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Blood, The Journal of The American Society of Hematology is published 25 times (in two volumes) per year by The American Society of Hematology (ASH).

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American Society of Hematology

Publications in this journal

• JAK2 V617F down-modulates MPL.

  Authors: Angela G Fleischman, Jeffrey W Tyner

  Blood. 119(20):4579-80.

• Chopped and diced: Dicer1 deletion generates myeloid dysplasia.

  Authors: Dwayne L Barber

  Blood. 119(20):4581-2.

• Human Langerhans cells are immature in melanoma sentinel lymph nodes.

  Authors: Gianni Gerlini, Paola Di Gennaro, Giulia Mariotti, Carmelo Urso, Alberto Chiarugi, Roberto Caporale, Nicola Pimpinelli, Lorenzo Borgognoni

  Blood. 119(20):4807-8.

• Genomic loss of patient-specific HLA in acute myeloid leukemia relapse after well-matched unrelated donor HSCT.

  Authors: Cristina Toffalori, Irene Cavattoni, Sara Deola, Sara Mastaglio, Fabio Giglio, Benedetta Mazzi, Andrea Assanelli, Jacopo Peccatori, Claudio Bordignon, Chiara Bonini, Sergio Cortelazzo, Fabio Ciceri, Katharina Fleischhauer, Luca Vago

  Blood. 119(20):4813-5.

• A perspective on the selection of unrelated donors and cord blood units for transplantation.

  Authors: Stephen R Spellman, Mary Eapen, Brent R Logan, Carlheinz Mueller, Pablo Rubinstein, Michelle I Setterholm, Ann E Woolfrey, Mary M Horowitz, Dennis L Confer, Carolyn K Hurley

  Blood.

  Selection of a suitable graft for allogeneic hematopoietic stem cell transplantation involves consideration of both donor and recipient characteristics. Of primary importance is sufficientSelection of a suitable graft for allogeneic hematopoietic stem cell transplantation involves consideration of both donor and recipient characteristics. Of primary importance is sufficient donor-recipient human leukocyte antigen (HLA) matching to ensure engraftment and acceptable rates of graft-versus-host disease. In this perspective, the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research (CIBMTR) provide guidelines, based on large studies correlating graft characteristics with clinical transplantation outcomes, on appropriate typing strategies and matching criteria for unrelated adult donor and cord blood graft selection.

• Osteoblastic N-Cadherin is not required for microenvironmental support and regulation of hematopoietic stem and progenitor cells.

  Authors: Olga Bromberg, Benjamin J Frisch, Jonathan M Weber, Rebecca L Porter, Roberto Civitelli, Laura M Calvi

  Blood.

  Hematopoietic stem cell (HSC) regulation is highly dependent on interactions with the marrow microenvironment. Controversy exists on N-Cadherin's role in support of HSCs. Specifically it is unknownHematopoietic stem cell (HSC) regulation is highly dependent on interactions with the marrow microenvironment. Controversy exists on N-Cadherin's role in support of HSCs. Specifically it is unknown if microenvironmental N-Cadherin is required for normal marrow microarchitecture and for hematopoiesis. To determine if osteoblastic N-cadherin is required for HSC regulation we employed a genetic murine model in which deletion of Cdh2, the gene encoding N-cadherin, has been targeted to cells of the osteoblastic lineage. Targeted deletion of N-cadherin resulted in an age-dependent bone phenotype, ultimately characterized by decreased mineralized bone, but no difference in steady state HSC numbers or function at any time tested, and normal recovery from myeloablative injury. Intermittent parathyroid hormone (PTH) treatment is well established as anabolic to bone, and to increase marrow HSCs through microenvironmental interactions. Lack of osteoblastic N-cadherin did not block the bone anabolic or the HSC effects of PTH treatment. This report demonstrates that osteoblastic N-cadherin is not required for regulation of steady state hematopoiesis, HSC response to myeloablation, or for rapid expansion of HSCs through intermittent treatment with PTH.

• CD62L- memory T cells enhance T-cell regeneration after allogeneic stem cell transplantation by eliminating host resistance in mice.

  Authors: Jifeng Zhang, Brice E Barefoot, Wenjian Mo, Divino Deoliveira, Jessica Son, Xiuyu Cui, Elizabeth Ramsburg, Benny J Chen

  Blood.

  A major challenge in allogeneic hematopoietic cell transplantation is how to transfer T cell immunity without causing graft-versus-host disease (GVHD). Effector memory T cells (CD62L(-)) are a cellA major challenge in allogeneic hematopoietic cell transplantation is how to transfer T cell immunity without causing graft-versus-host disease (GVHD). Effector memory T cells (CD62L(-)) are a cell subset that can potentially address this challenge because they do not induce GVHD. In the current study, we investigated how CD62L(-) T cells contributed to phenotypic and functional T cell reconstitution post transplantation. Upon transfer into allogeneic recipients, CD62L(-) T cells were activated and expressed multiple cytokines and cytotoxic molecules. CD62L(-) T cells were able to deplete host radioresistant T cells and facilitatate hematopoietic engraftment, resulting in enhanced de novo T cell regeneration. Enhanced functional immune reconstitution was demonstrated in CD62L(-) T cell recipients using a tumor and an influenza virus challenge model. Even though CD62L(-) T cells are able to respond to alloantigens and deplete host radioresistant immune cells in GVHD recipients, alloreactive CD62L(-) T cells lost the reactivity over time and were eventually tolerant to alloantigens as a result of prolonged antigen exposure, suggesting a mechanism by which CD62L(-) T cells were able to eliminate host resistance without causing GVHD. These data further highlight the unique characteristics of CD62L(-) T cells and their potential applications in clinical hematopoietic cell transplantation.

• Hitting the target in MCL.

  Authors: Michael Crump

  Blood. 119(20):4580-1.

• NHERF-2 silences the silencers.

  Authors: Jack L Arbiser

  Blood. 119(20):4582-4.

• Generation of Th17 from human naive CD4+ T cells preferentially occurs from FOXP3+ Tregs upon costimulation via CD28 or CD5.

  Authors: Maha Ayyoub, Caroline Raffin, Danila Valmori

  Blood. 119(20):4810-2.

• WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.

  Authors: Qian Liu, Haoqian Chen, Teresa Ojode, Xiangxi Gao, Sandra Anaya-O'Brien, Nicholas A Turner, Jean Ulrick, Rosamma Decastro, Corin Kelly, Adela R Cardones, Stuart H Gold, Eugene I Hwang, Daniel S Wechsler, Harry L Malech, Philip M Murphy, David H McDermott

  Blood.

  WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections and myelokathexis (defective neutrophil egress from bone marrow).WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections and myelokathexis (defective neutrophil egress from bone marrow). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G→A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated ~2-fold increased signaling in calcium flux and chemotaxis assays relative to wild type CXCR4; however CXCR4(E343K) had a reduced effect on blocking normal receptor downregulation from the cell surface. Thus, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.

• Platelets and platelet-like particles mediate intercellular RNA transfer.

  Authors: Antonina Risitano, Lea M Beaulieu, Olga Vitseva, Jane E Freedman

  Blood.

  The role of platelets in hemostasis and thrombosis is clearly established; however, the mechanisms by which platelets mediate inflammatory and immune pathways are less well understood. PlateletsThe role of platelets in hemostasis and thrombosis is clearly established; however, the mechanisms by which platelets mediate inflammatory and immune pathways are less well understood. Platelets interact and modulate the function of blood and vascular cells by releasing bioactive molecules. Although the platelet is anucleate, it contains transcripts that may mirror disease. Platelet mRNA is only associated with low-level protein translation, however, platelets have a unique membrane structure allowing for the passage of small molecules, leading to the possibility that its cytoplasmic RNA may be passed to nucleated cells. To examine this question, platelet-like particles with labeled RNA were co-cultured with vascular cells. Co-culture of platelet-like particles with activated THP-1, monocytic, and endothelial cells led to visual and functional RNA transfer. Post-transfer microarray gene expression analysis of THP-1 cells showed an increase in HBG1/HBG2 and HBA1/HBA2 expression which was directly related to the transfer. Infusion of wild-type platelets into a TLR2 deficient mouse model established in vivo confirmation of select platelet RNA transfer to leukocytes. By specifically transferring green fluorescent protein, it was also observed that external RNA was functional in the recipient cells. The observation that platelets possess the capacity to transfer cytosolic RNA suggests a new function for platelets in the regulation of vascular homeostasis.

• Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice.

  Authors: Grace M Thomas, Carla Carbo, Brian R Curtis, Kimberly Martinod, Irina B Mazo, Daphne Schatzberg, Stephen M Cifuni, Tobias A Fuchs, Ulrich H von Andrian, John H Hartwig, Richard H Aster, Denisa D Wagner

  Blood.

  Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related death. The biological processes contributing to TRALI are poorly understood. All blood products can causeTransfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related death. The biological processes contributing to TRALI are poorly understood. All blood products can cause TRALI, and no specific treatment is available. A "two-event model" has been proposed as the trigger. The first event may include surgery, trauma or infection; the second involves the transfusion of anti-leukocyte antibodies or bioactive lipids within the blood product. Together, these events induce neutrophil activation in the lungs, causing endothelial damage and capillary leakage. Neutrophils, in response to pathogens or under stress, can release their chromatin coated with granule contents, thus forming neutrophil extracellular traps (NETs). Although protective against infection, these NETs are injurious to tissue. Here we show that NET biomarkers are present in TRALI patients' blood and that NETs are produced in vitro by primed human neutrophils when challenged with anti-HNA-3a antibodies previously implicated in TRALI. NETs are found in alveoli of mice experiencing antibody-mediated TRALI. DNase 1 inhalation prevents their alveolar accumulation and improves arterial oxygen saturation even when administered 90 minutes after TRALI onset. We suggest that NETs form in the lungs during TRALI, contribute to the disease process and thus could be targeted to prevent or treat TRALI.

• Mutated regions of nucleophosmin 1 (NPM1) elicit both CD4+ and CD8+ T cell responses in patients with acute myeloid leukemia.

  Authors: Jochen Greiner, Yoko Ono, Susanne Hofmann, Anita Schmitt, Elmar Mehring, Marlies Götz, Philippe Guillaume, Konstanze Döhner, Joannis Mytilineos, Hartmut Döhner, Michael Schmitt

  Blood.

  Mutations in the nucleophosmin gene (NPM1(mut)) are one of the most frequent molecular alterations in AML and immune responses might contribute to the favorable prognosis of AML patients withMutations in the nucleophosmin gene (NPM1(mut)) are one of the most frequent molecular alterations in AML and immune responses might contribute to the favorable prognosis of AML patients with NPM1(mut). In this work, we could demonstrate both CD4+ and CD8+ T cell responses against NPM1(mut). Ten peptides derived from NPM1(wt) and NPM1(mut) were subjected to ELISpot analysis in 33 healthy volunteers and 27 AML patients. Tetramer assays against most interesting epitopes were performed and chromium release assays were used to show the cytotoxicity of peptide-specific T cells. Moreover, HLA-DR-binding epitopes were used to test the role of CD4+ T cells in NPM1 immunogenicity. Two epitopes (#1,#3) derived from NPM1(mut) induced CD8+ T cell responses. 33% of the NPM1(mut) AML patients showed immune responses against #1 and 44% against #3. Specific lysis of leukemic blasts was detected. To obtain robust immune responses against tumor cells, the activation of CD4+ T cells is crucial. Therefore, overlapping peptides (OL) were analyzed in ELISpot assays and OL8 showed favorable results to activate both CD8+ and CD4+ T cells. Taken together, NPM1(mut) induces specific T cell responses of CD4+ and CD8+ T cells and thus presents a promising target for specific immunotherapies in AML.

• Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia patient samples.

  Authors: Keiki Kumano, Shunya Arai, Masataka Hosoi, Kazuki Taoka, Naoya Takayama, Makoto Otsu, Genta Nagae, Koki Ueda, Kumi Nakazaki, Yasuhiko Kamikubo, Koji Eto, Hiroyuki Aburatani, Hiromitsu Nakauchi, Mineo Kurokawa

  Blood.

  Induced pluripotent stem cells (iPSCs) can be generated by the expression of defined transcription factors not only from normal tissue, but also from malignant cells. Cancer-derived iPSCs areInduced pluripotent stem cells (iPSCs) can be generated by the expression of defined transcription factors not only from normal tissue, but also from malignant cells. Cancer-derived iPSCs are expected to provide a novel experimental opportunity to establish the disease model. We generated iPSCs from imatinib-sensitive chronic myelogenous leukemia (CML) patient samples. Remarkably, the CML-iPSCs were resistant to imatinib although they consistently expressed BCR-ABL oncoprotein. In CML-iPSCs, the phosphorylation of ERK1/2, AKT, and JNK, which are essential for the maintenance of both BCR-ABL (+) leukemia cells and iPSCs, were unchanged after imatinib treatment, whereas the phosphorylation of STAT5 and CRKL was significantly decreased. These results suggest that the signaling for iPSCs maintenance compensates for the inhibition of BCR-ABL. CML-iPSC-derived hematopoietic cells recovered the sensitivity to imatinib although CD34(+)38(-)90(+)45(+) immature cells were resistant to imatinib, which recapitulated the pathophysiological feature of the initial CML. CML-iPSCs provide us with a novel platform to investigate CML pathogenesis on the basis of patient-derived samples.

• Immunopharmacological response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab.

  Authors: Matthias Klinger, Christian Brandl, Gerhard Zugmaier, Youssef Hijazi, Ralf C Bargou, Max S Topp, Nicola Gökbuget, Svenja Neumann, Mariele Goebeler, Andreas Viardot, Matthias Stelljes, Monika Brüggemann, Dieter Hoelzer, Evelyn Degenhard, Dirk Nagorsen, Patrick A Baeuerle, Andreas Wolf, Peter Kufer

  Blood.

  T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acuteT cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acute lymphoblastic leukemia (MRD(+) B-ALL). Here, we report that lymphocytes in all patients of a phase 2 study responded to continuous infusion of blinatumomab in a strikingly similar fashion. After start of infusion, B cell counts dropped to less than one B cell/µl within an average of two days and remained essentially undetectable for the entire treatment period. By contrast, T cell counts in all patients declined to a nadir within less than one day and recovered to baseline within a few days. T cells then expanded and on average more than doubled over baseline within 2-3 weeks under continued infusion of blinatumomab. A significant percentage of reappearing CD8(+) and CD4(+) T cells newly expressed activation marker CD69. Shortly after start of infusion, a transient release of cytokines dominated by IL-10, IL-6 and IFN-γ was observed, which no longer occurred upon start of a second treatment cycle. The response of lymphocytes in leukemic patients to continuous infusion of blinatumomab helps to better understand the mode of action of this and other globally T cell-engaging antibodies. The trial is registered with www.ClinicalTrials.gov Identifier NCT00560794.

• Deferasirox significantly reduces iron overload in non-transfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study.

  Authors: Ali Taher, John Porter, Vip Viprakasit, Antonis Kattamis, Suporn Chuncharunee, Pranee Sutcharitchan, Noppadol Siritanaratkul, Renzo Galanello, Zeynep Karakas, Tomasz Lawniczek, Jacqueline Ros, Yiyun Zhang, Dany Habr, Maria Domenica Cappellini

  Blood.

  Non-transfusion-dependent thalassemia (NTDT) patients may develop iron overload and associated complications, despite occasional/no transfusions. The 1-year, randomized, double-blind,Non-transfusion-dependent thalassemia (NTDT) patients may develop iron overload and associated complications, despite occasional/no transfusions. The 1-year, randomized, double-blind, placebo-controlled THALASSA trial assessed efficacy and safety of deferasirox in iron-overloaded NTDT patients. 166 patients were randomized in a 2:1:2:1 ratio to starting doses 5 mg/kg/day deferasirox/placebo, or 10mg/kg/day deferasirox/placebo. Mean±SD actual deferasirox dose received over the study in the 5 and 10 mg/kg/day starting dose cohorts was 5.7±1.4 and 11.5±2.9mg/kg/day, respectively. At 1 year, LIC significantly decreased versus placebo (least-squares mean [LSM]±SE): -2.33±.7 (P = .001) and -4.18±.69 mg Fe/g dw (P < .001) for deferasirox 5 and 10mg/kg/day groups, respectively (baseline values [mean±SD]: 13.11±7.29 and 14.56±7.92 mg Fe/g dw). Similarly, serum ferritin significantly decreased versus placebo by LSM -235 and -337 ng/mL for deferasirox 5 and 10 mg/kg/day groups, respectively (P < .001). In placebo patients, LIC and serum ferritin increased from baseline by .38 mg Fe/g dw and 115 ng/mL (LSM), respectively. Most common drug-related AEs were nausea (n = 11, 6.6%), rash (n = 8, 4.8%) and diarrhea (n = 6, 3.6%). This is the first randomized study to show iron chelation with deferasirox significantly reduces iron overload in NTDT patients, with a similar frequency of overall AEs as placebo.

• Granule exocytosis is required for platelet spreading: differential sorting of α-granules expressing VAMP-7.

  Authors: Christian G Peters, Alan D Michelson, Robert Flaumenhaft

  Blood.

  There has been recent controversy as to whether platelet α-granules represent a single granule population or are composed of different subpopulations that serve discrete functions. To address thisThere has been recent controversy as to whether platelet α-granules represent a single granule population or are composed of different subpopulations that serve discrete functions. To address this question, we evaluated the localization of vesicle-associated membrane proteins (VAMPs) in spread platelets to determine whether platelets actively sort a specific subpopulation of α-granules to the periphery during spreading. Immunofluorescence microscopy demonstrated that granules expressing VAMP-3 and VAMP-8 localized to the central granulomere of spread platelets along with the granule cargos von Willebrand factor and serotonin. In contrast, granules expressing VAMP-7 translocated to the periphery of spread platelets along with the α-granule cargos TIMP2 and VEFG. Time-lapse microscopy demonstrated that α-granules expressing VAMP-7 actively moved from the granulomere to the periphery during spreading. Platelets from a patient with gray platelet syndrome lacked α-granules and demonstrated only minimal spreading. Similarly, spreading was impaired in platelets obtained from Unc13d(Jinx) mice, which are deficient in Munc13-4 and have an exocytosis defect. These studies identify a new α-granule subtype expressing VAMP-7 that moves to the periphery during spreading, supporting the premise that α-granules are heterogeneous and demonstrating that granule exocytosis is required for platelet spreading.

• Transcytosis of HTLV-1 across a tight human epithelial barrier and infection of sub-epithelial dendritic cells.

  Authors: Sandra Martin-Latil, Nina-Francesca Gnädig, Adeline Mallet, Marion Desdouits, Florence Guivel-Benhassine, Patricia Jeannin, Marie-Christine Prevost, Olivier Schwartz, Antoine Gessain, Simona Ozden, Pierre-Emmanuel Ceccaldi

  Blood.

  Human T-Cell Leukemia Virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). In addition toHuman T-Cell Leukemia Virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). In addition to blood transfusion or sexual transmission, HTLV-1 is transmitted mainly through prolonged breastfeeding, and such infection represents a major risk for ATLL development. Although HTLV-1-infected lymphocytes can be retrieved from maternal milk, the mechanisms of HTLV-1 transmission through the digestive tract remain unknown. We assessed HTLV-1 transport across epithelial barrier using an in vitro model. Our results show that during co-culture with HTLV-1-infected lymphocytes, the epithelial barrier integrity was maintained, since neither morphological nor functional alterations of the cell monolayer were observed. Enterocytes were not susceptible to HTLV-1 infection, but free infectious HTLV-1 virions could cross the epithelial barrier via transcytosis mechanism. Such virions were shown to be able to infect productively human dendritic cells located beneath the epithelial barrier. Our data indicate that HTLV-1 crosses the tight epithelial barrier without disruption or infection of the epithelium, to further infect target cells such as dendritic cells. This study provides the first data pertaining to the mode of HTLV-1 transport across a tight epithelial barrier as it could occur during mother-to-child HTLV-1 transmission during breastfeeding.

• Single nucleotide polymorphisms and outcome risk in unrelated mismatched hematopoietic stem cell transplantation: an exploration study.

  Authors: Christian Harkensee, Akira Oka, Makoto Onizuka, Peter G Middleton, Hidetoshi Inoko, Kouyuki Hirayasu, Koichi Kashiwase, Toshio Yabe, Hirofumi Nakaoka, Andrew R Gennery, Kiyoshi Ando, Yasuo Morishima

  Blood.

  Genetic risk factors contribute to adverse outcome of haematopoietic stem cell transplantation (HSCT). Mismatching of the Human Leukocyte Antigen (HLA) complex most strongly determines outcomes,Genetic risk factors contribute to adverse outcome of haematopoietic stem cell transplantation (HSCT). Mismatching of the Human Leukocyte Antigen (HLA) complex most strongly determines outcomes, while non-HLA genetic polymorphisms are also having an impact. Although the majority of HSCT are mismatched, only few studies have investigated the effects of non-HLA polymorphisms in the unrelated HSCT and HLA mismatched setting. To understand these effects, we genotyped 41 previously studied single nucleotide polymorphisms (SNP) in two independent, large cohorts of HSCT donor-recipient pairs (n=460 and 462 pairs) from a homogenous genetic background. The study population was chosen to pragmatically represent a large clinically homogeneous group (acute leukaemia), allowing all degrees of HLA matching. The TNF-1031 donor-recipient genotype mismatch association with acute graft-versus-host disease (GVHD) grade 4 was the only consistent association identified. Analysis of a subgroup of higher HLA matching showed consistent associations of the recipient IL2-330 GT genotype with risk of chronic GVHD, and the donor CTLA4-CT60 GG genotype with protection from acute GVHD. These associations are strong candidates for prediction of risk in a clinical setting. This study shows that non-HLA gene polymorphisms are of relevance for predicting HSCT outcome even for HLA mismatched transplants.

• Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results.

  Authors: Issa F Khouri, Rima M Saliba, William D Erwin, Barry I Samuels, Martin Korbling, L Jeffrey Medeiros, Rosamar Valverde, Amin M Alousi, Paolo Anderlini, Qaiser Bashir [......] Alison M Gulbis, Marcos de Lima, Chitra Hosing, Partow Kebriaei, Uday R Popat, Nathan Fowler, Sattva S Neelapu, Felipe Samaniego, Richard E Champlin, Homer A Macapinlac

  Blood.

  In 2008, we reported favorable 5-year outcomes of nonmyeloablative allogeneic stem cell transplantation after fludarabine, cyclophosphamide, rituximab (FCR) conditioning for relapsed andIn 2008, we reported favorable 5-year outcomes of nonmyeloablative allogeneic stem cell transplantation after fludarabine, cyclophosphamide, rituximab (FCR) conditioning for relapsed and chemosensitive follicular lymphoma. However, innovative strategies were still needed to treat patients with chemo-refractory disease. We therefore subsequently performed a trial in which (90)Y-ibritumomab tiuxetan (0.4 mCi/kg) was added to the FC conditioning regimen ((90)YFC). Here, we report updated results of the FCR trial and outcomes after (90)YFC. FCR group (N=47). Since the last update, one patient developed recurrent disease. With a median follow-up of 107 months (range 72-142), the 11-year overall (OS) and progression-free survival (PFS) rates were 78%, and 72%. (90)YFC group (N=26). More patients in the (90)YFC group had chemo-refractory disease than did those in the FCR group (38% and 0%, P < .001). With a median follow-up of 33 months (range,17-94 months), the 3-year PFS rates for patients with chemo-refractory and chemosensitive disease were 80% and 87% (P = .7). The low frequency of relapse observed after a long follow-up interval of 9 years in the FCR group suggests that these patients are cured of their disease. The addition of (90)Y to the conditioning regimen appears to be effective in patients with chemo-refractory disease. This trial is registered at www.ClinicalTrials.gov number, NCT00048737.

• The COPII pathway and hematologic disease.

  Authors: Rami Khoriaty, Matthew P Vasievich, David Ginsburg

  Blood.

  Multiple diseases, hematologic and non-hematologic, result from defects in the early secretory pathway. Congenital dyserythropoietic anemia type II (CDAII) and combined deficiency of coagulationMultiple diseases, hematologic and non-hematologic, result from defects in the early secretory pathway. Congenital dyserythropoietic anemia type II (CDAII) and combined deficiency of coagulation factors V and VIII (F5F8D) are the two known hematologic diseases that result from defects in the ER-to-Golgi transport system. CDAII is caused by mutations in the SEC23B gene, which encodes a core component of the Coat Protein Complex II (COPII). F5F8D results from mutations in either LMAN1 (lectin mannose-binding protein 1) or MCFD2 (multiple coagulation factor deficiency protein 2), which encode the ER cargo receptor complex LMAN1-MCFD2. These diseases and their molecular pathogenesis are the focus of this review.

• Multiple SNP testing improves risk prediction of first venous thrombosis.

  Authors: Hugoline G de Haan, Irene D Bezemer, Carine J M Doggen, Saskia Le Cessie, Pieter H Reitsma, Andre R Arellano, Carmen H Tong, James J Devlin, Lance A Bare, Frits R Rosendaal, Carla Y Vossen

  Blood.

  There are no risk models available yet that accurately predict an individual's risk for developing venous thrombosis. Our aim was therefore to explore whether inclusion of establishedThere are no risk models available yet that accurately predict an individual's risk for developing venous thrombosis. Our aim was therefore to explore whether inclusion of established thrombosis-associated SNPs in a venous thrombosis risk model improves the risk prediction. We calculated genetic risk scores by counting risk-increasing alleles from 31 venous thrombosis-associated SNPs for subjects of a large case-control study including 2712 patients and 4634 controls (MEGA). Genetic risk scores based on all 31 SNPs or on the 5 most strongly associated SNPs performed similarly (areas under receiver-operating characteristic curves (AUCs) of 0.70 and 0.69 respectively). For the 5-SNP risk score, the odds ratios for venous thrombosis ranged from 0.37 (95% CI 0.25-0.53) for individuals with 0 risk alleles to 7.48 (95% CI 4.49-12.46) for individuals with ≥6 risk alleles. The AUC of a risk model based on known non-genetic risk factors was 0.77 (95% CI 0.76-0.78). Combining the non-genetic and genetic risk models improved the AUC to 0.82 (95% CI 0.81-0.83), indicating good diagnostic accuracy. In order to become clinically useful, subgroups of high-risk individuals must be identified in whom genetic profiling will also be cost-effective.

• Targeting anti-apoptotic A1/Bfl-1 by in vivo RNAi reveals multiple roles in leukocyte development in mice.

  Authors: Eleonora Ottina, Francesca Grespi, Denise Tischner, Claudia Soratroi, Stephan Geley, Andreas Ploner, Holger M Reichardt, Andreas Villunger, Marco J Herold

  Blood.

  Gene-targeting studies in mice have identified the essential roles of most pro-survival Bcl-2 family members in normal physiology and under conditions of stress. The function of one member,Gene-targeting studies in mice have identified the essential roles of most pro-survival Bcl-2 family members in normal physiology and under conditions of stress. The function of one member, Bcl2a1/Bfl-1/A1, is only poorly understood due to quadruplication of the gene locus in mice, hindering conventional knockout studies. To overcome this problem, we generated mouse models allowing traceable constitutive or reversible ablation of A1 in the hematopoietic system by RNA interference. Knockdown of A1 impaired early stages of T cell differentiation, B cell homeostasis and sensitized transitional as well as follicular B cells to apoptosis induced by ligation of the B cell receptor. As a consequence B cell proliferation in response to mitogens was severely impaired while that of T cells appeared unaffected. Furthermore, depending on the extent of A1 knockdown, granulocytes showed increased spontaneous death in culture or failed to accumulate in significant numbers in vivo. These models highlight the critical role of A1 in leukocyte development and homeostasis, constituting valuable tools for investigating presumed roles of this Bcl-2 family member in immunity, tumorigenesis and drug-resistance.

• Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study.

  Authors: Susanne Holzhauer, Neil A Goldenberg, Ralf Junker, Christine Heller, Monika Stoll, Daniela Manner, Rolf Mesters, Anne Krümpel, Michael Stach, Ulrike Nowak-Göttl

  Blood.

  Screening for inherited thrombophilia (IT) is controversial, individuals at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first and secondScreening for inherited thrombophilia (IT) is controversial, individuals at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first and second degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (Hazard Ratio [HR] 7.6, 95% CI, 4.00-14.45]; P<0.001) and highest among carriers of antithrombin, protein C, or protein S deficiency (HR 25.7, 95% CI12.2-54.2]; P<0.001). Annual incidences of VTE were 2.82% (95% confidence interval [95%CI], 1.63-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12-0.53%) for factor II G202010A, 0.25% (0.12-0.53%) for factor V G1691A, and 0.10% (0.06-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S and antithrombin deficiency we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess if thromboembolism can be prevented in this high risk population.

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