Download Cover Figure Editorials and Perspectives Original Articles

April 2009
Table of Contents
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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.
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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.
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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
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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
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Letters to the Editor
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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/