding patients with high hyperdiploidy (> 51 chromosomes), t(g;22), t(1;19), or 11q23 rearrangement, the ETV6/RUNX1(+) samples remained significantly more sensitive to doxorubicin (P = .001) and etoposide (P = .001). For the other drugs tested (amsacrine, cytarabine, dexamethasone, prednisolone, vincristine, 6-thioguanine, and 4-hydroper-oxy-cyclophosphamide), no significant difference in cellular drug sensitivity was found. In conclusion, we found that the presence of the t(12;21) translocation in childhood precursor B-ALL is associated with a high tumor cell sensitivity to doxorubicin and etoposide. High throughput techniques should now be used to elucidate the cellular mechanisms by which ETV6/RUNX1 gene fusion is linked to increased sensitivity to these drugs.

  • 12.
    Grabowski, Pawel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Karlsson, Karin
    Tobin, Gerard
    Aleskog, Anna
    Thunberg, Ulf
    Laurell, Anna
    Sundström, Christer
    Rosenquist, Richard
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, no 12, p. 4807-4812Article in journal (Refereed)
    Abstract [en]

    B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin VH genes have better outcome than unmutated cases. VH-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, VH gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the VH-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining VH mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes.

  • 13.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Höglund, Martin
    Stenke, Leif
    Wållberg Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sandin, Fredrik
    Björkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevärn, Berit
    Olsson-Strömberg, Ulla
    Wadenvik, Hans
    Richter, Johan
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Increased Prevalence of Prior Malignancies and Autoimmune Diseases in Patients Diagnosed with Chronic Myeloid Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 14.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Leif, Stenke
    Hoglund, Martin
    Sandin, Fredrik
    Bjorkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevärn, Berit
    Olsson-Stromberg, Ulla
    Richter, Johan
    Wadenvik, Hans
    Wallvik, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Second Malignancies Following Treatment of Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 15. Hammer, Anne Sofie Borg
    et al.
    Juul-Dam, Kristian
    Sandahl, Julie Damgaard
    Abrahamsson, Jonas
    Balwierz, Walentyna
    Guilmatre, Audrey
    Haltrich, Iren
    Jahnukainen, Kirsi
    Kolb, E. Anders
    Kovacs, Gabor
    Leverger, Guy
    Locatelli, Franco
    Masetti, Riccardo
    Norén-Nyström, Ulrika
    Umeå University.
    Raimondi, Susana C.
    Rasche, Mareike
    Reinhardt, Dirk
    Taki, Tomohiko
    Tomizawa, Daisuke
    Zeller, Bernward
    Hasle, Henrik
    Kjeldsen, Eigil
    Hypodiploidy in Childhood Acute Myeloid Leukemia: A Retrospective Cohort Study within the International Berlin-Frankfurt-Munster Study Group2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Article in journal (Other academic)
  • 16. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    De Bont, Evelina S.
    de Haas, Valerie
    De Moerloose, Barbara
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ha, Shau Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Reedijk, Ardine
    Saks, Kadri
    Zeller, Bernward
    Anthracycline Type during Induction Associated with Outcome in Pediatric t(8;21) and Inv(16) AML2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 17. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur Gisli
    Lausen, Birgitte
    Palle, Josefine
    Zeller, Bernward
    Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 20042012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 5, p. 978-984Article in journal (Refereed)
    Abstract [en]

    There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m(2) and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of venoocclusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541). (Blood. 2012;120(5):978-984)

  • 18. Hosnijeh, Fatemeh Saberi
    et al.
    Lan, Qing
    Rothman, Nathaniel
    Liu, Chin San
    Cheng, Wen-Ling
    Nieters, Alexandra
    Guldberg, Per
    Tjonneland, Anne
    Campa, Daniele
    Martino, Alessandro
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Krogh, Vittorio
    Tumino, Rosario
    Panico, Salvatore
    Masala, Giovanna
    Weiderpass, Elisabete
    Castano, Jose Maria Huerta
    Ardanaz, Eva
    Sala, Nuria
    Dorronsoro, Miren
    Quiros, J. Ramon
    Sanchez, Maria-Jose
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ann Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Malm, Johan
    Borgquist, Signe
    Peeters, Petra H.
    Bueno-de-Mesquita, H. Bas
    Wareham, Nick
    Khaw, Kay-Tee
    Travis, Ruth C.
    Brennan, Paul
    Siddiq, Afshan
    Riboli, Elio
    Vineis, Paolo
    Vermeulen, Roel
    Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 4, p. 530-535Article in journal (Refereed)
    Abstract [en]

    It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n=102) with increasing mtDNA copy number (odds ratio=1.34, 1.44, and 1.80 for quartiles 2-4, respectively; Ptrend=.001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis.

  • 19.
    Höglund, Andreas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nilsson, Lisa M.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Plym Forshell, Linus
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Maclean, Kirsteen H.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nilsson, Jonas A.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine2009In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 18, p. 4281-4288Article in journal (Refereed)
    Abstract [en]

    Decitabine (also referred to as 5-aza-2'-deoxycytidine) is a drug that has recently been approved by the Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome (MDS). The mechanism of action is believed to be the blocking of DNA methylation and thereby reactivating silenced genes involved in harnessing MDS. When analyzing reactivation of genes involved in Burkitt lymphoma (BL), we discovered that decitabine also sensitizes tumor cells by inducing DNA damage. This sensitization is grossly augmented by the MYC oncogene, which is overexpressed in BL, and occurs in cells lacking a functional p53 tumor suppressor pathway. In p53-deficient BL cells and p53(-/-) mouse embryo fibroblasts, Myc overrides a transient G2-block exerted by decitabine via activation of Chk1. This triggers aneuploidy and cell death that correlates with, but can occur in the absence of, Epstein-Barr virus (EBV) reactivation, caspase activation, and/or expression of the BH3-only protein Puma. In vivo modeling of Myc-induced lymphoma suggests that decitabine constitutes a potential new drug against lymphoma that would selectively sensitize tumor cells but spare normal tissue.

  • 20. Höglund, Martin
    et al.
    Sandin, Fredrik
    Hellström, Karin
    Björeman, Mats
    Björkholm, Magnus
    Brune, Mats
    Dreimane, Arta
    Ekblom, Marja
    Lehmann, Sören
    Ljungman, Per
    Malm, Claes
    Markevärn, Berit
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Myhr-Eriksson, Kristina
    Ohm, Lotta
    Olsson-Strömberg, Ulla
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wadenvik, Hans
    Simonsson, Bengt
    Stenke, Leif
    Richter, Johan
    Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 7, p. 1284-1292Article in journal (Refereed)
    Abstract [en]

    Clinical management guidelines on malignant disorders are generally based on data from clinical trials with selected patient cohorts. In Sweden, more than 95% of all patients diagnosed with chronic myeloid leukemia (CML) are reported to the national CML registry, providing unique possibilities to compile population-based information. This report is based on registry data from 2002 to 2010, when a total of 779 patients (425 men, 354 women; median age, 60 years) were diagnosed with CML (93% chronic, 5% accelerated, and 2% blastic phase) corresponding to an annual incidence of 0.9/100 000. In 2002, approximately half of the patients received a tyrosine kinase inhibitor as initial therapy, a proportion that increased to 94% for younger (<70 years) and 79% for older (>80 years) patients during 2007-2009. With a median follow-up of 61 months, the relative survival at 5 years was close to 1.0 for patients younger than 60 years and 0.9 for those aged 60 to 80 years, but only 0.6 for those older than 80 years. At 12 months, 3% had progressed to accelerated or blastic phase. Sokal, but not European Treatment and Outcome Study, high-risk scores were significantly linked to inferior overall and relative survival. Patients living in university vs nonuniversity catchment areas more often received tyrosine kinase inhibitors up front but showed comparable survival.

  • 21. Ilander, Mette Matilda
    et al.
    Olsson-Strömberg, Ulla
    Lahteenmaki, Hanna
    Tiina, Kasanen
    Koskenvesa, Perttu
    Söderlund, Stina
    Höglund, Martin
    Markevärn, Berit
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lotfi, Kourosh
    Malm, Claes
    Lubking, Anna
    Ekblom, Marja
    Holm, Elena
    Bjoreman, Mats
    Lehmann, Soren
    Stenke, Leif
    Ohm, Lotta
    Majeed, Waleed
    Pfirrmann, Markus
    Muller, Martin C.
    Guilhot, Joelle
    Ehrencrona, Hans
    Hjorth-Hansen, Henrik
    Saussele, Susanne
    Mahon, Francois-Xavier
    Porkka, Kimmo
    Richter, Johan
    Mustjoki, Satu
    Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and Impaired Function of NK-Cells2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 22. Ilander, Mette
    et al.
    Schlums, Heinrich
    Olsson-Stromberg, Ulla
    Lahteenmäki, Hanna
    Kasanen, Tiina
    Koskenvesa, Perttu
    Söderlund, Stina
    Höglund, Martin
    Markevärn, Berit
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lotfi, Kourosh
    Malm, Claes
    Lubking, Anna
    Ekblom, Marja
    Holm, Elena
    Björeman, Mats
    Lehmann, Soren
    Stenke, Leif
    Ohm, Lotta
    Majeed, Waleed
    Muller, Martin C
    Ehrencrona, Hans
    Hjorth-Hansen, Henrik
    Saussele, Susanne
    Mahon, Francois-Xavier
    Porkka, Kimmo
    Guilhot, Joelle
    Bryceson, Yenan
    Richter, Johan
    Mustjoki, Satu
    Mature, Adaptive-like CD56(DIM) NK Cells in Chronic Myeloid Leukemia Patients in Treatment Free Remission2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 23. Inaba, Hiroto
    et al.
    Zhou, Yinmei
    Abla, Oussama
    Adachi, Souichi
    Auvrignon, Anne
    Beverloo, H. Berna
    de Bont, Eveline
    Chang, Tai-Tsung
    Creutzig, Ursula
    Dastugue, Nicole
    Dworzak, Michael
    Elitzur, Sarah
    Fynn, Alcira
    Forestier, Erik
    Umeå University Hospital, Umea, Sweden.
    Hasle, Henrik
    Liang, Der-Cherng
    Lee, Vincent
    Locatelli, Franco
    Masetti, Riccardo
    De Moerloose, Barbara
    Reinhardt, Dirk
    Rodriguez, Laura
    Shen, Shuhong
    Taga, Takashi
    Tomizawa, Daisuke
    Yeoh, Allen E. J.
    Zimmermann, Martin
    Raimondi, Susana C.
    Pediatric Acute Megakaryoblastic Leukemia without Down Syndrome: A Retrospective Study by the International Berlin-Frankfurt-Munster Study Group (I-BFMSG)2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 24. Inaba, Hiroto
    et al.
    Zhou, Yinmei
    Abla, Oussama
    Adachi, Souichi
    Auvrignon, Anne
    Beverloo, H. Berna
    de Bont, Eveline
    Chang, Tai-Tsung
    Creutzig, Ursula
    Dworzak, Michael
    Elitzur, Sarah
    Fynn, Alcira
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Nordic Society for Pediatric Hematology and Oncology, Stockholm, Sweden.
    Hasle, Henrik
    Liang, Der-Cherng
    Lee, Vincent
    Locatelli, Franco
    Masetti, Riccardo
    De Moerloose, Barbara
    Reinhardt, Dirk
    Rodriguez, Laura
    Van Roy, Nadine
    Shen, Shuhong
    Taga, Takashi
    Tomizawa, Daisuke
    Yeoh, Allen E. J.
    Zimmermann, Martin
    Raimondi, Susana C.
    Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 13, p. 1575-1584Article in journal (Refereed)
    Abstract [en]

    Comprehensive clinical studies of patients with acute megakaryoblastic leukemia (AMKL) are lacking. We performed an international retrospective study on 490 patients (age <= 18 years) with non-Down syndrome de novo AMKL diagnosed from 1989 to 2009. Patients with AMKL (median age 1.53 years) comprised 7.8% of pediatric AML. Five-year event-free (EFS) and overall survival (OS) were 43.7% +/- 2.7% and 49.0% +/- 2.7%, respectively. Patients diagnosed in 2000 to 2009 were treated with higher cytarabine doses and had better EFS (P = .037) and OS (P = .003) than those diagnosed in 1989 to 1999. Transplantation in first remission did not improve survival. Cytogenetic data were available for 372 (75.9%) patients: hypodiploid (n = 18, 4.8%), normal karyotype (n = 49, 13.2%), pseudodiploid (n = 119, 32.0%), 47 to 50 chromosomes (n = 142, 38.2%), and >50 chromosomes (n=44, 11.8%). Chromosome gain occurred in 195 of 372 (52.4%) patients: +21 (n = 106, 28.5%), +19 (n = 93, 25.0%), +8 (n = 77, 20.7%). Losses occurred in 65 patients (17.5%): -7 (n = 13, 3.5%). Common structural chromosomal aberrations were t(1; 22)(p13; q13) (n = 51, 13.7%) and 11q23 rearrangements (n = 38, 10.2%); t(9; 11)(p22; q23) occurred in 21 patients. On the basis of frequency and prognosis, AMKL can be classified to 3 risk groups: good risk-7p abnormalities; poor risk-normal karyotypes, -7, 9p abnormalities including t(9;11)(p22;q23)/MLL-MLLT3, -13/13q-, and -15; and intermediate risk-others including t(1;22)(p13;q13)/OTT-MAL (RBM15-MKL1) and 11q23/MLL except t(9;11). Risk-based innovative therapy is needed to improve patient outcomes.

  • 25. Iolascon, Achille
    et al.
    Heimpel, Hermann
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tamary, Hannah
    Congenital dyserythropoietic anemias: molecular insights and diagnostic approach2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 13, p. 2162-2166Article in journal (Refereed)
    Abstract [en]

    The congenital dyserythropoietic anemias (CDAs) are hereditary disorders characterized by distinct morphologic abnormalities of marrow erythroblasts. The unveiling of the genes mutated in the major CDA subgroups (I-CDAN1 and II-SEC23B) has now been completed with the recent identification of the CDA III gene (KIF23). KIF23 encodes mitotic kinesin-like protein 1, which plays a critical role in cytokinesis, whereas the cellular role of the proteins encoded by CDAN1 and SEC23B is still unknown. CDA variants with mutations in erythroid transcription factor genes (KLF1 and GATA-1) have been recently identified. Molecular diagnosis of CDA is now possible in most patients.

  • 26. Junlen, Henna Riikka
    et al.
    Peterson, Stefan
    Kimby, Eva
    Lockmer, Sandra
    Linden, Ola
    Nilsson-Ehle, Herman
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hagberg, Hans
    Radlund, Anders
    Hagberg, Oskar
    Wahlin, Björn E.
    Follicular Lymphoma Survival in Sweden in the Rituximab Era2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 27. Karlsson, Lene
    et al.
    Nyvold, Charlotte Guldborg
    Palmqvist, Lars
    Tierens, Anne
    Hasle, Henrik
    Lausen, Birgitte
    Jonsson, Olafur G.
    Juergensen, Gitte Wulff
    Ebbesen, Lene Hyldahl
    Kuchenbauer, Florian
    Forestier, Erik
    Umeå University, Sweden.
    Abrahamsson, Jonas
    Fogelstrand, Linda
    Quantification of Fusion Transcripts Reveals Slower Treatment Kinetics As Compared with Multiparameter Flow Cytometry during Induction Treatment of Acute Myeloid Leukemia in Children2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Article in journal (Other academic)
  • 28. Kimby, Eva
    et al.
    Östenstad, Björn
    Brown, Peter de Nully
    Holte, Harald, Jr.
    Hagberg, Hans
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Linden, Ola
    Nordström, Marie
    Sundström, Christer
    Rituximab (R) in Combination with Interferon-a2a (IFN) Versus Single R in Patients with Follicular or Other CD20+Low-Grade (indolent) Lymphoma. Final Results From a Randomized Phase III Study From the Nordic Lymphoma Group2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 21Article in journal (Other academic)
  • 29. Kolstad, Arne
    et al.
    Madsbu, Ulf
    Dahle, Jostein
    Stokke, Caroline
    Bach-Gansmo, Tore
    Londalen, Ayca Muftuler
    Holtedahl, Jon Erik
    Revheim, Mona Elisabeth
    Bruland, Oyvind
    Bolstad, Bjorg
    Bolstad, Nils
    Tierens, Anne
    Larsen, Roy Hartvig
    Alfheim, Jan Alan
    Delabie, Jan
    Signe, Spetalen
    Erlanson, Martin
    Ruda, Stine Nygaard
    Holte, Harald
    A Phase I Study of (177)lu-DOTA-HH1 (Betalutin) Radioimmunotherapy for Patients with Relapsed CD37+Non-Hodgkin's B Cell Lymphoma2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 30. Kristinsson, Sigurdur Y
    et al.
    Pfeiffer, Ruth M
    Björkholm, Magnus
    Goldin, Lynn R
    Schulman, Sam
    Blimark, Cecilie
    Mellqvist, Ulf-Henrik
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Turesson, Ingemar
    Landgren, Ola
    Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study2010In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, no 24, p. 4991-4998Article in journal (Refereed)
    Abstract [en]

    Patients with multiple myeloma (MM) have an increased risk of venous thrombosis. Interestingly, excess risk of venous thromboembolism has been observed among patients with monoclonal gammopathy of undetermined significance (MGUS). Using population-based data from Sweden, we assessed the risks of venous and arterial thrombosis in 18,627 MM and 5326 MGUS patients diagnosed from 1958 to 2006, compared with 70,991 and 20,161 matched controls, respectively. At 1, 5, and 10 years after MM diagnosis, there was an increased risk of venous thrombosis: hazard ratios (95% confidence intervals) were 7.5 (6.4-8.9), 4.6 (4.1-5.1), and 4.1 (3.8-4.5), respectively. The corresponding results for arterial thrombosis were 1.9 (1.8-2.1), 1.5 (1.4-1.6), and 1.5 (1.4-1.5). At 1, 5, and 10 years after MGUS diagnosis, hazard ratios were 3.4 (2.5-4.6), 2.1 (1.7-2.5), and 2.1 (1.8-2.4) for venous thrombosis. The corresponding risks for arterial thrombosis were 1.7 (1.5-1.9), 1.3 (1.2-1.4), and 1.3 (1.3-1.4). IgG/IgA (but not IgM) MGUS patients had increased risks for venous and arterial thrombosis. Risks for thrombosis did not vary by M-protein concentration (> 10.0 g/L or < 10.0 g/L) at diagnosis. MGUS patients with (vs without) thrombosis had no excess risk of MM or Waldenström macroglobulinemia. Our findings are of relevance for future studies and for improvement of thrombosis prophylaxis strategies.

  • 31. Kristinsson, Sigurdur Y
    et al.
    Tang, Min
    Pfeiffer, Ruth M
    Björkholm, Magnus
    Blimark, Cecilie
    Mellqvist, Ulf-Henrik
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Turesson, Ingemar
    Landgren, Ola
    Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study2010In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 116, no 15, p. 2651-2655Article in journal (Refereed)
    Abstract [en]

    Patients with multiple myeloma (MM) have an increased risk of fractures. On the basis of small numbers, patients with monoclonal gammopathy of undetermined significance (MGUS) have been reported to have an increased fracture risk. Using population-based data from Sweden, we assessed the risks of fractures in 5326 MGUS patients diagnosed from 1958 to 2006, compared with 20 161 matched controls. MGUS patients had an increased risk of any fracture at 5 (hazard ratio [HR] = 1.74; 95% confidence interval [CI], 1.58-1.92) and 10 (HR = 1.61; 95% CI, 1.49-1.74) years. The risk was significantly higher for axial (skull, vertebral/pelvis, and sternum/costae) compared with distal (arm and leg) fractures (P < .001). On the basis of 10 years of follow-up, there was an increased risk of vertebral/pelvic (HR = 2.37; 95% CI, 2.02-2.78), sternal/costae (HR = 1.93; 95% CI, 1.5-2.48), arm (HR = 1.23; 95% CI, 1.06-1.43), leg (HR = 1.40; 95% CI, 1.26-1.56), and other/multiple fractures (HR = 4.25; 95% CI, 3.29-5.51). Risks for fractures did not differ by isotype or M protein concentration at diagnosis. MGUS patients with (versus without) fractures had no excess risk of MM or Waldenström macroglobulinemia. Our results suggest that bone alterations are present in early myelomagenesis. Our findings may have implications for the development of better prophylaxis for bone disease in MGUS, and they provide novel clues on pathogenesis of MM bone disease.

  • 32. Landgren, Ola
    et al.
    Kristinsson, Sigurdur Y
    Goldin, Lynn R
    Caporaso, Neil E
    Blimark, Cecilie
    Mellqvist, Ulf-Henrik
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Björkholm, Magnus
    Turesson, Ingemar
    Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden.2009In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 114, no 4, p. 791-795Article in journal (Refereed)
    Abstract [en]

    Familial clustering of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS) has been observed in case reports and in smaller studies. Using population-based data from Sweden, we identified 4458 MGUS patients, 17505 population-based controls, and first-degree relatives of patients (n = 14621) and controls (n = 58387) with the aim to assess risk of MGUS and lymphoproliferative malignancies among first-degree relatives of MGUS patients. Compared with relatives of controls, relatives of MGUS patients had increased risk of MGUS (relative risk [RR] = 2.8; 1.4-5.6), multiple myeloma (MM; RR = 2.9; 1.9-4.3), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM; RR = 4.0; 1.5-11), and chronic lymphocytic leukemia (CLL; RR = 2.0; 1.2-2.3). Relatives of patients with IgG/IgA MGUS had a 4.0-fold (1.7-9.2), 2.9-fold (1.7-4.9), and 20-fold (2.3-170) elevated risk of developing MGUS, MM, and LPL/WM, respectively. Relatives of IgM MGUS patients had 5.0-fold (1.1-23) increased CLL risk and nonsignificant excess MM and LPL/WM risks. The results were very similar when we assessed risk by type of first-degree relative, age at MGUS (above/below 65 years), or sex. Risk of non-Hodgkin lymphoma or Hodgkin lymphoma was not increased among MGUS relatives. Among first-degree relatives of a nationwide MGUS cohort, we found elevated risks of MGUS, MM, LPL/WM, and CLL, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.

  • 33. Lehmann, Soren
    et al.
    Lazarevic, Vladimir
    Hörstedt, Ann-Sofi
    Hulegårdh, Erik
    Nilsson, Christer
    Antunovic, Petar
    Derolf, Åsa Rangert
    Möllgård, Lars
    Uggla, Bertil
    Vennström, Lovisa
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Höglund, Martin
    Stockelberg, Dick
    Juliusson, Gunnar
    Poor Outcome in Secondary Acute Myeloid Leukemia (AML): A First Report From the Population-Based Swedish Acute Leukemia Registry2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 21Article in journal (Other academic)
  • 34.
    Li, Aihong
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Rue, Montse
    Zhou, Jianbiao
    Wang, Hongjun
    Goldwasser, Meredith A
    Neuberg, Donna
    Dalton, Virginia
    Zuckerman, David
    Lyons, Cheryl
    Silverman, Lewis B
    Sallan, Stephen E
    Gribben, John G
    Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis.2004In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 103, no 12, p. 4602-9Article in journal (Refereed)
    Abstract [en]

    Sequence analysis of the immunoglobulin heavy chain genes (IgH) has demonstrated preferential usage of specific variable (V), diversity (D), and joining (J) genes at different stages of B-cell development and in B-cell malignancies, and this has provided insight into B-cell maturation and selection. Knowledge of the association between rearrangement patterns based on updated databases and clinical characteristics of pediatric acute lymphoblastic leukemia (ALL) is limited. We analyzed 381 IgH sequences identified at presentation in 317 children with B-lineage ALL and assessed the V(H)D(H)J(H) gene utilization profiles. The D(H)J(H)-proximal V(H) segments and the D(H)2 gene family were significantly overrepresented. Only 21% of V(H)-J(H) joinings were potentially productive, a finding associated with a trend toward an increased risk of relapse. These results suggest that physical location at the V(H) locus is involved in preferential usage of D(H)J(H)-proximal V(H) segments whereas D(H) and J(H) segment usage is governed by position-independent molecular mechanisms. Molecular pathophysiology appears relevant to clinical outcome in patients who have only productive rearrangements, and specific rearrangement patterns are associated with differences in the tumor biology of childhood ALL.

  • 35.
    Li, Aihong
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zhou, Jianbiao
    Zuckerman, David
    Rue, Montse
    Dalton, Virginia
    Lyons, Cheryl
    Silverman, Lewis B
    Sallan, Stephen E
    Gribben, John G
    Sequence analysis of clonal immunoglobulin and T-cell receptor gene rearrangements in children with acute lymphoblastic leukemia at diagnosis and at relapse: implications for pathogenesis and for the clinical utility of PCR-based methods of minimal residual disease detection.2003In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 102, no 13, p. 4520-4526Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements provide clonal markers useful for diagnosis and measurement of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). We analyzed the sequences of Ig and TCR gene rearrangements obtained at presentation and relapse in 41 children with ALL to study clonal stability, which has important implications for monitoring MRD, during the course of the disease. In 42%, all original Ig and/or TCR sequences were conserved. In 24%, one original sequence was preserved but the other lost, and in 14% the original sequences were conserved with new sequences identified at relapse. In 20% only new sequences were found at relapse. Using primers designed from the novel relapse sequences, the relapse clone could be identified as subdominant clones in the diagnostic sample in 8 of 14 patients. Alteration of these clonal gene rearrangements is a common feature in childhood ALL. MRD detection should include multiple gene targets to minimize false-negative samples or include also multicolor flow cytometry. In some cases the leukemic progenitor cell might arise earlier in lineage before DHJH recombination but retain the capacity to further differentiate into cells capable of altering the pattern of Ig and/or TCR rearrangements.

  • 36.
    Li, Shu Shun
    et al.
    Umeå University, Faculty of Medicine, Clinical Microbiology, Clinical Immunology.
    Liu, Zhiwen
    Uzunel, Mehmet
    Sundqvist, Karl-Gösta
    Endogenous thrombospondin-1 is a cell-surface ligand for regulation of integrin-dependent T-lymphocyte adhesion.2006In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 108, no 9, p. 3112-3120Article in journal (Refereed)
    Abstract [en]

    Lymphocyte adhesion to cells and extracellular matrix (ECM) via integrins plays a pivotal role for the function of the immune system. We show here that endogenous thrombospondin-1 (TSP-1) is a cell-surface ligand for cis interaction of surface receptors in T lymphocytes controlled by integrins and the T-cell antigen receptor (TCR/CD3). Stimulation of CD3 triggers rapid surface expression of TSP-1 in quiescent T cells, whereas activated cells express TSP-1 constitutively. Endogenous TSP-1 is attached to lipoprotein receptor-related protein 1 (LRP1/CD91) and calreticulin (CRT) on the cell surface through its NH2-terminal domain. Adhesion via integrins to ICAM-1 or ECM components up-regulates TSP turnover dramatically from a low level in nonadherent cells, whereas CD3 stimulation inhibits TSP turnover through interference with CD91/CRT-mediated internalization. Integrin-associated protein (IAP/CD47) is essential for TSP turnover and adhesion through interaction with the C-terminal domain of TSP-1 in response to triggering signals delivered at the NH2-terminal. These results indicate that endogenous TSP-1 connects separate cell-surface receptors functionally and regulates T-cell adhesion.

  • 37.
    Liljeholm, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Irvine, Andrew F
    Vikberg, Ann-Louise
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Month, Stacy
    Sandström, Herbert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Mishima, Masanori
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23.2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020Article in journal (Refereed)
    Abstract [en]

    Haplotype analysis and targeted next-generation resequencing allowed us to identify a mutation in the KIF23 gene and to show its association with an autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III). The region at 15q23 where CDA III was mapped in a large Swedish family was targeted by array-based sequence capture in a female diagnosed with CDA III and her healthy sister. Prioritization of all detected sequence changes revealed 10 variants unique for the CDA III patient. Among those variants, a novel mutation c.2747C>G (p.P916R) was found in KIF23, which encodes mitotic kinesin-like protein 1 (MKLP1). This variant segregates with CDA III in the Swedish and American families but was not found in 356 control individuals. RNA expression of the 2 known splice isoforms of KIF23 as well as a novel one lacking the exons 17 and 18 was detected in a broad range of human tissues. RNA interference-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23/MKLP1, a conserved mitotic kinesin crucial for cytokinesis.

  • 38.
    Lindqvist, Ebba K.
    et al.
    Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
    Goldin, Lynn R.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, United States.
    Landgren, Ola
    Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States.
    Blimark, Cecilie
    Department of Medicine, Section of Hematology and Coagulation, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Mellqvist, Ulf-Henrik
    Department of Medicine, Section of Hematology and Coagulation, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Turesson, Ingemar
    Department of Hematology, Skane University Hospital, Malmo, Sweden.
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Björkholm, Magnus
    Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
    Kristinsson, Sigurdur Y.
    Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
    Personal and family history of immune-related conditions increase the risk of plasma cell disorders: a population-based study2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 24, p. 6284-6291Article in journal (Refereed)
    Abstract [en]

    The associations between immune-related conditions and multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) have previously been investigated with inconsistent results. In a large population-based study, we identified 19 112 patients with MM, 5403 patients with MGUS, 96 617 matched control subjects, and 262 931 first-degree relatives. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MM and MGUS with immune-related conditions by use of logistic regression. A personal history of all infections combined was associated with a significantly increased risk of MM (OR = 1.2; 95% CI, 1.1-1.3), and a personal history of all conditions in the categories infections (OR = 1.6; 95% CI, 1.5-1.7), inflammatory conditions (OR = 1.4; 95% CI, 1.2-1.5), and autoimmune diseases (OR = 2.1; 95% CI, 1.9-2.4) was associated with a significantly increased risk of MGUS. Several specific immune-related conditions elevated the risk of MM and/or MGUS. A family history of autoimmune disease was associated with a significantly increased risk of MGUS (OR = 1.1; 95% CI, 1.00-1.2), but not MM. Our findings suggest that immune-related conditions and/or their treatment are of importance in the etiology of MGUS and possibly MM. The association of both personal and family history of autoimmune disease with MGUS indicates the potential for shared susceptibility for these conditions. (Blood. 2011; 118(24): 6284-6291)

  • 39. MacDonald, Brian A
    et al.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Grant, Marianne A
    Pfaff, Kathleen L
    Holthaus, Kathryn
    Zon, Leonard I
    Kalluri, Raghu
    Zebrafish to humans: evolution of the alpha3-chain of type IV collagen and emergence of the autoimmune epitopes associated with Goodpasture syndrome.2006In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 107, no 5, p. 1908-1915Article in journal (Refereed)
  • 40. Mansouri, Larry
    et al.
    Noerenberg, Daniel
    Young, Emma
    Mylonas, Elena
    Abdulla, Maysaa
    Frick, Mareike
    Asmar, Fazila
    Ljungstroem, Viktor
    Schneider, Markus
    Yoshida, Kenichi
    Skaftason, Aron
    Pandzic, Tatjana
    Gonzalez, Blanca
    Tasidou, Anna
    Waldhueter, Nils
    Rivas-Delgado, Alfredo
    Angelopoulou, Maria
    Ziepert, Marita
    Arends, Christopher Maximilian
    Couronne, Lucile
    Lenze, Dido
    Baldus, Claudia D.
    Bastard, Christian
    Okosun, Jessica
    Fitzgibbon, Jude
    Doerken, Bernd
    Drexler, Hans G.
    Roos-Weil, Damien
    Schmitt, Clemens A.
    Munch-Petersen, Helga D.
    Zenz, Thorsten
    Hansmann, Martin-Leo
    Strefford, Jonathan C.
    Enblad, Gunilla
    Bernard, Olivier A.
    Ralfkiaer, Elisabeth
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Korkolopoulou, Penelope
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Papadaki, Theodora
    Gronbaek, Kirsten
    Lopez-Guillermo, Armando
    Ogawa, Seishi
    Kuppers, Ralf
    Stamatopoulos, Kostas
    Stavroyianni, Niki
    Kanellis, George
    Rosenwald, Andreas
    Campo, Elias
    Amini, Rose-Marie
    Ott, German
    Vassilakopoulos, Theodoros P.
    Hummel, Michael
    Rosenquist, Richard
    Damm, Frederik
    Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. 2666-2670Article in journal (Refereed)
    Abstract [en]

    We recently reported a truncating deletion in the NFKBIE gene, which encodes IkB epsilon, a negative feedback regulator of NF-kB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (< 2%), slightly higher frequencies were seen in diffuse large B- cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P =.022) and displayed inferior outcome compared with wild- type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy P = .022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P =.003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-kB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

  • 41. Meeths, Marie
    et al.
    Chiang, Samuel C. C.
    Wood, Stephanie M.
    Entesarian, Miriam
    Schlums, Heinrich
    Bang, Benedicte
    Nordenskjold, Edvard
    Björklund, Caroline
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jakovljevic, Gordana
    Jazbec, Janez
    Hasle, Henrik
    Holmqvist, Britt-Marie
    Rajic, Ljubica
    Pfeifer, Susan
    Rosthoj, Steen
    Sabel, Magnus
    Salmi, Toivo T.
    Stokland, Tore
    Winiarski, Jacek
    Ljunggren, Hans-Gustaf
    Fadeel, Bengt
    Nordenskjold, Magnus
    Henter, Jan-Inge
    Bryceson, Yenan T.
    Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 22, p. 5783-5793Article in journal (Refereed)
    Abstract [en]

    Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies. (Blood. 2011;118(22):5783-5793)

  • 42. Mellqvist, Ulf-Henrik
    et al.
    Gimsing, Peter
    Hjertner, Oyvind
    Lenhoff, Stig
    Laane, Edward
    Remes, Kari
    Steingrimsdottir, Hlif
    Abildgaard, Niels
    Ahlberg, Lucia
    Blimark, Cecilie
    Dahl, Inger Marie
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gedde-Dahl, Tobias
    Gregersen, Henrik
    Gruber, Astrid
    Guldbrandsen, Nina
    Haukas, Einar
    Carlson, Kristina
    Kvam, Ann Kristin
    Nahi, Hareth
    Lindas, Roald
    Andersen, Niels Frost
    Turesson, Ingemar
    Waage, Anders
    Westin, Jan
    Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, no 23, p. 4647-4654Article in journal (Refereed)
    Abstract [en]

    The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the >= VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.

  • 43. Milani, Lili
    et al.
    Lundmark, Anders
    Kiialainen, Anna
    Nordlund, Jessica
    Flaegstad, Trond
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Heyman, Mats
    Jonmundsson, Gudmundur
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Söderhäll, Stefan
    Gustafsson, Mats G
    Lönnerholm, Gudmar
    Syvänen, Ann-Christine
    DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia.2010In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, no 6, p. 1214-25Article in journal (Refereed)
    Abstract [en]

    Despite improvements in the prognosis of childhood acute lymphoblastic leukemia (ALL), subgroups of patients would benefit from alternative treatment approaches. Our aim was to identify genes with DNA methylation profiles that could identify such groups. We determined the methylation levels of 1320 CpG sites in regulatory regions of 416 genes in cells from 401 children diagnosed with ALL. Hierarchical clustering of 300 CpG sites distinguished between T-lineage ALL and B-cell precursor (BCP) ALL and between the main cytogenetic subtypes of BCP ALL. It also stratified patients with high hyperdiploidy and t(12;21) ALL into 2 subgroups with different probability of relapse. By using supervised learning, we constructed multivariate classifiers by external cross-validation procedures. We identified 40 genes that consistently contributed to accurate discrimination between the main subtypes of BCP ALL and gene sets that discriminated between subtypes of ALL and between ALL and controls in pairwise classification analyses. We also identified 20 individual genes with DNA methylation levels that predicted relapse of leukemia. Thus, methylation analysis should be explored as a method to improve stratification of ALL patients. The genes highlighted in our study are not enriched to specific pathways, but the gene expression levels are inversely correlated to the methylation levels.

  • 44. Nahi, Hareth
    et al.
    Liwing, Johan
    Aldrin, Anders
    Andreasson, Johan
    Blimark, Cecilie
    Carlson, Kristina
    Enestig, Jon
    Flogegard, Max
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gruber, Astrid
    Johansson, Peter
    Kviele, Helene
    Lauri, Birgitta
    Mellqvist, Ulf-Henrik
    Nasman, Per
    Swedin, Agneta
    Svensson, Magnus
    Uttervall, Katarina
    Aschan, Johan
    Is Multiple Myeloma a Chronic Disease?: A Population Based Study Comparing 1843 Patients to a Matched Swedish Population2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 21Article in journal (Other academic)
  • 45. Nilsson, Christer
    et al.
    Hulegardh, Erik
    Lazarevic, Vladimir
    Garelius, Hege
    Derolf, Asa Rangert
    Mollgard, Lars
    Wennstrom, Lovisa
    Uggla, Bertil
    Antunovic, Petar
    Myhr-Eriksson, Kristina
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Höglund, Martin
    Juliusson, Gunnar
    Stockelberg, Dick
    Sören, Lehmann
    Allogeneic Transplantation in First Remission Improves Outcome in Secondary Acute Myeloid Leukemia2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 46.
    Nilsson, R. Jonas A.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Balaj, Leonora
    Hulleman, Esther
    van Rijn, Sjoerd
    Pegtel, D. Michiel
    Walraven, Maudy
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gerritsen, Winald R.
    Verheul, Henk M.
    Vandertop, W. Peter
    Noske, David P.
    Skog, Johan
    Wurdinger, Thomas
    Blood platelets contain tumor-derived RNA biomarkers2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 13, p. 3680-3683Article in journal (Refereed)
    Abstract [en]

    Diagnostic platforms providing biomarkers that are highly predictive for diagnosing, monitoring, and stratifying cancer patients are key instruments in the development of personalized medicine. We demonstrate that tumor cells transfer (mutant) RNA into blood platelets in vitro and in vivo, and show that blood platelets isolated from glioma and prostate cancer patients contain the cancer-associated RNA biomarkers EGFRvIII and PCA3, respectively. In addition, gene-expression profiling revealed a distinct RNA signature in platelets from glioma patients compared with normal control subjects. Because platelets are easily accessible and isolated, they may form an attractive platform for the companion diagnostics of cancer.

  • 47. Norrback, Karl Fredrik
    et al.
    Dahlenborg, Katarina
    Carlsson, Roland
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomerase activation in normal B lymphocytes and non-Hodgkin's lymphomas1996In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 88, no 1, p. 222-229Article in journal (Refereed)
    Abstract [en]

    Activation of telomerase seems to be a prerequisite for immortalization and is found in permanent cell lines and most malignant tumors. Normal somatic cells are generally telomerase negative, except for bone marrow stem cells. Weak activity is also present in peripheral blood cells. In the present study strong telomerase activity was demonstrated in vivo in normal mature cells of the immune system, as well as in malignant lymphomas. Benign lymph nodes had lower telomerase activity than benign tonsils, which exhibited intermediate to high activity comparable with findings in malignant lymphomas. In benign tonsils the activity seemed to be restricted to germinal center B cells. In benign lymphoid tissues telomerase activity correlated with B-cell numbers and cell proliferation, but this was not observed in the lymphoma group. High-grade lymphomas exhibited higher levels of telomerase compared with low-grade cases. The data showed that in vivo activation of telomerase is a characteristic feature of germinal center B cells. Different signals for activation of telomerase are likely to exist, one of them being immune stimulation. The data suggest that telomerase activity in malignant lymphomas can be explained by an "induction and retention" model, ie, transformation occurs in a normal, mature B cell with reactivated telomerase, which is retained in the neoplastic clone.

  • 48.
    Norrback, Karl-Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Enblad, Gunilla
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sundström, Christer
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomerase activity in Hodgkin's disease1998In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 92, no 2, p. 567-573Article in journal (Refereed)
    Abstract [en]

    Telomere maintenance executed by the action of telomerase seems to be a prerequisite for immortalization. Telomerase is found in most cell lines and malignant tumors. A telomerase-independent mechanism for telomere maintenance in Hodgkin's disease has been proposed in the absence of detectable telomerase activity. In this study, telomerase activity was detected in 31 of 77 Hodgkin's disease samples and a strong correlation between eosinophilia and absence of detectable telomerase activity was found. Purified eosinophils and specifically eosinophil-derived neurotoxin and eosinophilic cationic protein, both ribonucleases, were found to degrade telomerase. Purified neutrophils also exhibited weak telomerase degradative activity. Reanalysis of previously telomerase-negative Hodgkin's disease samples with eosinophilia using ribonuclease inhibitors resulted in the detection of telomerase activity. Ribonuclease-containing cells in vivo thus have a considerable impact on the detectability of telomerase. In Hodgkin's disease samples without eosinophilia, 24 of 27 exhibited telomerase activity at decreased levels compared with non-Hodgkin's lymphomas and at increased levels compared with reactive nodes indicative of a telomerase positive tumor component in Hodgkin's disease. Telomerase positivity of the Hodgkin's and Reed-Sternberg cells in vivo was also supported by high levels of telomerase expression in Hodgkin's disease cell lines. Based on our data, Hodgkin's lymphomas are potential targets for antitelomerase therapy.

  • 49.
    Oldenborg, Per-Arne
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Gresham, Hattie D
    Chen, Yongmei
    Izui, Shozo
    Lindberg, Frederik P
    Lethal autoimmune hemolytic anemia in CD47-deficient nonobese diabetic (NOD) mice.2002In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 99, no 10, p. 3500-4Article in journal (Refereed)
    Abstract [en]

    The glycoprotein CD47 (integrin-associated protein, IAP) is present on the surface of virtually all cells, including red blood cells (RBCs). CD47 acts like a marker of self by ligating the macrophage inhibitory receptor signal regulatory protein alpha (SIRPalpha). In this manner mild reactivity of wild-type RBCs with macrophage phagocytic receptors is tolerated, whereas otherwise identical CD47-deficient RBCs are rapidly eliminated. We show here that virtually all CD47-deficient nonobese diabetic (NOD) mice spontaneously develop severe lethal autoimmune hemolytic anemia (AIHA) at 180 to 280 days of age, whereas none of the control CD47(+) NOD mice develop lethal AIHA at least during the first year of life. This phenotype is at least partially due to a markedly increased rate of elimination of opsonized CD47(-/-) compared to CD47(+) RBCs. Similarly, CD47(-/-)C57BL/6 mice were much more sensitive than their wild-type counterparts to experimental passive AIHA induced by anti-RBC monoclonal antibodies. Thus, CD47-SIRPalpha signaling can have a profound influence on the severity of AIHA, making manipulation of this signaling pathway a theoretically appealing avenue in the treatment of the disease.

  • 50.
    Olsson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology. Histologi med cellbiologi.
    Bruhns, Pierre
    Frazier, William A
    Ravetch, Jeffrey V
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Integrative Medical Biology, Histology and Cell Biology. Histologi med cellbiologi.
    Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia.2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, no 9, p. 3577-3582Article in journal (Refereed)
    Abstract [en]

    Interaction between target cell CD47 and the inhibitory macrophage receptor signal regulatory protein alpha (SIRPalpha) counteracts macrophage phagocytosis of CD47-expressing host cells. As platelets also express CD47, we asked whether inhibitory CD47/SIRPalpha signaling regulates normal platelet turnover and clearance of platelets in immune thrombocytopenic purpura (ITP). CD47(-/-) mice had a mild spontaneous thrombocytopenia, which was not due to a decreased platelet half-life as a result of increased expression of P-selectin, CD61, or phosphatidylserine. In contrast, CD47(-/-) platelets were rapidly cleared when transfused into CD47(+/+) recipients, whereas CD47(+/-) platelets had a nearly normal half-life in CD47(+/+) mice under nonautoimmune conditions. CD47(-/-) mice were more sensitive to ITP, as compared with CD47(+/+) mice. In vitro, macrophage phagocytosis of immunoglobulin G (IgG)-opsonized CD47(-/-) platelets was significantly higher than that for equally opsonized CD47(+/+) platelets. However, when SIRPalpha was blocked, phagocytosis of CD47(+/+) platelets increased to the level of CD47(-/-) platelets. Phagocytosis of opsonized CD47(+/-) platelets was higher than that for CD47(+/+) platelets, but lower than that for CD47(-/-) platelets, suggesting a gene-dose effect of CD47 in this system. In conclusion, we suggest that inhibitory CD47/SIRPalpha signaling is involved in regulating platelet phagocytosis in ITP, and that targeting SIRPalpha may be a new means of reducing platelet clearance in ITP.

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