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April 2009 Table of Contents <Di tuccioeclcje 459 Cover Figure Autoimmune hemophilia at rescue Pier Mannuccio Mannucci and Flora Peyvandi Acquired hemophilia is much more clinically severe than congenital hemophilia, and is more difficult to diagnose, also because cases are seen in an array of clinical settings that are not usually equipped to tackle them. In this perspective article Drs. Mannucci and Peyvandi examine the management of this condition. See related article on page 566. Model of immune interactions with myelodysplastic syndromes and the response to treatment. This illustration is taken from the perspective article by Barrett and Sloand on page 449. clcje Editorials and Perspectives Original Articles 447 Regulation of LMO2 mRNA and protein expression in erythroid differentiation Stephen J. Brandt and Mark J. Koury Proliferation, differentiation, and survival of erythroid progenitors are ultimately controlled through activation and repression of specific genetic programs. In this perspective article, Drs. Brandt and Koury examine the role of LIM domain-only protein 2 (LMO2) as an important transcriptional regulator in erythropoiesis. See related article on page 479. 449 470 Cord blood transplantation: state of the art Eliane Gluckman and Vanderson Rocha Therapy-related myeloid neoplasms Richard A. Larson Therapy-related myeloid neoplasm is the term recently proposed by the World Health Organization to cover the spectrum of malignant disorders previously described as therapy-related myelodysplastic syndrome or therapyrelated acute myeloid leukemia. In this perspective article, Dr. Larson explores the important question of whether the poor prognosis of these conditions reflects t-MN per se or, rather, associated findings such as complex cytogenetics that are also seen, although less frequently, in de novo myeloid neoplasms. See related article on page 542. Interleukin-1 regulates hematopoietic progenitor and stem cells in the midgestation mouse fetal liver Claudia Orelio, Marian Peeters, Esther Haak, Karin van der Horn, and Elaine Dzierzak Lymphocytes Proteasome inhibition induces apoptosis in primary human natural killer cells and suppresses NKp46-mediated cytotoxicity Xiangling Wang, Astrid Ottosson, Chunyan Ji, Xiaoli Feng, Magnus Nordenskjöld, Jan-Inge Henter, Bengt Fadeel, and Chengyun Zheng Bortezomib is a synthetic small molecule inhibitor of the chymotryptic activity of the 26S proteasome. Effects of bortezomib on normal immune cells have also been previously reported. This study adds to observations on the effects of bortezomib on natural killer (NK) cells. Effects include induction of apoptosis in resting NK cells, together with suppression of NK-mediated cytotoxicity via the NKp46 pathway. The concern is raised that treatment with bortezomib could interfere with NK cell-mediated attack on tumor cells, or on infected cells. Cord blood is an unlimited source of hematopoietic stem cells for allogeneic hematopoietic stem cell transplant. In this perspective article, Drs. Gluckman and Rocha examine the current status and the new challenges of cord blood transplant. See related article on page 536. 454 Hematopoietic Stem Cells Interleukin-1 is known to play a role in modulating the hematopoietic stem cell activity in the aorta-gonadmesonephros region of the developing embryo. This study extends this notion, showing that IL-1 and its receptor are also involved in the physiological regulation of the proliferation and differentiation of the hematopoietic stem/progenitor cells of murine fetal liver. Autoimmune mechanisms in the pathophysiology of myelodysplastic syndromes and their clinical relevance A. John Barrett and Elaine Sloand Accumulating evidence has shown that marrow failure in some patients with myelodysplastic syndrome is associated with autoimmunity, T-cell mediated myelosuppression and cytokine-induced cytopenias. In this perspective article, Drs. Barrett and Sloand expound on auto-immunity in myelodysplastic syndromes, in particular focusing on what has been learned from study of patients with trisomy 8. See related article on page 496. 451 462 479 Erythropoiesis MicroRNA 223-dependent expression of LMO2 regulates normal erythropoiesis Nadia Felli, Francesca Pedini, Paolo Romania, Mauro Biffoni, Ornella Morsilli, Germana Castelli, Simona Santoro, Simona Chicarella, Antonio Sorrentino, Cesare Peschle, and Giovanna Marziali Erythropoiesis is tightly controlled by transcription factors, one of which is the LIM domain-only protein LMO2, but little is still known of the involvement of microRNAs (miRs) in erythroid cell development. This article shows that miR-223 downregulates the expression of LMO2 Haematologica/The Hematology Journal 2009; vol. 94; no. 4- April 2009 http://www.haematologica.org/ April 2009 Table of Contents and thereby blocks erythroid differentiation. Se related perspective article on page 447. 487 Bone Marrow Failure Diagnosis of Fanconi anemia in a cohort of 87 patients with bone marrow failure Fernando O. Pinto, Thierry Leblanc, Delphine Chamousset, Gwenaelle Le Roux, Benoit Brethon, Bruno Cassinat, Jérôme Larghero, Jean-Pierre de Villartay, Dominique Stoppa-Lyonnet, André Baruchel, Gérard Socié, Eliane Gluckman, and Jean Soulier Fanconi anemia is a genetically heterogeneous disease characterized by chromosomal instability, congenital malformations and bone marrow failure. Its diagnosis currently relies on history, physical examination and positive chromosome breakage tests. This study proposes a diagnostic strategy based on a combination of molecular and functional assays on peripheral blood and fibroblasts that allows early and accurate confirmation or rejection of Fanconi anemia diagnosis in patients with bone marrow failure. 496 518 528 Myelodysplastic Syndromes Stem Cell Transplantation Genetic similarity of chromosome 6 between patients receiving hematopoietic stem cell transplantation and HLA matched sibling donors Hannu Turpeinen, Liisa Volin, Lauri Nikkinen, Pauli Ojala, Aarno Palotie, Janna Saarela, and Jukka Partanen Donors of hematopoietic stem cell transplants (HSCT) are selected for recipient-matched HLA alleles in order to minimize graft-versus-host disease (GvHD). In sibling donors, linkage disequilibrium can lead to sharing of the whole HLA region. To analyze genetic differences in chromosome 6 outside that region, single nucleotide polymorphism markers were examined in this study. Differences and similarities in these markers varied greatly among transplantation pairs, indicating that they could contribute to risk of GvHD or relapse after matched HSCT. Immune mediated autologous cytotoxicity against hematopoietic precursor cells in patients with myelodysplastic syndrome Martine E.D. Chamuleau, Theresia M. Westers, Linda van Dreunen, Judith Groenland, Adri Zevenbergen, Corien M. Eeltink, Gert J. Ossenkoppele, and Arjan A. van de Loosdrecht 536 Chronic Lymphocytic Leukemia Caspase-independent type III programmed cell death in chronic lymphocytic leukemia: the key role of the F-actin cytoskeleton Sandrine Barbier, Laurent Chatre, Marlène Bras, Patricia Sancho, Gaël Roué, Clémence Virely, Victor J. Yuste, Sylvie Baudet, Manuel Rubio, Josep E. Esquerda, Marika Sarfati, Hélène Merle-Béral, and Santos A. Susin Stimulation of the CD47 membrane receptor activates an original mechanism of cell death in chronic lymphocytic leukemia (CLL) cells that is caspase-independent. This study provides an exhaustive characterization of the CD47 anti-tumor signaling in CLL that may help to define new targets for further therapeutic strategies. Molecular allelokaryotyping of T-cell prolymphocytic leukemia cells with high density single nucleotide polymorphism arrays identifies novel common genomic lesions and acquired uniparental disomy Daniel Nowak, Emilie Le Toriellec, Marc-Henri Stern, Norihiko Kawamata, Tadayuki Akagi, Martin J. Dyer, Wolf-Karsten Hofmann, Seishi Ogawa and H. Phillip Koeffler T-cell prolymphocytic leukemia is a rare aggressive lymphoproliferative disease with a mature T-cell phenotype and characteristic genomic rearrangements of 14q11. This study identifies numerous new potential target genes in common breakpoints, deletions and regions of acquired uniparental disomy. The response observed in some patients with myelodysplastic syndrome following treatment with antithymocyte globulin suggests that the immune system plays a role in at least some of these cases. This paper describes an activated adaptive immune system combined with autologous killer function of NK cells in patients with myelodysplastic syndromes. See related perspective article on page 449. 507 Chronic Lymphocytic Leukemia Stem Cell Transplantation Cord blood stem cells for hematopoietic stem cell transplantation in the UK: how big should the bank be? Sergio Querol Ghulam J. Mufti, Steven G.E. Marsh, Antonio Pagliuca, Ann-Margaret Little, Bronwen E. Shaw, Robert Jeffery, Joan Garcia, John M. Goldman, and J. Alejandro Madrigal The need for umbilical cord blood units as an alternative source of hematopoietic stem cells for transplantation is increasing. This study defines the optimal size of a cord blood bank for a population of various ethnic background. See related perspective article on page 451. 542 Stem Cell Transplantation Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation Nicolaus Kröger, Ronald Brand, Anja van Biezen, Axel Zander, Judith Dierlamm, Dietger Niederwieser, Agnès Devergie, Tapani Ruutu, Jackie Cornish, Per Ljung-man, Alois Gratwohl, Catherine Cordonnier, Dietrich Beelen, Eric Deconinck, Argiris Symeonidis, Haematologica/The Hematology Journal 2009; vol. 94; no. 4- April 2009 http://www.haematologica.org/ April 2009 Table of Contents Theo de Witte for the Myelodysplastic Syndromes Subcommittee of The Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) After successful treatment of malignant diseases, therapyrelated myelodysplastic syndrome and acute myeloid leukemia have emerged as significant problems. This study shows that allogeneic stem cell transplantation can cure a significant portion of these patients. See related perspective article on page 542. Brief Reports 576 Hodgkin’s Lymphoma Classical Hodgkin’s lymphoma in adults: Guidelines of the Italian Society of Hematology, the Italian Society of Experimental Haematology, and the Italian Group for Bone Marrow Transplantation on initial work-up, management, and follow-up Ercole Brusamolino, Andrea Bacigalupo, Giovanni Barosi, Giampaolo Biti, Paolo Gobbi, Alessandro Levis, Monia Marchetti, Armando Santoro, Pier Luigi Zinzani, and Sante Tura During the last decades, survival of patients treated for classical Hodgkin’s lymphoma (HL) has improved substantially, and the overall cure rate for this neoplasm is about 80-85% at present. This article provides practice guidelines for the initial workup, therapy and follow-up of classical Hodgkin’s lymphoma. Extensive recommendations are given to prospectively limit the risk of therapy-related gonadic damage and to preserve fertility. 566 581 Platelet Disorders Haploinsufficiency of the platelet p2y12 gene in a family with congenital bleeding diathesis Gessica Fontana, Jerry Ware, and Marco Cattaneo The platelet P2Y12 receptor plays a very important role both in thrombosis and hemostasis. This report describes haploinsufficiency of the platelet P2Y12 gene in a family with congenital bleeding diathesis. 585 Disorders of Hemostasis International recommendations on the diagnosis and treatment of patients with acquired hemophilia A Angela Huth-Kühne, Francesco Baudo, Peter Collins, Jørgen Ingerslev, Craig M. Kessler, Hervé Lévesque, Maria Eva Mingot Castellano, Midori Shima, and Jean St-Louis Acquired hemophilia A is a rare bleeding disorder with an incidence of approximately 1.5 cases/million/year1 and is characterized by autoantibodies directed against circulating coagulation factor (F) VIII. Due to the variable bleeding phenotype of this disorder, the clinical picture ranges from life-threatening and traumatic bleeds to mild or no bleeding tendency. This article provides a set of international practice guidelines based on our collective clinical experience in treating patients with this condition. See related perspective article on page 459. SOCS3 tyrosine phosphorylation as a potential bio-marker for myeloproliferative neoplasms associated with mutant JAK2 kinases Joanne Elliott, Yvonne Suessmuth, Linda M. Scott, Krystyna Nahlik, Mary Frances McMullin, Stefan N. Constantinescu, Anthony R. Green and James A. Johnston JAK2 (V617F) and various exon 12 mutations are implicated in the pathogenesis of myeloproliferative neoplasms. It is known that JAK2 (V617F) causes phosphorylation of SOCS3, and the authors demonstrate that this is also true for the JAK2 exon 12 mutants. Data are presented that propose SOCS3 tyrosine phosphorylation as a novel bio-marker of JAK2 mutation positive myeloproliferative neoplasms. Decision Making and Problem Solving 550 Myeloproliferative Disorders Disorders of Hemostasis Deletion of five residues from the coiled coil of fibrinogen (Bb Asn167_Glu171del) associated with bleeding and hypodysfibrinogenemia Stephen O. Brennan, Ryan L. Davis, Robin Lowen, and Anna Ruskova Genotype:phenotype correlation in dysfibrinogenemia remains unpredictable, and so additions to clinical data are valuable. In this report, the authors identify a novel mutation resulting in loss of 5 amino acids from the fibrinogen B‚ chain and causing hypodysfibrinogenemia. The mutation is associated with bleeding in this family but caution is counseled in attributing this directly or entirely to the abnormal fibrinogen. 589 Thrombosis Functional consequences of the prothrombotic SERPINC1 rs2227589 polymorphism on antithrombin levels Ana I. Antón, Raúl Teruel, Javier Corral, Antonia Miñano, Irene Martínez-Martínez, Adriana Ordóñez, Vicente Vicente, and Beatriz Sánchez-Vega This study examines the functional consequences of a SNP in the antithrombin SERPINC1 gene. The results suggest a biological explanation for the relationship between the SNP and venous thrombosis. Haematologica/The Hematology Journal 2009; vol. 94; no. 4- April 2009 http://www.haematologica.org/ April 2009 Table of Contents Letters to the Editor 593 594 596 Errata Corrige 598 Thalassemia Syndrome A novel (εγδβ)0-thalassemia deletion associated with an α globin gene triplication leading to a severe transfusion dependant fotal thalassemic syndrome Christian Rose, Julien Rossignol, Anne Lambilliotte, Sandrine Depret, Nathalie Le Metayer, Serge Pissard Modulation of erythroid adhesion receptors expression by hydroxyurea in children with sickle cell disease. Haematologica 2008 Apr; 93:502-510. Odièvre MH, Bony V, Benkerrou M, Lapouméroulie C, Alberti C, Ducrocq R, Jacqz-Aigrain E, Elion J, and Cartron JP. Myeloproliferative Disorders Successful unrelated donor stem cell transplantation for advanced myelofibrosis in an adult patient with history of orthotopic liver transplantation Jolanta B. Perz, Ute Hegenbart, Nicolaus Kroeger, Gerd Otto, Anthony D. Ho, Peter Dreger Malignant Lymphomas Continuing Medical Education Therapy-related myelodysplastic syndrome and acute myeloid leukemia Classical Hodgkin’s lymphoma CIITA or RFX coding region loss of function mutations occur rarely in diffuse large B cell lymphoma cases and cell lines with low levels of major histocompatibility complex class II expression Lisa M. Rimsza, Wing C. Chan, Randy D. Gascoyne, Elias Campo, Elaine S. Jaffe, Louis M. Staudt, Jan Delabie, Andreas Rosenwald, Shawn P. Murphy Diagnosis of Fanconi anemia in patients with bone marrow failure Immune-mediated autologous cytotoxicity against hematopoietic precursor cells in myelodysplastic syndrome Haematologica/The Hematology Journal 2009; vol. 94; no. 4- April 2009 http://www.haematologica.org/