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  • 1.
    Baliakas, Panagiotis
    et al.
    Uppsala Univ, Sweden.
    Tesi, Bianca
    Karolinska Univ Hosp, Sweden.
    Wartiovaara-Kautto, Ulla
    Helsinki Univ Hosp, Finland.
    Stray-Pedersen, Asbjorg
    Oslo Univ Hosp, Norway.
    Friis, Lone Smidstrup
    Copenhagen Univ Hosp, Denmark.
    Dybedal, Ingunn
    Oslo Univ Hosp, Norway.
    Hovland, Randi
    Haukeland Hosp, Norway.
    Jahnukainen, Kirsi
    Helsinki Univ Hosp, Finland.
    Raaschou-Jensen, Klas
    Odense Univ Hosp, Denmark.
    Ljungman, Per
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Rustad, Cecilie F.
    Oslo Univ Hosp, Norway.
    Lautrup, Charlotte K.
    Aalborg Univ Hosp, Denmark.
    Kilpivaara, Outi
    Univ Helsinki, Finland; Univ Helsinki, Finland.
    Kittang, Astrid Olsnes
    Haukeland Hosp, Norway.
    Gronbaek, Kirsten
    Copenhagen Univ Hosp, Denmark.
    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.
    Hellstrom-Lindberg, Eva
    Karolinska Univ Hosp, Sweden.
    Andersen, Mette K.
    Copenhagen Univ Hosp, Denmark.
    Nordic Guidelines for Germline Predisposition to Myeloid Neoplasms in Adults: Recommendations for Genetic Diagnosis, Clinical Management and Follow-up2019In: HEMASPHERE, Vol. 3, no 6, article id UNSP e321Article in journal (Refereed)
    Abstract [en]

    Myeloid neoplasms (MNs) with germline predisposition have recently been recognized as novel entities in the latest World Health Organization (WHO) classification for MNs. Individuals with MNs due to germline predisposition exhibit increased risk for the development of MNs, mainly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Setting the diagnosis of MN with germline predisposition is of crucial clinical significance since it may tailor therapy, dictate the selection of donor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), determine the conditioning regimen, enable relevant prophylactic measures and early intervention or contribute to avoid unnecessary or even harmful medication. Finally, it allows for genetic counseling and follow-up of at-risk family members. Identification of these patients in the clinical setting is challenging, as there is no consensus due to lack of evidence regarding the criteria defining the patients who should be tested for these conditions. In addition, even in cases with a strong suspicion of a MN with germline predisposition, no standard diagnostic algorithm is available. We present the first version of the Nordic recommendations for diagnostics, surveillance and management including considerations for allo-HSCT for patients and carriers of a germline mutation predisposing to the development of MNs.

  • 2.
    Baudet, Anna
    et al.
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden; Department of Haematopoietic Stem Cell Transplantation Lund University Lund Sweden .
    Ek, Fredrik
    Department of Chemical Biology and Therapeutics Lund University Lund Sweden.
    Davidsson, Josef
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Soneji, Shamit
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Olsson, Roger
    Department of Chemical Biology and Therapeutics Lund University Lund Sweden.
    Magnusson, Mattias
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Cammenga, Jörg
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden;Department of Chemical Biology and Therapeutics Lund University Lund Sweden .
    Juliusson, Gunnar
    Department of Haematopoietic Stem Cell Transplantation Lund University Lund Sweden; Departments of Haematology Skanes University Hospital Lund University Lund Sweden.
    Small molecule screen identifies differentiation-promoting compounds targeting genetically diverse acute myeloid leukaemia2016In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 175, no 2, p. 342-346Article in journal (Other academic)
  • 3.
    Behrens, Kira
    et al.
    Leibniz Institute Expt Virol, Germany; Walter and Eliza Hall Institute Medical Research, Australia.
    Maul, Katrin
    Leibniz Institute Expt Virol, Germany.
    Tekin, Nilguen
    Leibniz Institute Expt Virol, Germany; Leibniz Institute Expt Virol, Germany.
    Kriebitzsch, Neele
    Leibniz Institute Expt Virol, Germany.
    Indenbirken, Daniela
    Leibniz Institute Expt Virol, Germany.
    Prassolov, Vladimir
    Engelhardt Institute Molecular Biol, Russia.
    Mueller, Ursula
    Leibniz Institute Expt Virol, Germany.
    Serve, Hubert
    Goethe University of Frankfurt, Germany.
    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.
    Stocking, Carol
    Leibniz Institute Expt Virol, Germany.
    RUNX1 cooperates with FLT3-ITD to induce leukemia2017In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 214, no 3, p. 737-752Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) is induced by the cooperative action of deregulated genes that perturb self-renewal, proliferation, and differentiation. Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AML, confer poor prognosis, and stimulate myeloproliferation. AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. In this study, to understand this paradox, we investigated the impact of RUNX1 and FLT3-ITD coexpression. FLT3-ITD directly impacts on RUNX1 activity, whereby up-regulated and phosphorylated RUNX1 cooperates with FLT3-ITD to induce AML. Inactivating RUNX1 in tumors releases the differentiation block and down-regulates genes controlling ribosome biogenesis. We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML. These results establish and elucidate the unanticipated oncogenic function of RUNX1 in AML. We predict that blocking RUNX1 activity will greatly enhance current therapeutic approaches using FLT3 inhibitors.

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    fulltext
  • 4.
    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.

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  • 5.
    Engert, Andreas
    et al.
    University of Cologne, Germany.
    Balduini, Carlo
    IRCCS Policlin San Matteo Fdn, Italy.
    Brand, Anneke
    Leids University, Netherlands.
    Coiffier, Bertrand
    University of Lyon 1, France.
    Cordonnier, Catherine
    Hop University of Henri Mondor, France.
    Doehner, Hartmut
    University of Klinikum Ulm, Germany.
    Duyvene de Wit, Thom
    European Hematol Assoc, Netherlands.
    Eichinger, Sabine
    Medical University of Wien, Austria.
    Fibbe, Willem
    Leids University, Netherlands.
    Green, Tony
    Cambridge Institute Medical Research, England.
    de Haas, Fleur
    European Hematol Assoc, Netherlands.
    Iolascon, Achille
    University of Naples Federico II, Italy.
    Jaffredo, Thierry
    University of Paris 06, France.
    Rodeghiero, Francesco
    Osped San Bortolo, Italy.
    Salles, Gilles
    University of Lyon, France.
    Jacob Schuringa, Jan
    University of Groningen, Netherlands.
    Andre, Marc
    Catholic University of Louvain, Belgium.
    Andre-Schmutz, Isabelle
    University of Paris 05, France.
    Bacigalupo, Andrea
    Osped San Martino Genova, Italy.
    Bochud, Pierre-Yves
    University of Lausanne, Switzerland.
    den Boer, Monique
    Erasmus MC, Netherlands.
    Bonini, Chiara
    University of Milan, Italy.
    Camaschella, Clara
    San Raffaele Institute, Italy.
    Cant, Andrew
    Great North Childrens Hospital, England.
    Domenica Cappellini, Maria
    University of Milan, Italy.
    Cazzola, Mario
    University of Pavia, Italy.
    Lo Celso, Cristina
    Imperial Coll London, England.
    Dimopoulos, Meletios
    University of Athens, Greece.
    Douay, Luc
    University of Paris 06, France.
    Dzierzak, Elaine
    University of Edinburgh, Scotland.
    Einsele, Hermann
    University of Wurzburg, Germany.
    Ferreri, Andres
    Ist Science San Raffaele, Italy.
    De Franceschi, Lucia
    University of Verona, Italy.
    Gaulard, Philippe
    Hop Henri Mondor, France.
    Gottgens, Berthold
    University of Cambridge, England.
    Greinacher, Andreas
    University of Medical Greifswald, Germany; Ernst Moritz Arndt University of Greifswald, Germany.
    Gresele, Paolo
    University of Perugia, Italy.
    Gribben, John
    Queen Mary University of London, England.
    de Haan, Gerald
    University of Groningen, Netherlands.
    Hansen, John-Bjarne
    University of Tromso, Norway.
    Hochhaus, Andreas
    University of Klinikum Jena, Germany.
    Kadir, Rezan
    Royal Free Hospital, England.
    Kaveri, Srini
    Institute National Sante and Rech Med, France.
    Kouskoff, Valerie
    University of Manchester, England.
    Kuehne, Thomas
    University of Kinderspital Beider Basel, Switzerland.
    Kyrle, Paul
    Medical University of Wien, Austria.
    Ljungman, Per
    Karolinska Institute, Sweden.
    Maschmeyer, Georg
    Klinikum Ernst Von Bergmann, Germany.
    Mendez-Ferrer, Simon
    University of Cambridge, England.
    Milsom, Michael
    Deutsch Krebsforschungszentrum Neuenheimer Feld, Germany.
    Mummery, Christine
    Leids University, Netherlands.
    Ossenkoppele, Gert
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Pecci, Alessandro
    University of Pavia, Italy.
    Peyvandi, Flora
    University of Milan, Italy.
    Philipsen, Sjaak
    Erasmus MC, Netherlands.
    Reitsma, Pieter
    Leids University, Netherlands.
    Maria Ribera, Jose
    Institute Catala Oncol, Spain.
    Risitano, Antonio
    University of Naples Federico II, Italy.
    Rivella, Stefano
    Weill Medical Coll, NY USA.
    Ruf, Wolfram
    Johannes Gutenberg University of Mainz, Germany.
    Schroeder, Timm
    Swiss Federal Institute Technology, Switzerland.
    Scully, Marie
    University of Coll London Hospital, England.
    Socie, Gerard
    Hop St Louis, France.
    Staal, Frank
    Leids University, Netherlands.
    Stanworth, Simon
    John Radcliffe Hospital, England.
    Stauder, Reinhard
    Medical University of Innsbruck, Austria.
    Stilgenbauer, Stephan
    University of Klinikum Ulm, Germany.
    Tamary, Hannah
    Schneider Childrens Medical Centre Israel, Israel.
    Theilgaard-Monch, Kim
    University of Copenhagen, Denmark.
    Lay Thein, Swee
    Kings Coll London, England.
    Tilly, Herve
    University of Rouen, France.
    Trneny, Marek
    Charles University of Prague, Czech Republic.
    Vainchenker, William
    Institute Gustave Roussy, France.
    Maria Vannucchi, Alessandro
    University of Florence, Italy.
    Viscoli, Claudio
    University of Genoa, Italy.
    Vrielink, Hans
    Sanquin Research, Netherlands.
    Zaaijer, Hans
    Sanquin Research, Netherlands.
    Zanella, Alberto
    Osped Maggiore Policlin, Italy.
    Zolla, Lello
    University of Tuscia, Italy.
    Jan Zwaginga, Jaap
    Leids University, Netherlands.
    Aguilar Martinez, Patricia
    Hop St Eloi, France.
    van den Akker, Emile
    Sanquin Research, Netherlands.
    Allard, Shubha
    Barts Health NHS Trust and NHS Blood and Transplant, England.
    Anagnou, Nicholas
    University of Athens, Greece.
    Andolfo, Immacolata
    University of Naples Federico II, Italy.
    Andrau, Jean-Christophe
    Institute Genet Molecular Montpellier, France.
    Angelucci, Emanuele
    Osp A Businco, Italy.
    Anstee, David
    NHSBT Blood Centre, England.
    Aurer, Igor
    University of Zagreb, Croatia.
    Avet-Loiseau, Herve
    Centre Hospital University of Toulouse, France.
    Aydinok, Yesim
    Ege University, Turkey.
    Bakchoul, Tamam
    University of Medical Greifswald, Germany.
    Balduini, Alessandra
    IRCCS Policlin San Matteo Fdn, Italy.
    Barcellini, Wilma
    Osped Maggiore Policlin, Italy.
    Baruch, Dominique
    University of Paris 05, France.
    Baruchel, Andre
    Hop University of Robert Dabre, France.
    Bayry, Jagadeesh
    Institute National Sante and Rech Med, France.
    Bento, Celeste
    Centre Hospital and University of Coimbra, Portugal.
    van den Berg, Anke
    University of Groningen, Netherlands.
    Bernardi, Rosa
    Ist Science San Raffaele, Italy.
    Bianchi, Paola
    Osped Maggiore Policlin, Italy.
    Bigas, Anna
    Institute Hospital del Mar Investgac Med, Spain.
    Biondi, Andrea
    University of Milano Bicocca, Italy.
    Bohonek, Milos
    Central Mil Hospital, Czech Republic.
    Bonnet, Dominique
    Francis Crick Institute, England.
    Borchmann, Peter
    University Hospital Cologne Int, Germany.
    Borregaard, Niels
    University of Copenhagen, Denmark.
    Braekkan, Sigrid
    University of Tromso, Norway.
    van den Brink, Marcel
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Brodin, Ellen
    University of Sykehuset Nordic Norge, Norway.
    Bullinger, Lars
    University of Klin Ulm, Germany.
    Buske, Christian
    University of Klinikum Ulm, Germany.
    Butzeck, Barbara
    European Federat Assoc Patients Haemochromatosis, France.
    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.
    Campo, Elias
    University of Barcelona, Spain.
    Carbone, Antonino
    Centre Riferimento Oncol, Italy.
    Cervantes, Francisco
    University of Barcelona, Spain.
    Cesaro, Simone
    Policlin GB Rossi, Italy.
    Charbord, Pierre
    University of Paris 06, France.
    Claas, Frans
    Leids University, Netherlands.
    Cohen, Hannah
    Imperial Coll London, England.
    Conard, Jacqueline
    Hop Hotel Dieu, France.
    Coppo, Paul
    Hop St Antoine, France.
    Vives Corrons, Joan-Lluis
    University of Barcelona, Spain.
    da Costa, Lydie
    Hop Robert Debre, France.
    Davi, Frederic
    University of Paris 06, France.
    Delwel, Ruud
    Erasmus MC, Netherlands.
    Dianzani, Irma
    University of Turin, Italy.
    Domanovic, Dragoslav
    European Centre Disease Prevent and Control, Sweden.
    Donnelly, Peter
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Dovc Drnovsek, Tadeja
    Zavod RS Transfuzijsko Med, Slovenia.
    Dreyling, Martin
    University of Munich, Germany.
    Du, Ming-Qing
    University of Cambridge, England.
    Dufour, Carlo
    Ist Giannina Gaslini, Italy.
    Durand, Charles
    University of Paris 06, France.
    Efremov, Dimitar
    Int Centre Genet Engn and Biotechnol, Italy.
    Eleftheriou, Androulla
    Thalassaemia Int Fed, Cyprus.
    Elion, Jacques
    University of Paris Diderot, France.
    Emonts, Marieke
    Great North Childrens Hospital, England.
    Engelhardt, Monika
    University of Klinikum Freiburg, Germany.
    Ezine, Sophie
    University of Paris 05, France.
    Falkenburg, Fred
    Leids University, Netherlands.
    Favier, Remi
    Hop Enfants A Trousseau, France.
    Federico, Massimo
    University of Modena and Reggio Emilia, Italy.
    Fenaux, Pierre
    Hop St Louis, France.
    Fitzgibbon, Jude
    Queen Mary University of London, England.
    Flygare, Johan
    Lund University, Sweden.
    Foa, Robin
    University of Roma La Sapienza, Italy.
    Forrester, Lesley
    University of Edinburgh, Scotland.
    Galacteros, Frederic
    Hop University of Henri Mondor, France.
    Garagiola, Isabella
    University of Milan, Italy.
    Gardiner, Chris
    University of Oxford, England.
    Garraud, Olivier
    University of St Etienne, France.
    van Geet, Christel
    Katholieke University of Leuven, Belgium.
    Geiger, Hartmut
    University of Klinikum Ulm, Germany.
    Geissler, Jan
    CML Advocates Network, Switzerland.
    Germing, Ulrich
    University of Klinikum Dusseldorf, Germany.
    Ghevaert, Cedric
    University of Cambridge, England.
    Girelli, Domenico
    Institute Cochin, France.
    Godeau, Bertrand
    Hop University of Henri Mondor, France.
    Goekbuget, Nicola
    University of Klinikum Frankfurt, Germany.
    Goldschmidt, Hartmut
    University of Klinikum Heidelberg, Germany.
    Goodeve, Anne
    University of Sheffield, England.
    Graf, Thomas
    Centre Genom Regulat, Spain.
    Graziadei, Giovanna
    University of Milan, Italy.
    Griesshammer, Martin
    Muhlenkreisklin, Germany.
    Gruel, Yves
    Hop Trousseau, France.
    Guilhot, Francois
    University of Poitiers, France.
    von Gunten, Stephan
    University of Bern, Switzerland.
    Gyssens, Inge
    University of Hasselt, Belgium.
    Halter, Jorg
    University of Spital Basel, Switzerland.
    Harrison, Claire
    Guys and St Thomas, England.
    Harteveld, Cornelis
    Leids University, Netherlands.
    Hellstrom-Lindberg, Eva
    Karolinska Institute, Sweden.
    Hermine, Olivier
    University of Paris 05, France.
    Higgs, Douglas
    University of Oxford, England.
    Hillmen, Peter
    University of Leeds, England.
    Hirsch, Hans
    University of Basel, Switzerland.
    Hoskin, Peter
    Mt Vernon Hospital, England.
    Huls, Gerwin
    University of Groningen, Netherlands.
    Inati, Adlette
    Lebanese American University, Lebanon.
    Johnson, Peter
    University of Southampton, England.
    Kattamis, Antonis
    University of Athens, Greece.
    Kiefel, Volker
    University of Medical Rostock, Germany.
    Kleanthous, Marina
    Cyprus School Molecular Med, Cyprus.
    Klump, Hannes
    University of Klinikum Essen, Germany.
    Krause, Daniela
    Georg Speyer Haus Institute Tumorbiol and Expt Therapy, Germany.
    Kremer Hovinga, Johanna
    University of Bern, Switzerland.
    Lacaud, Georges
    University of Manchester, England.
    Lacroix-Desmazes, Sebastien
    Institute National Sante and Rech Med, France.
    Landman-Parker, Judith
    Hop Armand Trousseau, France.
    LeGouill, Steven
    University of Nantes, France.
    Lenz, Georg
    University of Klinikum Munster, Germany.
    von Lilienfeld-Toal, Marie
    University of Klinikum Jena, Germany.
    von Lindern, Marieke
    Sanquin Research, Netherlands.
    Lopez-Guillermo, Armando
    Hospital Clin Barcelona, Spain.
    Lopriore, Enrico
    Leiden University of Medical Centre, Netherlands.
    Lozano, Miguel
    University of Barcelona, Spain.
    MacIntyre, Elizabeth
    University of Paris 05, France.
    Makris, Michael
    Royal Hallamshire Hospital, England; University of Sheffield, England.
    Mannhalter, Christine
    Medical University of Wien, Austria.
    Martens, Joost
    Radboud University of Nijmegen, Netherlands.
    Mathas, Stephan
    Charite University of Medical Berlin, Germany.
    Matzdorff, Axel
    Caritasclin Saarbrucken, Germany.
    Medvinsky, Alexander
    University of Edinburgh, Scotland.
    Menendez, Pablo
    University of Barcelona, Spain.
    Rita Migliaccio, Anna
    Mt Sinai Hospital, NY 10029 USA.
    Miharada, Kenichi
    Lund University, Sweden.
    Mikulska, Malgorzata
    University of Genoa, Italy.
    Minard, Veronique
    Institute Gustave Roussy, France.
    Montalban, Carlos
    MD Anderson Cancer Centre Madrid, Spain.
    de Montalembert, Mariane
    Necker Enfants Malades University Hospital, France.
    Montserrat, Emili
    Hospital Clin Barcelona, Spain.
    Morange, Pierre-Emmanuel
    Aix Marseille University, France.
    Mountford, Joanne
    University of Glasgow, Scotland.
    Muckenthaler, Martina
    University of Klinikum Heidelberg, Germany.
    Mueller-Tidow, Carsten
    University of Klinikum Halle, Germany.
    Mumford, Andrew
    University of Bristol, England.
    Nadel, Bertrand
    University of Mediterranee, France.
    Navarro, Jose-Tomas
    Institute Catala Oncol, Spain.
    el Nemer, Wassim
    INSERM, France.
    Noizat-Pirenne, France
    Etab Francais Sang, France.
    OMahony, Brian
    European Haemophilia Consortium, Belgium.
    Oldenburg, Johannes
    University of Klinikum Bonn, Germany.
    Olsson, Martin
    Lund University, Sweden.
    Oostendorp, Robert
    Technical University of Munich, Germany.
    Palumbo, Antonio
    University of Turin, Italy.
    Passamonti, Francesco
    Osp Circolo and Fdn Macchi, Italy.
    Patient, Roger
    University of Oxford, England.
    Peffault de Latour, Regis
    NIH, MD 20892 USA.
    Pflumio, Francoise
    Institute Rech Radiobiol Cellulaire and Molecular IRCM, France.
    Pierelli, Luca
    University of Roma La Sapienza, Italy.
    Piga, Antonio
    University of Turin, Italy.
    Pollard, Debra
    Royal Free Hospital, England.
    Raaijmakers, Marc
    Erasmus MC, Netherlands.
    Radford, John
    University of Manchester, England.
    Rambach, Ralf
    DLH, Germany.
    Koneti Rao, A.
    Temple University of School Med, PA USA.
    Raslova, Hana
    University of Paris Sud, France.
    Rebulla, Paolo
    Ops Maggiore, Italy.
    Rees, David
    Kings Coll Hospital London, England.
    Ribrag, Vincent
    Institute Gustave Roussy, France.
    Rijneveld, Anita
    Erasmus MC, Netherlands.
    Rinalducci, Sara
    University of Tuscia, Italy.
    Robak, Tadeusz
    University of Medical Lodz, Poland.
    Roberts, Irene
    University of Oxford, England.
    Rodrigues, Charlene
    Great North Childrens Hospital, England.
    Rosendaal, Frits
    Leids University, Netherlands.
    Rosenwald, Andreas
    University of Wurzburg, Germany.
    Rule, Simon
    Derriford Hospital, England.
    Russo, Roberta
    University of Naples Federico II, Italy.
    Saglio, Guiseppe
    University of Turin, Italy.
    Sanchez, Mayka
    IJC, Spain.
    Scharf, Ruediger E.
    University of Dusseldorf, Germany.
    Schlenke, Peter
    Medical University of Graz, Austria.
    Semple, John
    St Michaels Hospital, Canada.
    Sierra, Jorge
    Hospital Santa Creu I Sant Pau, Spain.
    So-Osman, Cynthia
    Sanquin Research, Netherlands.
    Manuel Soria, Jose
    Hospital Santa Creu I Sant Pau, Spain.
    Stamatopoulos, Kostas
    Institute Appl Bioscience, Greece.
    Stegmayr, Bernd
    Umeå University, Sweden.
    Stunnenberg, Henk
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Swinkels, Dorine
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Pedro Taborda Barata, Joao
    University of Lisbon, Portugal.
    Taghon, Tom
    University of Ghent, Belgium.
    Taher, Ali
    Amer University of Beirut Medical Centre, Lebanon.
    Terpos, Evangelos
    National and Kapodistrian University of Athes, Greece.
    Daniel Tissot, Jean
    University of Lausanne, Switzerland.
    Touw, Ivo
    Erasmus MC, Netherlands.
    Toye, Ash
    University of Bristol, England.
    Trappe, Ralf
    Charite University of Medical Berlin, Germany.
    Unal, Sule
    Hacettepe University, Turkey.
    Vaulont, Sophie
    Institute Cochin, France.
    Viprakasit, Vip
    Mahidol University, Thailand.
    Vitolo, Umberto
    University of Turin, Italy.
    van Wijk, Richard
    University of Medical Centre Utrecht, Netherlands.
    Wojtowicz, Agnieszka
    CHU Vaudois, Switzerland.
    Zeerleder, Sacha
    Sanquin Research, Netherlands.
    Zieger, Barbara
    University of Klinikum Freiburg, Germany.
    The European Hematology Association Roadmap for European Hematology Research: a consensus document2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 2, p. 115-208Article in journal (Refereed)
    Abstract [en]

    The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine sections in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.

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  • 6.
    Eriksson, Mia
    et al.
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Peña-Martínez, Pablo
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Ramakrishnan, Ramprasad
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Chapellier, Marion
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Högberg, Carl
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Glowacki, Gabriella
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Orsmark-Pietras, Christina
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Velasco-Hernández, Talía
    Department of Molecular Hematology, Lund University, Lund, Sweden.
    Lazarevic, Vladimir Lj
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Juliusson, Gunnar
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, 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.
    Mulloy, James C
    Division of Experimental Hematology and Cancer Biology, Cincinnati Childrens Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
    Richter, Johan
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Fioretos, Thoas
    Department of Clinical Genetics, Lund, Sweden.
    Ebert, Benjamin L.
    Division of Hematology, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, USA.
    Järås, Marcus
    Department of Clinical Genetics, Lund, Sweden.
    Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NF?B-dependent differentiation of AML cells2017In: Blood advances, ISSN 2473-9529, Vol. 1, no 23, p. 2046-2057Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities. Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary AML CD34+CD38-cells relative to corresponding normal bone marrow cells. Activating the TLR1/TLR2 complex by the agonist Pam3CSK4 inMLL-AF9-driven human AML resulted in induction of apoptosis by p38 MAPK-dependent activation of Caspase 3 and myeloid differentiation in a NF?B-dependent manner. By using murineTrp53 -/- MLL-AF9AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murineAML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined toMLL-rearranged AML. We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects. Ex vivo Pam3CSK4 treatment inhibited murine and human leukemia-initiating cells, whereas murine normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected. Consistent with these findings, primary human AML cells across several genetic subtypes of AML were more vulnerable for TLR1/TLR2 activation relative to normal human HSPCs. In theMLL-AF9AML mouse model, treatment with Pam3CSK4 provided proof of concept for in vivo therapeutic efficacy. Our results demonstrate that TLR1 and TLR2 are upregulated on primitive AML cells and that agonistic targeting of TLR1/TLR2 forces AML cells into apoptosis by p38 MAPK-dependent activation of Caspase 3, and differentiation by activating NF?B, thus revealing a new putative strategy for therapeutically targeting AML cells.

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  • 7.
    Gonzalez, Javier Martin
    et al.
    Univ Copenhagen, Denmark.
    Baudet, Aurelie
    Lund Univ, Sweden.
    Abelechian, Sahar
    Univ Copenhagen, Denmark.
    Bonderup, Kasper
    Univ Copenhagen, Denmark.
    dAltri, Teresa
    Univ Copenhagen, Denmark.
    Porse, Bo
    Univ Copenhagen, Denmark.
    Brakebusch, Cord
    Univ Copenhagen, Denmark.
    Juliusson, Gunnar
    Lund Univ, Sweden; 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. Lund Univ, Sweden.
    A new genetic tool to improve immune-compromised mouse models: Derivation and CRISPR/Cas9-mediated targeting of NRG embryonic stem cell lines2018In: Genesis, ISSN 1526-954X, E-ISSN 1526-968X, Vol. 56, no 9, article id e23238Article in journal (Refereed)
    Abstract [en]

    Development of human hematopoietic stem cells and differentiation of embryonic stem (ES) cells/induced pluripotent stem (iPS) cells to hematopoietic stem cells are poorly understood. NOD (Non-obese diabetic)-derived mouse strains, such as NSG (NOD-Scid-il2Rg) or NRG (NOD-Rag1-il2Rg), are the best available models for studying the function of fetal and adult human hematopoietic cells as well as ES/iPS cell-derived hematopoietic stem cells. Unfortunately, engraftment of human hematopoietic stem cells is very variable in these models. Introduction of additional permissive mutations into these complex genetic backgrounds of the NRG/NSG mice by natural breeding is a very demanding task in terms of time and resources. Specifically, since the genetic elements defining the NSG/NRG phenotypes have not yet been fully characterized, intense backcrossing is required to ensure transmission of the full phenotype. Here we describe the derivation of embryonic stem cell (ESC) lines from NRG pre-implantation embryos generated by in vitro fertilization followed by the CRISPR/CAS9 targeting of the Gata-2 locus. After injection into morula stage embryos, cells from three tested lines gave rise to chimeric adult mice showing high contribution of the ESCs (70%-100%), assessed by coat color. Moreover, these lines have been successfully targeted using Cas9/CRISPR technology, and the mutant cells have been shown to remain germ line competent. Therefore, these new NRG ESC lines combined with genome editing nucleases bring a powerful genetic tool that facilitates the generation of new NOD-based mouse models with the aim to improve the existing xenograft models.

  • 8.
    Hayden, Patrick J.
    et al.
    St James Hosp, Ireland.
    Iacobelli, Simona
    Tor Vergata Univ Rome, Italy.
    Antonio Perez-Simon, Jose
    Hosp Univ Virgen Rocio, Spain; Univ Seville, Spain.
    van Biezen, Anja
    Leiden EBMT Data Off, Netherlands.
    Minnema, Monique
    Univ Med Ctr Utrecht, Netherlands.
    Niittyvuopio, Riitta
    HUCH Comprehens Canc Ctr, Finland.
    Schoenland, Stefan
    Heidelberg Univ, Germany.
    Meijer, Ellen
    Vrije Univ Amsterdam Med Ctr, Netherlands.
    Blaise, Didier
    Marseille Inst Paoli Calmettes, France.
    Milpied, Noel
    CHU Bordeaux, France.
    Marquez-Malaver, Francisco J.
    Hosp Univ Virgen Rocio, Spain; Univ Seville, Spain.
    Veelken, Joan Hendrik
    Leiden Univ, Netherlands.
    Maertens, Johan
    Univ Hosp Gasthuisberg, Belgium.
    Michallet, Mauricette
    Ctr Hosp Lyon Sud, France.
    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.
    NGuyen, Stephanie
    Hop La Pitie Salpetriere, France.
    Niederwieser, Dietger
    Univ Hosp Leipzig, Germany.
    Hunault-Berger, Mathilde
    CHRU Angers, France.
    Bourhis, Jean Henri
    Gustave Roussy Inst Cancerol, France.
    Passweg, Jakob
    Univ Hosp Basel, Switzerland.
    Bermudez, Arancha
    FEA Serv Hematol, Spain.
    Chalandon, Yves
    Hop Univ Geneve, Switzerland; Univ Geneva, Switzerland.
    Yakoub-Agha, Ibrahim
    Hop Claude Huriez, France.
    Garderet, Laurent
    Hosp St Antoine, France.
    Kroeger, Nicolaus
    Univ Hosp Eppendorf, Germany.
    Conditioning-based outcomes after allogeneic transplantation for myeloma following a prior autologous transplant (1991-2012) on behalf of EBMT CMWPIn: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609Article in journal (Refereed)
    Abstract [en]

    Objectives The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma-reduced intensity conditioning (RIC), non-myeloablative (NMA), myeloablative conditioning (MAC) or Auto-AlloHCT-on outcomes in patients who had had a prior autologous transplant. Methods A retrospective analysis of the EBMT database (1991-2012) was performed. Results A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto-Allo transplants. At a median follow-up of 54 months, the probabilities of overall survival (OS) at 5 years were 39% (95% CI 31%-47%), 45% (95% CI 32%-57%), 19% (95% CI 6%-32%) and 34% (95% CI 17%-51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P = .004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR = 4.1, P amp;lt; .001) but not after 2002 (HR = 1.2, P = .276). Conclusion From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches.

  • 9.
    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.

  • 10.
    Juliusson, Gunnar
    et al.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Hagberg, Oskar
    Lund Univ, Sweden.
    Lazarevic, Vladimir Lj
    Skane Univ Hosp, Sweden.
    Olander, Emma
    Sundsvall Hosp, 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.
    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.
    Wennstrom, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Mollgard, Lars
    Sahlgrens Univ Hosp, Sweden.
    Brune, Mats
    Sahlgrens Univ Hosp, Sweden.
    Jadersten, Martin
    Karolinska Univ Hosp, Sweden.
    Deneberg, Stefan
    Karolinska Univ Hosp, Sweden.
    Lehmann, Soren
    Karolinska Univ Hosp, Sweden; Uppsala Univ, Sweden.
    Derolf, Asa Rangert
    Karolinska Univ Hosp, Sweden.
    Hoglund, Martin
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Improved survival of men 50 to 75 years old with acute myeloid leukemia over a 20-year period2019In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 134, no 18, p. 1558-1561Article in journal (Other academic)
    Abstract [en]

    n/a

  • 11.
    Juliusson, Gunnar
    et al.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Jadersten, Martin
    Karolinska Univ Hosp, Sweden.
    Deneberg, Stefan
    Karolinska Univ Hosp, Sweden.
    Lehmann, Soren
    Karolinska Univ Hosp, Sweden; Uppsala Univ, Sweden.
    Mollgard, Lars
    Sahlgrens Univ Hosp, Sweden.
    Wennstrom, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Antunovic, Petar
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Cammenga, Jörg
    Linköping University, Department of Biomedical and Clinical Sciences, 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.
    Lorenz, Fryderyk
    Norrland Univ Hosp, Sweden.
    Olander, Emma
    Sundsvall Hosp, Sweden.
    Lazarevic, Vladimir Lj
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Hoglund, Martin
    Uppsala Univ, Sweden.
    The prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age-dependent in the population-based setting2020In: BLOOD ADVANCES, ISSN 2473-9529, Vol. 4, no 6, p. 1094-1101Article in journal (Refereed)
    Abstract [en]

    In acute myeloid leukemia (AML) FLT3 internal tandem duplication (ITD) and nucleophosmin 1 (NPM1) mutations provide prognostic information with clinical relevance through choice of treatment, but the effect of age and sex on these molecular markers has not been evaluated. The Swedish AML Registry contains data on FLT3-ITD and NPM1 mutations dating to 2007, and 1570 adult patients younger than 75 years, excluding acute promyelocytic leukemia, had molecular results reported. Females more often had FLT3(ITD) and/or NPM1(mut) (FLT3(ITD) : female, 29%; male, 22% [P - .00151; NPM1(mut) : female, 36%; male, 27% [P < .0001]), and more males were double negative (female, 53%; male, 64%; P < .0001). Patients with FLT3(ITD) were younger than those without (59 vs 62 years; P = .023), in contrast to patients with NPM1(mut) (62 vs 60 years; P = .059). Interestingly, their prognostic effect had a strong dependence on age: FLT3(ITD) indicated poor survival in younger patients (<60 years; P = .00003), but had no effect in older patients (60-74 years; P = .5), whereas NPM1(mut) indicated better survival in older patients (P = .00002), but not in younger patients (P = .95). In FLT3(ITD)/NPM1(mut) patients, the survival was less dependent on age than in the other molecular subsets. These findings are likely to have clinical relevance for risk grouping, study design, and choice of therapy.

  • 12.
    Lazarevic, Vladimir Lj
    et al.
    Skane Univ Hosp, Sweden.
    Bredberg, Anders
    Lund Univ, Sweden.
    Lorenz, Fryderyk
    Norrland Univ Hosp, Sweden.
    Ohlander, Emma
    Sundsvall Hosp, 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.
    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.
    Wennstrom, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Mollgard, Lars
    Sahlgrens Univ Hosp, Sweden.
    Deneberg, Stefan
    Karolinska Univ Hosp, Sweden.
    Derolf, Asa
    Karolinska Univ Hosp, Sweden.
    Hoglund, Martin
    Acad Hosp, Sweden.
    Juliusson, Gunnar
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Acute myeloid leukemia in very old patients2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 12, p. E578-E580Article in journal (Other academic)
    Abstract [en]

    n/a

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  • 13.
    Lübking, Anna
    et al.
    Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
    Vosberg, Sebastian
    Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany .
    Konstandin, Nicola
    Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
    Dufour, Annika
    Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
    Graf, Alexander
    Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
    Krebs, Stefan
    Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
    Blum, Helmut
    Laboratory for Functional Genome Analysis at the Gene Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Weber, Axel
    Institut für Humangenetik, Universitätsklinikum Giessen und Marburg/Standort Giessen, Germany.
    Lenhoff, Stig
    Institut für Humangenetik, Universitätsklinikum Giessen und Marburg/Standort Giessen, Germany.
    Ehinger, Mats
    Department of Pathology, Skåne University Hospital, Lund, Sweden.
    Spiekermann, Karsten
    Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany .
    Greif, Philip
    Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany .
    Cammenga, Jörg
    Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden; Department of Molecular Medicine and Gene Therapy, Lund University, BMC A12, Lund, Sweden.
    Young woman with mild bone marrow dysplasia, GATA2 and ASXL1 mutation treated with allogeneic hematopoietic stem cell transplantation2015In: Leukemia Research Reports, ISSN 2213-0489, Vol. 4, no 2, p. 72-75Article in journal (Refereed)
    Abstract [en]

    Heterozygous mutations in GATA2 underlie different syndromes, previously described as monocytopenia and mycobacterial avium complex infection (MonoMAC); dendritic cell, monocytes, B- and NK lymphocytes deficiency (DCML); lymphedema, deafness and myelodysplasia (Emberger syndrome) and familiar myelodysplastic syndrome/acute myeloid leukemia (MDS / AML). Onset and severity of clinical symptoms vary and preceding cytopenias are not always present. We describe a case of symptomatic DCML deficiency and rather discrete bone marrow findings due to GATA2 mutation. Exome sequencing revealed a somatic ASXL1 mutation and the patient underwent allogeneic stem cell transplantation successfully. © 2015.

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  • 14.
    Mogilenko, Denis A.
    et al.
    Univ Lille, France.
    Haas, Joel T.
    Univ Lille, France.
    Lhomme, Laurent
    Univ Lille, France.
    Fleury, Sebastien
    Univ Lille, France.
    Quemener, Sandrine
    Univ Lille, France.
    Levavasseur, Matthieu
    Univ Lille, France; CHU Lille, France.
    Becquart, Coralie
    Univ Lille, France; CHU Lille, France.
    Wartelle, Julien
    Univ Lille, France.
    Bogomolova, Alexandra
    Univ Lille, France.
    Pineau, Laurent
    Univ Lille, France.
    Molendi-Coste, Olivier
    Univ Lille, France.
    Lancel, Steve
    Univ Lille, France.
    Dehondt, Helene
    Univ Lille, France.
    Gheeraert, Celine
    Univ Lille, France.
    Melchior, Aurelie
    Univ Lille, France.
    Dewas, Cedric
    Univ Lille, France.
    Nikitin, Artemii
    Univ Lille, France.
    Pic, Samuel
    Univ Lille, France.
    Rabhi, Nabil
    Univ Lille, France.
    Annicotte, Jean-Sebastien
    Univ Lille, France.
    Oyadomari, Seiichi
    Tokushima Univ, Japan.
    Velasco-Hernandez, Talia
    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.
    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.
    Foretz, Marc
    Univ Paris 05, France; Inst Cochin, France; CNRS, France.
    Viollet, Benoit
    Univ Paris 05, France; Inst Cochin, France; CNRS, France.
    Vukovic, Milica
    Queen Mary Univ London, England.
    Villacreces, Arnaud
    Queen Mary Univ London, England.
    Kranc, Kamil
    Queen Mary Univ London, England.
    Carmeliet, Peter
    VIB, Belgium; Univ Leuven, Belgium.
    Marot, Guillemette
    Univ Lille, France.
    Boulter, Alexis
    Univ Florida, FL 32610 USA.
    Tavernier, Simon
    Univ Ghent, Belgium; Univ Ghent, Belgium.
    Berod, Luciana
    TWINCORE, Germany.
    Longhi, Maria P.
    Queen Mary Univ London, England.
    Paget, Christophe
    Univ Tours, France.
    Janssens, Sophie
    Univ Ghent, Belgium.
    Staumont-Salle, Delphine
    Univ Lille, France; CHU Lille, France.
    Aksoy, Ezra
    Queen Mary Univ London, England.
    Staels, Bart
    Univ Lille, France.
    Dombrowicz, David
    Univ Lille, France.
    Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR2019In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 177, no 5, p. 1201-Article in journal (Refereed)
    Abstract [en]

    Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondria! reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

  • 15.
    Nagata, Yasunobu
    et al.
    Cleveland Clin, OH 44106 USA.
    Narumi, Satoshi
    Natl Res Inst Child Hlth and Dev, Japan.
    Guan, Yihong
    Cleveland Clin, OH 44106 USA.
    Przychodzen, Bartlomiej P.
    Cleveland Clin, OH 44106 USA.
    Hirsch, Cassandra M.
    Cleveland Clin, OH 44106 USA.
    Makishima, Hideki
    Kyoto Univ, Japan.
    Shima, Hirohito
    Natl Res Inst Child Hlth and Dev, Japan.
    Aly, Mai
    Cleveland Clin, OH 44106 USA; Assiut Univ, Egypt.
    Pastor, Victor
    Univ Freiburg, Germany.
    Kuzmanovic, Teodora
    Cleveland Clin, OH 44106 USA.
    Radivoyevitch, Tomas
    Cleveland Clin, OH 44106 USA; Cleveland Clin, OH 44106 USA.
    Adema, Vera
    Cleveland Clin, OH 44106 USA.
    Awada, Hassan
    Cleveland Clin, OH 44106 USA.
    Yoshida, Kenichi
    Kyoto Univ, Japan.
    Li, Samuel
    Case Western Reserve Univ, OH 44106 USA.
    Sole, Francesc
    Univ Autonoma Barcelona, Spain.
    Hanna, Rabi
    Cleveland Clin, OH 44106 USA.
    Jha, Babal K.
    Cleveland Clin, OH 44106 USA.
    LaFramboise, Thomas
    Case Western Reserve Univ, OH 44106 USA.
    Ogawa, Seishi
    Kyoto Univ, Japan.
    Sekeres, Mikkael A.
    Cleveland Clin, OH 44106 USA.
    Wlodarski, Marcin W.
    Univ Freiburg, Germany.
    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.
    Maciejewski, Jaroslaw P.
    Cleveland Clin, OH 44106 USA.
    Letter: Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132, no 21, p. 2309-2313Article in journal (Other academic)
    Abstract [en]

    n/a

  • 16.
    Osterroos, Albin
    et al.
    Uppsala Univ Hosp, Sweden.
    Eriksson, Anna
    Uppsala Univ Hosp, Sweden.
    Antunovic, Petar
    Linköping University, Department of Biomedical and Clinical Sciences, 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.
    Cammenga, Jörg
    Linköping University, Department of Biomedical and Clinical Sciences, 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.
    Deneberg, Stefan
    Karolinska Univ Hosp, Sweden.
    Lazarevic, Vladimir
    Skane Univ Hosp, Sweden.
    Lorenz, Fryderyk
    Umea Univ, Sweden.
    Mollgard, Lars
    Sahlgrens Univ Hosp, Sweden.
    Derolf, Asa R.
    Karolinska Inst, Sweden.
    Uggla, Bertil
    Orebro Univ, Sweden.
    Wennstrom, Lovisa
    Sahlgrens Acad, Sweden.
    Olander, Emma
    Sundsvall Hosp, Sweden.
    Hoglund, Martin
    Uppsala Univ Hosp, Sweden.
    Juliusson, Gunnar
    Lund Univ, Sweden.
    Lehmann, Soren
    Uppsala Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden.
    Real-world data on treatment patterns and outcomes of hypomethylating therapy in patients with newly diagnosed acute myeloid leukaemia aged >= 60 years2020In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141Article in journal (Other academic)
    Abstract [en]

    n/a

  • 17.
    Robin, Marie
    et al.
    Hop St Louis, France.
    Chevret, Sylvie
    Univ Paris 07, France.
    Koster, Linda
    EBMT Data Off Leiden, Netherlands.
    Wolschke, Christine
    Univ Hosp Eppendorf, Germany.
    Yakoub-Agha, Ibrahim
    Univ Lille, France.
    Bourhis, Jean Henri
    Univ Paris Saclay, France.
    Chevallier, Patrice
    CHU Nantes, France.
    Cornelissen, Jan J.
    Erasmus Univ, Netherlands.
    Remenyi, Peter
    St Istvan and St Laszlo Hosp, Hungary.
    Maertens, Johan
    Univ Hosp Gasthuisberg, Belgium.
    Poire, Xavier
    Clin Univ St Luc, Belgium.
    Craddock, Charles
    Queen Elizabeth Hosp, England.
    Socie, Gerard
    Hop St Louis, France.
    Itala-Remes, Maija
    HUCH Comprehens Canc Ctr, Finland.
    Schouten, Harry C.
    Univ Hosp Maastricht, Netherlands.
    Marchand, Tony
    CHU Rennes, France.
    Passweg, Jakob
    Univ Hosp, Switzerland.
    Blaise, Didier
    Aix Marseille Univ, France.
    Damaj, Gandhi
    CHU Caen, France.
    Ozkurt, Zubeyde Nur
    Gazi Univ, Turkey.
    Zuckerman, Tsila
    Rambam Med Ctr, Israel.
    Cluzeau, Thomas
    Univ Cote Azur, France.
    Labussiere-Wallet, Helene
    Ctr Hosp Lyon Sud, France.
    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.
    McLornan, Donal
    Kings Coll London, England.
    Chalandon, Yves
    Univ Geneva, Switzerland; Univ Geneva, Switzerland.
    Kroger, Nicolaus
    EBMT Data Off Leiden, Netherlands.
    Antilymphocyte globulin for matched sibling donor transplantation in patients with myelofibrosis2019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 6, p. 1230-1236Article in journal (Refereed)
    Abstract [en]

    The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n= 287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P= 0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versushost disease without increasing the risk of relapse.

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  • 18.
    Staffas, A.
    et al.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Arabanian, L. S.
    University of Gothenburg, Sweden.
    Wei, S. Y.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Jansson, A.
    Sahlgrens University Hospital, Sweden.
    Stahlman, S.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Johansson, P.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Fogelstrand, L.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, 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.
    Kuchenbauer, F.
    University Hospital Ulm, Germany.
    Palmqvist, L.
    University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
    Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice2017In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 36, no 11, p. 1516-1524Article in journal (Refereed)
    Abstract [en]

    HOXA9, MEIS1 and FLT3 are genes frequently upregulated in human acute myeloid leukemia. Hoxa9 and Meis1 also cooperate to induce aggressive AML with high Flt3 expression in mice, suggesting an important role for Flt3 in Hoxa9/Meis1-induced leukemogenesis. To define the role of Flt3 in AML with high Hoxa9/Meis1, we treated mice with Hoxa9/Meis1-induced AML with the Flt3 inhibitor AC220, used an Flt3-ligand (FL -/-) knockout model, and investigated whether overexpression of Flt3 could induce leukemia together with overexpression of Hoxa9. Flt3 inhibition by AC220 did not delay AML development in mice transplanted with bone marrow cells overexpressing Hoxa9 and Meis1. In addition, Hoxa9/Meis1 cells induced AML in FL -/- mice as rapid as in wild-type mice. However, FL -/- mice had reduced organ infiltration compared with wild-type mice, suggesting some Flt3 dependent effect on leukemic invasiveness. Interestingly, leukemic Hoxa9/Meis1 cells from sick mice expressed high levels of Flt3 regardless of presence of its ligand, showing that Flt3 is a passive marker on these cells. In line with this, combined engineered overexpression of Flt3 and Hoxa9 did not accelerate the progression to AML. We conclude that the Hoxa9- and Meis1-associated upregulation of Flt3 is not a requirement for leukemic progression induced by Hoxa9 and Meis1.

  • 19.
    Tesi, Bianca
    et al.
    Karolinska University Hospital Huddinge, Sweden; Karolinska Institute, Sweden.
    Davidsson, Josef
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Voss, Matthias
    Karolinska University Hospital Huddinge, Sweden.
    Rahikkala, Elisa
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Holmes, Tim D.
    Karolinska University Hospital Huddinge, Sweden; University of Bergen, Norway.
    Chiang, Samuel C. C.
    Karolinska University Hospital Huddinge, Sweden.
    Komulainen-Ebrahim, Jonna
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Gorcenco, Sorina
    Lund University, Sweden.
    Rundberg Nilsson, Alexandra
    Lund University, Sweden.
    Ripperger, Tim
    Hannover Medical Sch, Germany.
    Kokkonen, Hannaleena
    Oulu University Hospital, Finland.
    Bryder, David
    Lund University, Sweden.
    Fioretos, Thoas
    Lund University, Sweden.
    Henter, Jan-Inge
    Karolinska Institute, Sweden.
    Mottonen, Merja
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Niinimaki, Riitta
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Nilsson, Lars
    Skåne University Hospital, Sweden.
    Pronk, Cornelis Jan
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Puschmann, Andreas
    Lund University, Sweden.
    Qian, Hong
    Karolinska University Hospital Huddinge, Sweden.
    Uusimaa, Johanna
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Moilanen, Jukka
    University of Oulu, Finland; Oulu University Hospital, Finland.
    Tedgard, Ulf
    Skåne University Hospital, 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. Lund University, Sweden.
    Bryceson, Yenan T.
    Karolinska University Hospital Huddinge, Sweden; University of Bergen, Norway.
    Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms2017In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 129, no 16, p. 2266-2279Article in journal (Refereed)
    Abstract [en]

    Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either SAMD9L mutation, 3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cis SAMD9L truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34 1 hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-alpha or IFN-gamma induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in trans germ line SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with 27/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.

  • 20.
    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.

  • 21.
    Velasco-Hernandez, Talia
    et al.
    Lund University, Sweden; Lund University, Sweden.
    Sawen, Petter
    Lund University, Sweden.
    Bryder, David
    Lund University, 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; Lund University, Sweden; Skånes University Hospital, Sweden.
    Potential Pitfalls of the Mx1-Cre System: Implications for Experimental Modeling of Normal and Malignant Hematopoiesis2016In: Stem Cell Reports, ISSN 2213-6711, Vol. 7, no 1, p. 21-28Article in journal (Refereed)
    Abstract [en]

    Conditional knockout mice are commonly used to study the function of specific genes in hematopoiesis. Different promoters that drive Cre expression have been utilized, with the interferon-inducible Mx1-Cre still being the most commonly used "deleter strain in experimental hematology. However, different pitfalls associated with this system could lead to misinterpretation in functional studies. We present here two of these issues related to the use of Mx1-Cre: first, a high spontaneous recombination rate when applying commonly used techniques in experimental hematology, and second, undesired short-term consequences of the use of polyinosinic: polycytidylic acid, including changes in cellular phenotypes that, however, resolve within days. Our studies emphasize therefore that proper controls are crucial when modeling gene deletion using the Mx1-Cre transgene.

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  • 22.
    Velasco-Hernandez, Talia
    et al.
    Lund Univ, Sweden.
    Soneji, Shamit
    Lund Univ, Sweden.
    Hidalgo, Isabel
    Lund Univ, Sweden.
    Erlandsson, Eva
    Lund Univ, 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.
    Bryder, David
    Lund Univ, Sweden; Gothenburg Univ, Sweden.
    Hif-1 alpha Deletion May Lead to Adverse Treatment Effect in a Mouse Model of MLL-AF9-Driven AML2019In: Stem Cell Reports, ISSN 2213-6711, Vol. 12, no 1, p. 112-121Article in journal (Refereed)
    Abstract [en]

    Relapse of acute myeloid leukemia (AML) remains a significant clinical challenge due to limited therapeutic options and poor prognosis. Leukemic stem cells (LSCs) are the cellular units responsible for relapse in AML, and strategies that target LSCs are thus critical. One proposed potential strategy to this end is to break the quiescent state of LSCs, thereby sensitizing LSCs to conventional cytostatics. The hypoxia-inducible factor (HIF) pathway is a main driver of cellular quiescence and a potential therapeutic target, with precedence from both solid cancers and leukemias. Here, we used a conditional knockout Hif-1 alpha mouse model together with a standard chemotherapy regimen to evaluate LSC targeting in AML. Contrary to expectation, our studies revealed that Hif-1 alpha-deleted-leukemias displayed a faster disease progression after chemotherapy. Our studies thereby challenge the general notion of cancer stem cell sensitization by inhibition of the HIF pathway, and warrant caution when applying HIF inhibition in combination with chemotherapy in AML.

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