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  • Confirmed efficacy of etoposide and dexamethasone in HLH treatment: Long term results of the cooperative HLH-2004 study
    Blood (IF 13.164) Pub Date : 2017-01-01
    Elisabet Bergsten; AnnaCarin Horne; Maurizio Aricó; Itziar Astigarraga; R. Maarten Egeler; Alexandra H. Filipovich; Eiichi Ishii; Gritta Janka; Stephan Ladisch; Kai Lehmberg; Kenneth L. McClain; Milen Minkov; Scott Montgomery; Vasanta Nanduri; Diego Rosso; Jan-Inge Henter

    Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% CI, 48-60%), systemic therapy included etoposide, dexamethasone and, from week nine, cyclosporine A (CSA). HSCT was indicated in patients with familial/genetic, relapsing, or severe and persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. During 2004-2011, 369 children aged <18-years fulfilled the HLH-2004 inclusion criteria (5/8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At a median follow-up of 5.2 years, 230/369 (62%) patients were alive (5-year pSu 61%, 56-67%). The 5-year pSu in children with (n=168) and without (n=201) family history/genetically verified FHL was 59% (52-67%) and 64% (57-71%), respectively [familial occurrence (n=47): 58% (45-75%)]. Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was non-significantly reduced from 27% to 19% (P=.064 adjusted for age and gender). Time from start of therapy to HSCT was shorter compared to HLH-94 (P=.020 adjusted for age and gender) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% [verified FHL 70% (63-78%)]. Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements.HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly.

    更新日期:2017-09-21
  • Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia
    Blood (IF 13.164) Pub Date : 2017-01-01
    Karen Thudium Mueller; Shannon L. Maude; David L. Porter; Noelle Frey; Patricia Wood; Xia Han; Edward Waldron; Abhijit Chakraborty; Rakesh Awasthi; Bruce L. Levine; J. Joseph Melenhorst; Stephan A. Grupp; Carl H. June; Simon F. Lacey

    Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater Cmax and AUC values compared with nonresponding patients (P < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described herein are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy.

    更新日期:2017-09-21
  • Expanding and expounding the genomic map of CTCL
    Blood (IF 13.164) Pub Date : 2017-09-21
    Anjali Mishra; Pierluigi Porcu

    Over the past 3 years, a veritable explosion of genomic data has begun to shed much needed light on the mutational landscape of cutaneous T-cell lymphoma (CTCL). In this issue of Blood , [Park et al][1] expand the boundaries and improve the resolution of the known mutational map of CTCL.[1][2]The

    更新日期:2017-09-21
  • Diabetic kidney disease: as easy as aPC?
    Blood (IF 13.164) Pub Date : 2017-09-21
    James D. McFadyen; Mark E. Cooper

    In this issue of Blood , [Madhusudhan et al][1] elegantly demonstrate a novel role of the coagulation protease activated protein C (aPC) in maintaining endoplasmic reticulum (ER) homeostasis, and thus cellular metabolism, in the context of diabetic kidney disease (DKD).[1][2]![Figure][3]

    更新日期:2017-09-21
  • Transplant for NEMO: this and much, much more
    Blood (IF 13.164) Pub Date : 2017-09-21
    Dennis D. Hickstein; Luigi Notarangelo

    In this issue of Blood , [Miot et al][1] report encouraging results in a retrospective analysis of hematopoietic stem cell transplantation (HSCT) in 29 patients with hypomorphic mutations in the IKBKG gene encoding nuclear factor κB essential modulator (NEMO).[1][2]![Figure][3]Intensity

    更新日期:2017-09-21
  • Are outcomes of allografts for CLL still relevant?
    Blood (IF 13.164) Pub Date : 2017-09-21
    Thomas C. Shea

    In this issue of Blood , [Krämer et al][1] have provided a long-term update on the outcomes of patients enrolled in the German CLL Study Group CLL3X trial who underwent a matched related or unrelated allogeneic hematopoietic cell transplantation (allo-HCT) with a reduced-intensity fludarabine/

    更新日期:2017-09-21
  • New oncogenic subtypes in pediatric B-cell precursor acute lymphoblastic leukemia
    Blood (IF 13.164) Pub Date : 2017-09-21
    Henrik Lilljebjörn; Thoas Fioretos

    Until recently, 20% to 30% of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) could not be classified into any of the established molecular subtypes. Recent molecular studies of such cases have, however, further clarified their mutational spectrum and identified new oncogenic subtypes consisting of cases with DUX4 rearrangements, ETV6-RUNX1–like gene expression, MEF2D rearrangements, and ZNF384 rearrangements. In this review, we describe these new subtypes, which account for up to 50% of previously unclassified pediatric BCP-ALL cases.

    更新日期:2017-09-21
  • How I treat pediatric venous thromboembolism
    Blood (IF 13.164) Pub Date : 2017-09-21
    Guy Young

    The incidence of pediatric venous thromboembolism (VTE) has been increasing significantly over the past decade in part as a result of increased recognition of this serious disorder but more so because of the increased use of central venous catheters and other technological advancements involved in the care of ill children. Management of pediatric VTE is a complex undertaking, considering that the vast majority of children who develop this complication have serious underlying medical disorders. Although the incidence is rising, in comparison with adults, this remains a relatively rare disorder, and as such, large-scale clinical trials have not been completed, rendering management decisions to be based on extrapolation from adult data and the experience of the treating physician. Clearly, both are fraught with problems. Thus, day-to-day management remains more art than science until such time that the results from clinical trials (many of which are under way) become available. This edition of “How I Treat” describes the author’s experience in managing 3 common scenarios that one may encounter in pediatric thrombosis and suggests a logical approach to such situations. Furthermore, the author provides 3 algorithms to help guide management decisions.

    更新日期:2017-09-21
  • A MALT lymphoma prognostic index
    Blood (IF 13.164) Pub Date : 2017-09-21
    Catherine Thieblemont; Luciano Cascione; Annarita Conconi; Barbara Kiesewetter; Markus Raderer; Gianluca Gaidano; Maurizio Martelli; Daniele Laszlo; Bertrand Coiffier; Armando Lopez Guillermo; Valter Torri; Franco Cavalli; Peter W. Johnson; Emanuele Zucca

    There are no widely accepted prognostic indices for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). This study aimed to develop and validate a specific prognostic tool to personalize and optimize treatment of patients with MALT lymphoma. A prognostic index was built by Cox regression (stepwise selection) using data from 401 patients enrolled in the international randomized International Extranodal Lymphoma Study Group 19 (IELSG-19) trial (NCT 00210353). A validation set, including 633 patients, was obtained by merging 3 independent cohorts of MALT lymphoma patients. The 3 individual features maintaining the greatest prognostic significance for event-free survival (EFS, the main endpoint of the IELSG-19 trial) were age ≥70 years (hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.26-2.33), Ann Arbor stage III or IV (HR, 1.79; 95% CI ,1.35-2.38), and an elevated lactate dehydrogenase level (HR, 1.87; 95% CI, 1.27-2.77). The prognostic index (MALT-IPI) constructed using these 3 parameters identified 3 groups: low, intermediate, and high risk (corresponding to the presence of 0, 1, or ≥2 of these factors, respectively). The 5-year EFS rates in the low-, intermediate-, and high-risk groups were 70%, 56%, and 29%, respectively. The MALT-lymphoma International Prognostic Index (MALT-IPI) also significantly discriminated between patients with different progression-free, overall, and cause-specific survival. The prognostic utility was retained in gastric and nongastric lymphomas, in each treatment arm (chlorambucil, rituximab, and rituximab plus chlorambucil), and was confirmed in the validation set. The new index, MALT-IPI, is a simple, accessible, and effective tool to identify MALT lymphoma patients at risk of poor outcomes. It may help define appropriate treatment approaches for individual patients.

    更新日期:2017-09-21
  • Expression of PIM kinases in Reed-Sternberg cells fosters immune privilege and tumor cell survival in Hodgkin lymphoma
    Blood (IF 13.164) Pub Date : 2017-09-21
    Maciej Szydłowski; Monika Prochorec-Sobieszek; Anna Szumera-Ciećkiewicz; Edyta Derezińska; Grażyna Hoser; Danuta Wasilewska; Olga Szymańska-Giemza; Ewa Jabłońska; Emilia Białopiotrowicz; Tomasz Sewastianik; Anna Polak; Wojciech Czardybon; Michał Gałęzowski; Renata Windak; Jan Maciej Zaucha; Krzysztof Warzocha; Krzysztof Brzózka; Przemysław Juszczyński

    Reed-Sternberg (RS) cells of classical Hodgkin lymphoma (cHL) express multiple immunoregulatory proteins that shape the cHL microenvironment and allow tumor cells to evade immune surveillance. Expression of certain immunoregulatory proteins is modulated by prosurvival transcription factors, such as NFκB and STATs. Because these factors also induce expression of the oncogenic PIM1/2/3 serine/threonine kinases, and as PIMs modulate transcriptional activity of NFκB and STATs, we hypothesized that these kinases support RS cell survival and foster their immune privilege. Here, we investigated PIM1/2/3 expression in cHL and assessed their role in developing RS cell immune privilege and survival. PIM1/2/3 were ubiquitously expressed in primary and cultured RS cells, and their expression was driven by JAK-STAT and NFκB activity. Genetic or chemical PIM inhibition with a newly developed pan-PIM inhibitor, SEL24-B489, induced RS cell apoptosis. PIM inhibition decreased cap-dependent protein translation, blocked JAK-STAT signaling, and markedly attenuated NFκB-dependent gene expression. In a cHL xenograft model, SEL24-B489 delayed tumor growth by 95.8% (P = .0002). Furthermore, SEL24-B489 decreased the expression of multiple molecules engaged in developing the immunosuppressive microenvironment, including galectin-1 and PD-L1/2. In coculture experiments, T cells incubated with SEL24-B489-treated RS cells exhibited higher expression of activation markers than T cells coincubated with control RS cells. Taken together, our data indicate that PIM kinases in cHL exhibit pleiotropic effects, orchestrating tumor immune escape and supporting RS cell survival. Inhibition of PIM kinases decreases RS cell viability and disrupts signaling circuits that link these cells with their niches. Thus, PIM kinases are promising therapeutic targets in cHL.

    更新日期:2017-09-21
  • Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E)
    Blood (IF 13.164) Pub Date : 2017-09-21
    Joonhee Park; Jingyi Yang; Alexander T. Wenzel; Akshaya Ramachandran; Wung J. Lee; Jay C. Daniels; Juhyun Kim; Estela Martinez-Escala; Nduka Amankulor; Barbara Pro; Joan Guitart; Marc L. Mendillo; Jeffrey N. Savas; Titus J. Boggon; Jaehyuk Choi

    Cutaneous T-cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing T cell. In early-stage disease, lesions are limited to the skin, but in later-stage disease, the tumor cells can escape into the blood, the lymph nodes, and at times the visceral organs. To clarify the genomic basis of CTCL, we performed genomic analysis of 220 CTCLs. Our analyses identify 55 putative driver genes, including 17 genes not previously implicated in CTCL. These novel mutations are predicted to affect chromatin (BCOR, KDM6A, SMARCB1, TRRAP), immune surveillance (CD58, RFXAP), MAPK signaling (MAP2K1, NF1), NF-κB signaling (PRKCB, CSNK1A1), PI-3-kinase signaling (PIK3R1, VAV1), RHOA/cytoskeleton remodeling (ARHGEF3), RNA splicing (U2AF1), T-cell receptor signaling (PTPRN2, RLTPR), and T-cell differentiation (RARA). Our analyses identify recurrent mutations in 4 genes not previously identified in cancer. These include CK1α (encoded by CSNK1A1) (p.S27F; p.S27C), PTPRN2 (p.G526E), RARA (p.G303S), and RLTPR (p.Q575E). Last, we functionally validate CSNK1A1 and RLTPR as putative oncogenes. RLTPR encodes a recently described scaffolding protein in the T-cell receptor signaling pathway. We show that RLTPR (p.Q575E) increases binding of RLTPR to downstream components of the NF-κB signaling pathway, selectively upregulates the NF-κB pathway in activated T cells, and ultimately augments T-cell-receptor-dependent production of interleukin 2 by 34-fold. Collectively, our analysis provides novel insights into CTCL pathogenesis and elucidates the landscape of potentially targetable gene mutations.

    更新日期:2017-09-21
  • DARC extracellular domain remodeling in maturating reticulocytes explains Plasmodium vivax tropism
    Blood (IF 13.164) Pub Date : 2017-09-21
    Elina Ovchynnikova; Francesca Aglialoro; Arthur E. H. Bentlage; Gestur Vidarsson; Nichole D. Salinas; Marieke von Lindern; Niraj H. Tolia; Emile van den Akker

    Plasmodium vivax is the most prevalent parasite species that causes malaria in humans and exclusively infects reticulocytes. Reticulocyte infection is facilitated by P vivax Duffy binding protein (DBP), which utilizes DARC (Duffy antigen receptor for chemokines) as an entry point. However, the selective tropism of P vivax for transferrin receptor (CD71)-positive reticulocytes remained unexplained, given the constitutive expression of DARC during reticulocyte maturation. CD71/RNA double staining of reticulocytes enriched from adult peripheral blood reveals 4 distinct reticulocyte populations: CD71high/RNAhigh (∼0.016%), CD71low/RNAhigh (∼0.059%), CD71neg/RNAhigh (∼0.37%), CD71neg/RNAlow (∼0.55%), and erythrocytes CD71neg/RNAneg (∼99%). We hypothesized that selective association of DBP with a small population of immature reticulocytes could explain the preference of P vivax for reticulocytes. Binding of specific monoclonal anti-DARC antibodies and recombinant DBP to CD71high/RNAhigh reticulocytes was significantly higher compared with other reticulocyte populations and erythrocytes. Interestingly, the total DARC protein throughout reticulocyte maturation was constant. The data suggest that selective exposure of the DBP binding site within DARC is key to the preferential binding of DBP to immature reticulocytes, which is the potential mechanism underlying the preferential infection of a reticulocyte subset by P vivax.

    更新日期:2017-09-21
  • Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function
    Blood (IF 13.164) Pub Date : 2017-09-21
    Thati Madhusudhan; Hongjie Wang; Sanchita Ghosh; Wei Dong; Varun Kumar; Moh'd Mohanad Al-Dabet; Jayakumar Manoharan; Sumra Nazir; Ahmed Elwakiel; Fabian Bock; Shrey Kohli; Andi Marquardt; Ibrahim Sögüt; Khurrum Shahzad; Andreas J. Müller; Charles T. Esmon; Peter P. Nawroth; Jochen Reiser; Triantafyllos Chavakis; Wolfram Ruf; Berend Isermann

    Coagulation proteases have increasingly recognized functions beyond hemostasis and thrombosis. Disruption of activated protein C (aPC) or insulin signaling impair function of podocytes and ultimately cause dysfunction of the glomerular filtration barrier and diabetic kidney disease (DKD). We here show that insulin and aPC converge on a common spliced-X-box binding protein-1 (sXBP1) signaling pathway to maintain endoplasmic reticulum (ER) homeostasis. Analogous to insulin, physiological levels of aPC maintain ER proteostasis in DKD. Accordingly, genetically impaired protein C activation exacerbates maladaptive ER response, whereas genetic or pharmacological restoration of aPC maintains ER proteostasis in DKD models. Importantly, in mice with podocyte-specific deficiency of insulin receptor (INSR), aPC selectively restores the activity of the cytoprotective ER-transcription factor sXBP1 by temporally targeting INSR downstream signaling intermediates, the regulatory subunits of PI3Kinase, p85α and p85β. Genome-wide mapping of condition-specific XBP1-transcriptional regulatory patterns confirmed that concordant unfolded protein response target genes are involved in maintenance of ER proteostasis by both insulin and aPC. Thus, aPC efficiently employs disengaged insulin signaling components to reconfigure ER signaling and restore proteostasis. These results identify ER reprogramming as a novel hormonelike function of coagulation proteases and demonstrate that targeting insulin signaling intermediates may be a feasible therapeutic approach ameliorating defective insulin signaling.

    更新日期:2017-09-21
  • Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations
    Blood (IF 13.164) Pub Date : 2017-09-21
    Charline Miot; Kohsuke Imai; Chihaya Imai; Anthony J. Mancini; Zeynep Yesim Kucuk; Tokomki Kawai; Ryuta Nishikomori; Etsuro Ito; Isabelle Pellier; Sophie Dupuis Girod; Jeremie Rosain; Shinya Sasaki; Shanmuganathan Chandrakasan; Jana Pachlopnik Schmid; Tsubasa Okano; Estelle Colin; Alberto Olaya-Vargas; Marco Yamazaki-Nakashimada; Waseem Qasim; Sara Espinosa Padilla; Andrea Jones; Alfons Krol; Nyree Cole; Stephen Jolles; Jack Bleesing; Thomas Vraetz; Andrew R. Gennery; Mario Abinun; Tayfun Güngör; Beatriz Costa-Carvalho; Antonio Condino-Neto; Paul Veys; Steven M. Holland; Gulbu Uzel; Despina Moshous; Benedicte Neven; Stéphane Blanche; Stephan Ehl; Rainer Döffinger; Smita Y. Patel; Anne Puel; Jacinta Bustamante; Erwin W. Gelfand; Jean-Laurent Casanova; Jordan S. Orange; Capucine Picard

    X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.

    更新日期:2017-09-21
  • Circulating and skin-derived Sézary cells: clonal but with phenotypic plasticity
    Blood (IF 13.164) Pub Date : 2017-09-21
    Marie Roelens; Marc Delord; Caroline Ram-Wolff; Anne Marie-Cardine; Antonio Alberdi; Guitta Maki; Laurence Homyrda; Armand Bensussan; Martine Bagot; Antoine Toubert; Hélène Moins-Teisserenc

    To the editor:Sézary syndrome (SS) is a rare, aggressive leukemic form of primary cutaneous T-cell lymphoma.[1][1] The diagnostic criteria associate a clonal T-cell receptor (TCR) rearrangement with peripheral Sézary cell (SC) counts of ≥1 G/L, an increased CD4/CD8 ratio of ≥10, CD4+CD7−

    更新日期:2017-09-21
  • CCL3 is a key mediator for the leukemogenic effect of Ptpn11-activating mutations in the stem-cell microenvironment
    Blood (IF 13.164) Pub Date : 2017-09-21
    Lei Dong; Hong Zheng; Cheng-Kui Qu

    To the editor:Germ line–activating mutations of protein tyrosine phosphatase PTPN11 (Shp2), a positive regulator of the Ras signaling pathway,[1][1] account for more than 50% of patients with Noonan syndrome.[2][2] These patients have an increased risk of developing leukemias,[3][3] especially

    更新日期:2017-09-21
  • Circulatory and maturation kinetics of human monocyte subsets in vivo
    Blood (IF 13.164) Pub Date : 2017-09-21
    Tamar Tak; Julia Drylewicz; Lennart Conemans; Rob J. de Boer; Leo Koenderman; José A. M. Borghans; Kiki Tesselaar

    To the editor:Monocytes originate from the bone marrow (BM), are distributed in the bloodstream, and can differentiate in the tissue into skin macrophages or intestinal dendritic cells (DCs).[1][1] They play an essential role in the defense against pathogens[2][2] and are implicated in a range of

    更新日期:2017-09-21
  • Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial
    Blood (IF 13.164) Pub Date : 2017-09-21
    Isabelle Krämer; Stephan Stilgenbauer; Sascha Dietrich; Sebastian Böttcher; Matthias Zeis; Michael Stadler; Jörg Bittenbring; Lutz Uharek; Christof Scheid; Ute Hegenbart; Anthony Ho; Michael Hallek; Michael Kneba; Norbert Schmitz; Hartmut Döhner; Peter Dreger

    Contribution: I.K. analyzed data and wrote the paper; S.S., L.U., U.H., A.H., M.H., M.K., N.S., and H.D. designed and performed research; S.D., S.B., M.Z., M.S., J.B., and C.S. performed research; and P.D. designed and performed research, analyzed data, and wrote the paper. Conflict-of-interest disclosure: I.K. received honoraria from MSD and travel grants from Gilead. S.S. received consultancy fees, honoraria travel grants, and research funding from AbbVie, Boehringer Ingelheim, Amgen, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann-La Roche, and Sanofi. S.B. received honoraria and research funding from AbbVie; honoraria, travel grants and research funding from Hoffmann-LaRoche; and research funding from Celgene. U.H. received honoraria and financial support for conference participation from Jansen Cilag. M.H. received consultancy and speakers bureau fees from Pharmacyclics, LLC and an AbbVie and speakers bureau fees from Janssen. M.K. received consultancy fees, honoraria, travel grants, and research funding from Gilead and Roche; consultancy fees, honoraria, and travel grants from AbbVie and Janssen-Cilag; research funding from Amgen; and travel grants from Glaxo-SmithKline. P.D. received consultancy fees from Roche and Janssen and consultancy and speakers bureau fees from Novartis and Gilead. The remaining authors declare no competing financial interests. Correspondence: Isabelle Krämer, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg 69120, Germany; e-mail: isabelle.kraemer{at}med.uni-heidelberg.de.

    更新日期:2017-09-21
  • Persistence of the losing cord blood unit following double cord blood transplantation: finding the unseen
    Blood (IF 13.164) Pub Date : 2017-09-21
    Filippo Milano; Hilary Gammill; David C. Oliver; Sami B. Kanaan; J. Lee Nelson; Colleen Delaney

    To the editor:Double cord blood (CB) transplantation (dCBT) is an accepted treatment of patients with hematologic malignancies.[1][1],[2][2] In the vast majority of dCBT recipients, 1 unit emerges as the sole source of long-term hematopoiesis.[3][3] As measured by standard clinical testing for

    更新日期:2017-09-21
  • Philadelphia chromosome–positive B-lymphoblastic lymphoma involving the genitourinary system and bone at initial diagnosis and relapse
    Blood (IF 13.164) Pub Date : 2017-09-21
    Lan Zheng; Shimin Hu

    ![Figure][1]A 74-year-old man presented with bilateral testicular masses and back pain. A positron emission tomography scan showed increased metabolic activity in bilateral testes (panel A; ROI, region of interest; SUV, standardized uptake value), and lytic lesions in the left pubic

    更新日期:2017-09-21
  • Red cell fragments can mask severe thrombocytopenia
    Blood (IF 13.164) Pub Date : 2017-09-21
    Andrew J. Innes; Francis Matthey

    ![Figure][1]A 37-year-old man who had recently been treated for malaria while in Kenya presented with ongoing fevers and malaise as well as new headaches and hematuria. A complete blood count showed hemoglobin of 73 g/L, white blood count of 14.7 × 109/L, and platelets 266 × 109/L. There

    更新日期:2017-09-21
  • García-Sanz R. WM, MYD88, and CXCR4: following the thread. Blood. 2016;128(6):746-748.
    Blood (IF 13.164) Pub Date : 2017-09-21
    American Society of Hematology

    In the figure on page 747 in the 11 August 2016 issue, the labels “TLR7” should read “TLR4” and the labels “TLR4” should read “TLR7.” The errors have been corrected in the online version, which now differs from the print version

    更新日期:2017-09-21
  • Cellubrevin/Vesicle-Associated Membrane Protein-3 (VAMP-3)-mediated endocytosis and trafficking regulate platelet functions
    Blood (IF 13.164) Pub Date : 2017-01-01
    Meenakshi Banerjee; Smita Joshi; Jinchao Zhang; Carole L. Moncman; Shilpi Yadav; Beth A. Bouchard; Brian Storrie; Sidney W. Whiteheart

    Endocytosis is key to fibrinogen (Fg) uptake, trafficking of integrins (αIIbβ3, αvβ3) and purinergic receptors (P2Y1, P2Y12), and thus for normal platelet function. However, the molecular machinery required and possible trafficking routes are still ill-defined. To further identify elements of the platelet endocytic machinery, we examined the role of a vesicle-residing, Soluble N-ethylmaleimide Factor Attachment Protein Receptor (v-SNARE) called Cellubrevin/Vesicle-Associated Membrane Protein-3 (VAMP-3) in platelet function. While not required for normal platelet exocytosis or hemostasis, VAMP-3-/- mice had less platelet-associated Fg, indicating a defect in Fg uptake/storage. Other granule markers were unaffected. Direct experiments, both in vitro and in vivo, showed that loss of VAMP-3 led to a robust defect in uptake/storage of Fg in platelets and cultured megakaryocytes. Uptake of the fluid-phase marker, dextran, was only modestly affected. Time-dependent uptake and endocytic trafficking of Fg and dextran were followed using 3D-Structured Illumination Microscopy. Dextran uptake was rapid compared to Fg, but both cargoes progressed through Rab4+, Rab11+, and von Willebrand Factor (vWF)+ compartments in wild-type platelets in a time-dependent manner. In VAMP-3-/- platelets, the two cargoes showed limited colocalization with Rab4, Rab11, or vWF. Loss of VAMP-3 also affected some acute platelet functions, causing enhanced spreading on Fg and fibronectin and faster clot retraction compared to wild-type. Additionally, the rate of JAK2 phosphorylation, initiated through the thrombopoietin receptor (TPOR/Mpl) activation, was affected in VAMP-3-/- platelets. Collectively, our studies show that platelets are capable of a range of endocytosis steps with VAMP-3 being pivotal in these processes.

    更新日期:2017-09-20
  • Ectopic ILT3 controls BCR-dependent activation of Akt in B-cell chronic lymphocytic leukemia
    Blood (IF 13.164) Pub Date : 2017-01-01
    Vanessa Zurli; Giuliana Wimmer; Francesca Cattaneo; Veronica Candi; Emanuele Cencini; Alessandro Gozzetti; Donatella Raspadori; Giuseppe Campoccia; Francesca Sanseviero; Monica Bocchia; Cosima Tatiana Baldari; Anna Kabanova

    The high proportion of long-term non-progressors among chronic lymphocytic leukemia (CLL) patients suggests the existence of a regulatory network which restrains the proliferation of tumor B cells. The identification of molecular determinants composing such network is hence fundamental for our understanding of CLL pathogenesis. Based on our previous finding establishing a deficiency in the signaling adaptor p66Shc in CLL cells, we undertook to identify unique phenotypic traits caused by this defect. Here we show that a lack of p66Shc shapes the transcriptional profile of CLL cells and leads to an upregulation of the surface receptor ILT3, the immunoglobulin-like transcript 3 which is normally found on myeloid cells. The ectopic expression of ILT3 in CLL was a distinctive feature of neoplastic B cells and hematopoietic stem cells, thus identifying ILT3 as a selective marker of malignancy in CLL and the first example of phenotypic continuity between mature CLL cells and their progenitors in the bone marrow. ILT3 expression in CLL was found to be driven by Deltex1, a suppressor of antigen receptor signaling in lymphocytes. Triggering of ILT3 inhibited the activation of Akt kinase upon B cell receptor stimulation. This effect was achieved through the dynamic coalescence of ILT3, B cell receptors and phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 into inhibitory clusters at the cell surface. Collectively, our findings identify ILT3 as a signature molecule of p66Shc deficiency in CLL and indicate that ILT3 may functionally contribute to a regulatory network controlling tumor progression by suppressing the Akt pathway.

    更新日期:2017-09-20
  • Degree of Anemia, Indirect Markers of Hemolysis, and Vascular Complications of Sickle Cell Disease in Africa.
    Blood (IF 13.164) Pub Date : 2017-01-01
    Marie Dubert; Jacques Elion; Aissata Tolo; Dapa Aly Diallo; Saliou Diop; Ibrahima Diagne; Ibrahima Sanogo; Suzanne Belinga; Odette Guifo; Guillaume Wamba; Françoise Ngo Sack; Kouakou Boidy; Ismael Kamara; Youssouf Traore; Cheick Oumar Diakite; Valérie Gbonon; Blaise Felix Faye; Moussa Seck; Indou Deme Ly; David Chelo; Roland N'Guetta; Ibrahima Bara Diop; Bamba Gaye; Xavier Jouven; Brigitte Ranque

    The hyperhemolysis paradigm that describes overlapping "hyperhemolytic-endothelial dysfunction" and "high hemoglobin-hyperviscous" subphenotypes of sickle cell disease (SCD) patients is based on North American studies. We performed a transversal study nested in the CADRE cohort to analyze the association between steady-state hemolysis and vascular complications of SCD among sub-Saharan African patients. In Mali, Cameroon, and Ivory Coast, 2,407 SCD patients (1,751 SS-Sβ0, 495 SC and 161 Sβ+), aged three years old and over, were included at steady-state. Relative hemolytic intensity was estimated from a composite index derived from principal component analysis, which included bilirubin levels or clinical icterus, and lactate dehydrogenase levels. We assessed vascular complications (elevated tricuspid regurgitant jet velocity (TRV), microalbuminuria, leg ulcers, priapism, stroke, and osteonecrosis) by clinical examination, laboratory tests, and echocardiography. After adjustment for age, sex, country, and SCD phenotype, a low hemoglobin level was significantly associated with TRV and microalbuminuria in the whole population and with leg ulcers in SS-Sβ0 adults. A high hemolysis index was associated with microalbuminuria in the whole population and with elevated TRV, microalbuminuria, and leg ulcers in SS-Sβ0 adults, but these associations were no longer significant after adjustment for hemoglobin level. In conclusion, severe anemia at steady-state in SCD patients living in West and Central Africa is associated with elevated TRV, microalbuminuria, and leg ulcers, but these vascular complications are not independently associated with indirect markers of increased hemolysis. Other mechanisms leading to anemia, including malnutrition and infectious diseases, may also play a role in the development of SCD vasculopathy.

    更新日期:2017-09-20
  • Chimeric Antigen Receptor T-cell Therapies for Multiple Myeloma
    Blood (IF 13.164) Pub Date : 2017-01-01
    Lekha Mikkilineni; James N. Kochenderfer

    Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T-cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR T-cells against leukemia and lymphoma has encouraged development of CAR T-cell therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells. CAR T-cells targeting B-cell maturation antigen have demonstrated significant anti-myeloma activity in early clinical trials. Toxicities in these trials, including cytokine-release syndrome, have been similarto toxicities observed in CAR T-cell trials for leukemia. Targeting postulated CD19+ myeloma stem cells with anti-CD19 CAR T-cells is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte-activating molecule 7 (SLAMF7), and kappa light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of more than one antigen might often be required for effective treatment of MM with CAR T cells. Integration of CAR T cells with other myeloma therapies is an important area of future research. CAR T cell therapies for MM are at an early stage of development but have great promise to improve MM treatment.

    更新日期:2017-09-20
  • CK2β critically regulates thrombopoiesis and Ca2+-triggered platelet activation in arterial thrombosis in vivo
    Blood (IF 13.164) Pub Date : 2017-01-01
    Patrick Münzer; Britta Walker-Allgaier; Sascha Geue; Friederike Langhauser; Eva Geuss; David Stegner; Katja Aurbach; Daniela Semeniak; Madhumita Chatterjee; Irene Gonzalez Menendez; Melanie Märklin; Leticia Quintanilla-Martinez; Helmut R. Salih; David W. Litchfield; Thierry Buchou; Christoph Kleinschnitz; Florian Lang; Bernhard Nieswandt; Irina Pleines; Harald Schulze; Meinrad Gawaz; Oliver Borst

    Platelets, anucleated megakaryocyte-derived cells, play a major role in hemostasis and arterial thrombosis. While protein kinase Casein Kinase 2 (CK2) is readily detected in megakaryocytes and platelets, the impact of CK2-dependent signaling on megakaryocyte/platelet (patho-) physiology has remained elusive. The present study explored the impact of the CK2 regulatory β-subunit on platelet biogenesis and activation. Megakaryocyte/platelet-specific genetic deletion of CK2β (ck2β-/-) in mice resulted in a significant macrothrombocytopenia and an increased extramedullar megakaryopoiesis with enhanced proportion of premature platelets. While platelet lifespan was only mildly affected, ck2β-/- megakaryocytes displayed an abnormal microtubule structure with a drastically increased fragmentation within bone marrow and a significantly reduced proplatelet formation in vivo. In ck2β-/- platelets tubulin polymerization was disrupted resulting in an impaired thrombopoiesis and an abrogated IP3 receptor-dependent intracellular Ca2+ release. Presumably due to blunted increase of cytosolic Ca2+-concentration ([Ca2+]i), activation-dependent increases of alpha and dense granule secretion, integrin αIIbβ3 activation and aggregation were abrogated in ck2β-/- platelets. Accordingly, thrombus formation and stabilization under high arterial shear rates were significantly diminished and thrombotic vascular occlusion in vivo was significantly blunted in ck2β-/- mice accompanied by a slight prolongation of bleeding time. Following tMCAO, ck2β-/- mice displayed significantly reduced cerebral infarct volumes, developed significantly less neurological deficits and showed significantly better outcome after ischemic stroke than ck2βfl/fl mice. The present observations reveal CK2β as novel powerful regulator of thrombopoiesis, Ca2+-dependent platelet activation and arterial thrombosis in vivo.

    更新日期:2017-09-20
  • Emerging mechanisms of long noncoding RNA function during normal and malignant hematopoiesis
    Blood (IF 13.164) Pub Date : 2017-01-01
    Juan R. Alvarez-Dominguez; Harvey F. Lodish

    Long noncoding RNAs (lncRNAs) are increasingly recognized as vital components of gene programs controlling cell differentiation and function. Central to their functions is an ability to act as scaffolds or as decoys that recruit or sequester effector proteins from their DNA, RNA, or protein targets. lncRNA-modulated effectors include regulators of transcription, chromatin organization, RNA processing, and translation, such that lncRNAs can influence gene expression at multiple levels. Here we review the current understanding of how lncRNAs help coordinate gene expression to modulate cell fate in the hematopoietic system. We focus on a growing number of mechanistic studies to synthesize emerging principles of lncRNA function, emphasizing how they facilitate diversification of gene programming during development. We also survey how disrupted lncRNA function can contribute to malignant transformation, highlighting opportunities for therapeutic intervention in specific myeloid and lymphoid cancers. Finally, we discuss challenges and prospects for further elucidation of lncRNA mechanisms.

    更新日期:2017-09-20
  • Kinetics and Biomarkers of Severe Cytokine Release Syndrome after CD19 Chimeric Antigen Receptor-modified T Cell Therapy
    Blood (IF 13.164) Pub Date : 2017-01-01
    Kevin A. Hay; Laïla-Aïcha Hanafi; Daniel Li; Juliane Gust; W. Conrad Liles; Mark M. Wurfel; José A. López; Junmei Chen; Dominic Chung; Susanna Harju-Baker; Sindhu Cherian; Xueyan Chen; Stanley R. Riddell; David G. Maloney; Cameron J. Turtle

    Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor-modified T cells (CAR-T) has produced impressive antitumor responses in patients with refractory CD19+ B cell malignancies, but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR-T cells. CRS developed in 70% of patients, including 62.5% with grade 1-3 CRS (grade 1, 26%; grade 2, 32%; grade 3, 4.5%), 3.8% with grade 4 CRS, and 3.8% with grade 5 CRS. A majority of cases of grade ≥4 CRS occurred during CAR-T cell dose-finding. Multivariable analysis of baseline characteristics identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR-T cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR-T cells without selection of CD8+ central memory T cells as independent predictors of CRS. Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. Angiopoietin-2 and von Willebrand Factor, which are biomarkers of endothelial activation were increased during severe CRS, and also before lymphodepletion in patients who subsequently developed CRS. We describe a classification-tree algorithm to guide studies of early intervention after CAR-T cell infusion for patients at high risk of severe CRS. These data provide a framework for early intervention studies to facilitate safer application of effective CD19 CAR-T cell therapy.

    更新日期:2017-09-19
  • Ibrutinib for chronic graft-versus-host disease after failure of prior therapy
    Blood (IF 13.164) Pub Date : 2017-01-01
    David Miklos; Corey S. Cutler; Mukta Arora; Edmund K. Waller; Madan Jagasia; Iskra Pusic; Mary E. Flowers; Aaron C. Logan; Ryotaro Nakamura; Bruce R. Blazar; Yunfeng Li; Stephen Chang; Indu Lal; Jason Dubovsky; Danelle F. James; Lori Styles; Samantha Jaglowski

    Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton's tyrosine kinase in B cells and interleukin-2–inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 NIH criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥ 20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg/day at baseline to 0.12 mg/kg/day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥ 1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the US for treatment of adult patients with cGVHD after failure of one or more lines of systemic therapy. The study is registered to www.clinicaltrials.gov as NCT02195869.

    更新日期:2017-09-19
  • Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels
    Blood (IF 13.164) Pub Date : 2017-01-01
    Michelle Lavin; Sonia Aguila; Sonja Schneppenheim; Niall Dalton; Kenneth L. Jones; Jamie M. O'Sullivan; Niamh M. O'Connell; Kevin Ryan; Barry White; Mary Byrne; Marie Rafferty; Mairead M. Doyle; Margaret Nolan; Roger J.S. Preston; Ulrich Budde; Paula James; Jorge Di Paola; James S. O'Donnell

    Critical clinical questions remain unanswered regarding diagnosis and management of patients with Low VWF levels (30–50 IU/dL). To address these questions, the Low VWF Ireland Cohort (LoVIC) study investigated 126 patients registered with Low VWF. Interestingly, despite their marginally reduced plasma VWF levels, ISTH BAT and Condensed MCMDM-1 VWD scores both confirmed significant bleeding phenotypes in the majority of LoVIC patients. For example, among female patients with Low VWF, 77% had ISTH BAT scores ≥6. Importantly, bleeding tendency did not correlate with plasma VWF levels within the 30-50 IU/dL range. Furthermore, bleeding phenotypes could not be explained by concurrent hemostatic defects. Plasma FVIII:C/VWF:Ag ratios were significantly increased in LoVIC patients compared to controls (p<0.0001). In contrast, increased plasma VWF:pp/VWF:Ag ratios >3 were observed in only 6% of the LoVIC cohort. Furthermore, platelet-VWF:Ag and platelet-VWF:CB levels were both significantly reduced compared to controls (p<0.05). In response to DDAVP, peak VWF levels exceeded 100 IU/dL in 88% of patients. Importantly, the DDAVP response was sustained (VWF:Ag and VWF:RCo both remained >100 IU/dL after 4 hours in 72% subjects). In conclusion, our novel data suggest that Low VWF levels can be associated with significant bleeding, and are predominantly due to reductions in VWF synthesis and/or constitutive secretion. Although enhanced VWF clearance may contribute to the pathophysiology in some individuals with Low VWF, the absolute reduction in VWF plasma half-life is usually mild and not sufficient to significantly impact upon the duration of DDAVP-induced VWF response. This trial was registered at clinicaltrials.gov #NCT03167320.

    更新日期:2017-09-15
  • High-risk DLBCL: interim PET? Not yet
    Blood (IF 13.164) Pub Date : 2017-09-14
    Mark Hertzberg

    In this issue of Blood , [Casasnovas et al][1] demonstrate that among diffuse large B-cell (DLBCL) patients with age-adjusted International Prognostic Index (aaIPI) 2-3, the dose-dense immunochemotherapy (IC) regimen rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP

    更新日期:2017-09-15
  • Gene therapy: WAS (not) just for kids
    Blood (IF 13.164) Pub Date : 2017-09-14
    Donald B. Kohn

    In this issue of Blood , [Morris et al][1] describe application of autologous transplant/gene therapy for Wiskott-Aldrich syndrome (WAS), first demonstrated to be efficacious and safe in children, to bring relief to a severely affected adult.[1][2] In recent years, gene therapy for blood cell

    更新日期:2017-09-15
  • tPA and anger management for macrophages
    Blood (IF 13.164) Pub Date : 2017-09-14
    Lindsey A. Miles; Robert J. Parmer

    In this issue of Blood , [Mantuano et al][1] in the Gonias laboratory elucidate a novel, protease-independent signaling pathway by which tissue plasminogen activator (tPA) negatively regulates the innate immune response of macrophages and neutralizes lipopolysaccharide (LPS) toxicity in vivo.[1][2

    更新日期:2017-09-15
  • Brentuximab: is it time for a new “B” in ABVD?
    Blood (IF 13.164) Pub Date : 2017-09-14
    Deborah M. Stephens

    In this issue of Blood , [Connors et al][1] report promising 5-year outcomes that support the replacement of bleomycin with brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) for the front-line treatment of patients with advanced-stage Hodgkin lymphoma.[1][2]

    更新日期:2017-09-15
  • Erdheim-Chester disease: the “targeted” revolution
    Blood (IF 13.164) Pub Date : 2017-09-14
    Augusto Vaglio; Eli L. Diamond

    In this issue of Blood, [Cohen Aubart et al][1] present a large series of patients with Erdheim-Chester disease (ECD) treated with BRAF and MEK inhibitors and describe the disease trajectory in a subset of these patients after treatment withdrawal.[1][2] ![Figure][3] Proposed therapeutic

    更新日期:2017-09-15
  • Flexibility and innovation in the FDA’s novel regulatory approval strategies for hematologic drugs
    Blood (IF 13.164) Pub Date : 2017-09-14
    Ann T. Farrell; Kirsten B. Goldberg; Richard Pazdur

    The US Food and Drug Administration (FDA) negotiates the evidence necessary for drug approval with pharmaceutical sponsors. The resulting data package submitted in support of approval includes labeling that conveys the benefits and risks of a particular agent. Recent approvals in hematology

    更新日期:2017-09-15
  • MicroRNAs and acute myeloid leukemia: therapeutic implications and emerging concepts
    Blood (IF 13.164) Pub Date : 2017-09-14
    Jared A. Wallace; Ryan M. O’Connell

    Acute myeloid leukemia (AML) is a deadly hematologic malignancy characterized by the uncontrolled growth of immature myeloid cells. Over the past several decades, we have learned a tremendous amount regarding the genetic aberrations that govern disease development in AML. Among these are genes that encode noncoding RNAs, including the microRNA (miRNA) family. miRNAs are evolutionarily conserved small noncoding RNAs that display important physiological effects through their posttranscriptional regulation of messenger RNA targets. Over the past decade, studies have identified miRNAs as playing a role in nearly all aspects of AML disease development, including cellular proliferation, survival, and differentiation. These observations have led to the study of miRNAs as biomarkers of disease, and efforts to therapeutically manipulate miRNAs to improve disease outcome in AML are ongoing. Although much has been learned regarding the importance of miRNAs in AML disease initiation and progression, there are many unanswered questions and emerging facets of miRNA biology that add complexity to their roles in AML. Moving forward, answers to these questions will provide a greater level of understanding of miRNA biology and critical insights into the many translational applications for these small regulatory RNAs in AML.

    更新日期:2017-09-15
  • How I monitor long-term and late effects after blood or marrow transplantation
    Blood (IF 13.164) Pub Date : 2017-09-14
    Smita Bhatia; Saro H. Armenian; Wendy Landier

    Blood or marrow transplantation (BMT) is used with curative intent for hematologic malignancies. Conditional on surviving the first 2 years after BMT, 5-year survival generally exceeds 70%. However, the cumulative therapeutic exposures lead to premature onset of chronic health conditions, such that the 15-year cumulative incidence of severe or life-threatening chronic health conditions exceeds 40%, resulting in premature mortality. The high burden of morbidity, coupled with a long latency between BMT and the development of chronic health conditions necessitates life-long risk-based monitoring of the BMT survivors. The issues of how and when to screen BMT survivors for therapy-related complications and exacerbation of preexisting conditions are important and largely unanswered questions. For BMT survivors, screening recommendations must incorporate risks associated with pre-BMT therapy as well as risks related to transplant conditioning and graft-versus-host disease. Here, we describe our approach to monitoring BMT survivors for risk-based screening and early detection of key late-occurring or long-term complications using patient scenarios to illustrate our discussion.

    更新日期:2017-09-15
  • FDG-PET–driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study
    Blood (IF 13.164) Pub Date : 2017-09-14
    R.-O. Casasnovas; L. Ysebaert; C. Thieblemont; E. Bachy; P. Feugier; A. Delmer; S. Tricot; J. Gabarre; M. Andre; C. Fruchart; N. Mounier; R. Delarue; M. Meignan; A. Berriolo-Riedinger; S. Bardet; J.-F. Emile; J.-P. Jais; C. Haioun; H. Tilly; F. Morschhauser

    Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2−/PET4− patients were assigned SIC, PET2+/PET4− patients were assigned ASCT, and PET4+ patients were treated with the investigator’s choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4−/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P < .01), but progression-free survival (PFS) and overall survival (OS) were similar in both groups. PET2−/PET4− and PET2+/PET4− patients had similar outcomes. Using ΔSUVmax, 79% of the patients were PET2−/PET4−. ΔSUVmaxPET0-4 >70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.

    更新日期:2017-09-15
  • Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult
    Blood (IF 13.164) Pub Date : 2017-09-14
    Emma C. Morris; Thomas Fox; Ronjon Chakraverty; Rita Tendeiro; Katie Snell; Christine Rivat; Sarah Grace; Kimberly Gilmour; Sarita Workman; Karen Buckland; Katie Butler; Ronnie Chee; Alan D. Salama; Hazem Ibrahim; Havinder Hara; Cecile Duret; Fulvio Mavilio; Frances Male; Frederick D. Bushman; Anne Galy; Siobhan O. Burns; H. Bobby Gaspar; Adrian J. Thrasher

    Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proinflammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242.

    更新日期:2017-09-15
  • The cell polarity determinant CDC42 controls division symmetry to block leukemia cell differentiation
    Blood (IF 13.164) Pub Date : 2017-09-14
    Benjamin Mizukawa; Eric O’Brien; Daniel C. Moreira; Mark Wunderlich; Cindy L. Hochstetler; Xin Duan; Wei Liu; Emily Orr; H. Leighton Grimes; James C. Mulloy; Yi Zheng

    As a central regulator of cell polarity, the activity of CDC42 GTPase is tightly controlled in maintaining normal hematopoietic stem and progenitor cell (HSC/P) functions. We found that transformation of HSC/P to acute myeloid leukemia (AML) is associated with increased CDC42 expression and activity in leukemia cells. In a mouse model of AML, the loss of Cdc42 abrogates MLL-AF9–induced AML development. Furthermore, genetic ablation of CDC42 in both murine and human MLL-AF9 (MA9) cells decreased survival and induced differentiation of the clonogenic leukemia-initiating cells. We show that MLL-AF9 leukemia cells maintain cell polarity in the context of elevated Cdc42-guanosine triphosphate activity, similar to nonmalignant, young HSC/Ps. The loss of Cdc42 resulted in a shift to depolarized AML cells that is associated with a decrease in the frequency of symmetric and asymmetric cell divisions producing daughter cells capable of self-renewal. Importantly, we demonstrate that inducible CDC42 suppression in primary human AML cells blocks leukemia progression in a xenograft model. Thus, CDC42 loss suppresses AML cell polarity and division asymmetry, and CDC42 constitutes a useful target to alter leukemia-initiating cell fate for differentiation therapy.

    更新日期:2017-09-15
  • AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency
    Blood (IF 13.164) Pub Date : 2017-09-14
    Charles Kung; Jeff Hixon; Penelope A. Kosinski; Giovanni Cianchetta; Gavin Histen; Yue Chen; Collin Hill; Stefan Gross; Yaguang Si; Kendall Johnson; Byron DeLaBarre; Zhiyong Luo; Zhiwei Gu; Gui Yao; Huachun Tang; Cheng Fang; Yingxia Xu; Xiaobing Lv; Scott Biller; Shin-San Michael Su; Hua Yang; Janeta Popovici-Muller; Francesco Salituro; Lee Silverman; Lenny Dang

    Pyruvate kinase (PK) deficiency is a rare genetic disease that causes chronic hemolytic anemia. There are currently no targeted therapies for PK deficiency. Here, we describe the identification and characterization of AG-348, an allosteric activator of PK that is currently in clinical trials for the treatment of PK deficiency. We demonstrate that AG-348 can increase the activity of wild-type and mutant PK enzymes in biochemical assays and in patient red blood cells treated ex vivo. These data illustrate the potential for AG-348 to restore the glycolytic pathway activity in patients with PK deficiency and ultimately lead to clinical benefit.

    更新日期:2017-09-15
  • Strict tropism for CD71+/CD234+ human reticulocytes limits the zoonotic potential of Plasmodium cynomolgi
    Blood (IF 13.164) Pub Date : 2017-09-14
    Varakorn Kosaisavee; Rossarin Suwanarusk; Adeline C. Y. Chua; Dennis E. Kyle; Benoit Malleret; Rou Zhang; Mallika Imwong; Rawiwan Imerbsin; Ratawan Ubalee; Hugo Sámano-Sánchez; Bryan K. S. Yeung; Jessica J. Y. Ong; Eric Lombardini; François Nosten; Kevin S. W. Tan; Pablo Bifani; Georges Snounou; Laurent Rénia; Bruce Russell

    Two malaria parasites of Southeast Asian macaques, Plasmodium knowlesi and P cynomolgi, can infect humans experimentally. In Malaysia, where both species are common, zoonotic knowlesi malaria has recently become dominant, and cases are recorded throughout the region. By contrast, to date, only a single case of naturally acquired P cynomolgi has been found in humans. In this study, we show that whereas P cynomolgi merozoites invade monkey red blood cells indiscriminately in vitro, in humans, they are restricted to reticulocytes expressing both transferrin receptor 1 (Trf1 or CD71) and the Duffy antigen/chemokine receptor (DARC or CD234). This likely contributes to the paucity of detectable zoonotic cynomolgi malaria. We further describe postinvasion morphologic and rheologic alterations in P cynomolgi–infected human reticulocytes that are strikingly similar to those observed for P vivax. These observations stress the value of P cynomolgi as a model in the development of blood stage vaccines against vivax malaria.

    更新日期:2017-09-15
  • Tissue-type plasminogen activator regulates macrophage activation and innate immunity
    Blood (IF 13.164) Pub Date : 2017-09-14
    Elisabetta Mantuano; Pardis Azmoon; Coralie Brifault; Michael A. Banki; Andrew S. Gilder; Wendy M. Campana; Steven L. Gonias

    Tissue-type plasminogen activator (tPA) is the major intravascular activator of fibrinolysis and a ligand for receptors involved in cell signaling. In cultured macrophages, tPA inhibits the response to lipopolysaccharide (LPS) by a pathway that apparently requires low-density lipoprotein receptor-related protein-1 (LRP1). Herein, we show that the mechanism by which tPA neutralizes LPS involves rapid reversal of IκBα phosphorylation. tPA independently induced transient IκBα phosphorylation and extracellular signal-regulated kinase 1/2 (ERK1/2) activation in macrophages; however, these events did not trigger inflammatory mediator expression. The tPA signaling response was distinguished from the signature of signaling events elicited by proinflammatory LRP1 ligands, such as receptor-associated protein (RAP), which included sustained IκBα phosphorylation and activation of all 3 MAP kinases (ERK1/2, c-Jun kinase, and p38 MAP kinase). Enzymatically active and inactive tPA demonstrated similar immune modulatory activity. Intravascular administration of enzymatically inactive tPA in mice blocked the toxicity of LPS. In mice not treated with exogenous tPA, the plasma concentration of endogenous tPA increased 3-fold in response to LPS, to 116 ± 15 pM, but remained below the approximate threshold for eliciting anti-inflammatory cell signaling in macrophages (∼2.0 nM). This threshold is readily achieved in patients when tPA is administered therapeutically for stroke. In addition to LRP1, we demonstrate that the N-methyl-D-aspartic acid receptor (NMDA-R) is expressed by macrophages and essential for anti-inflammatory cell signaling and regulation of cytokine expression by tPA. The NMDA-R and Toll-like receptor-4 were not required for proinflammatory RAP signaling. By mediating the tPA response in macrophages, the NMDA-R provides a pathway by which the fibrinolysis system may regulate innate immunity.

    更新日期:2017-09-15
  • Five-year follow-up of brentuximab vedotin combined with ABVD or AVD for advanced-stage classical Hodgkin lymphoma
    Blood (IF 13.164) Pub Date : 2017-09-14
    Joseph M. Connors; Stephen M. Ansell; Michelle Fanale; Steven I. Park; Anas Younes

    Acknowledgments: The authors thank Elena Moon for data management at the British Columbia Cancer Agency, the patients who participated in this study, and the many physicians who supported this trial by referral of patients. Contribution: All authors participated in the study’s conception, data gathering, analysis, interpretation, and manuscript drafting. Conflict-of-interest disclosure: J.M.C.’s institution receives support for research from F Hoffmann-La Roche; Bristol-Myers Squibb; Takeda Pharmaceutical Company; and Seattle Genetics. S.I.P. receives research support from Seattle Genetics and Teva; serves on advisory boards for Cornerstone Pharmaceuticals and Teva; and serves on a speaker’s bureau for Gilead. S.M.A.’s institution receives support for research from Takeda Pharmaceutical Company and Seattle Genetics. A.Y. receives honoraria for consulting from Merck, Bristol-Myers Squibb, Bayer, Celgene, Incyte, Sanofi, Janssen R&D, Seattle Genetics, and Takeda Millennium; and research funding from Novartis, Johnson and Johnson, Curis, Roche, and Bristol-Myers Squibb. M.F. serves in a consulting role or on an advisory board for Bristol-Myers Squibb and Merck; receives honoraria from Seattle Genetics and Takeda; and receives research funding from Bristol-Myers Squibb, Merck, Takeda, and Seattle Genetics. Correspondence: Joseph M. Connors, British Columbia Cancer Agency Centre for Lymphoid Cancer, 600 West 10th Ave, Vancouver, BC, Canada V5Z 4E6; e-mail: jconnors{at}bccancer.bc.ca.

    更新日期:2017-09-15
  • Targeted therapies in 54 patients with Erdheim-Chester disease, including follow-up after interruption (the LOVE study)
    Blood (IF 13.164) Pub Date : 2017-09-14
    Fleur Cohen Aubart; Jean-François Emile; Fabrice Carrat; Frédéric Charlotte; Neila Benameur; Jean Donadieu; Philippe Maksud; Ahmed Idbaih; Stéphane Barete; Khê Hoang-Xuan; Zahir Amoura; Julien Haroche

    Publisher's Note: There is an [Inside Blood Commentary][1] on this article in this issue. To the editor: Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis that is characterized by the accumulation of foamy histiocytes in the retroperitoneum, long bones, and large vessel areas.[1

    更新日期:2017-09-15
  • Platelet soluble CD40-ligand level is associated with transfusion adverse reactions in a mixed threshold-and-hit model
    Blood (IF 13.164) Pub Date : 2017-09-14
    Fabrice Cognasse; Caroline Sut; Elisa Fromont; Sandrine Laradi; Hind Hamzeh-Cognasse; Olivier Garraud

    To the editor: Platelets are the principal source of soluble CD40-ligand (sCD40L) found in blood.[1][1] This biological response modifier has been reported to be a candidate mediator for acute reactions after platelet transfusions.[2][2] Serious adverse reactions (SARs) associated with excessive

    更新日期:2017-09-15
  • Hematologic relapse in AL amyloidosis after high-dose melphalan and stem cell transplantation
    Blood (IF 13.164) Pub Date : 2017-09-14
    Sabrina Browning; Karen Quillen; J. Mark Sloan; Gheorghe Doros; Shayna Sarosiek; Vaishali Sanchorawala

    To the editor: Light-chain (AL) amyloidosis is a rare disease in which an underlying clonal plasma cell population generates aberrant immunoglobulin light chains that misfold and form amyloid fibrils, which are deposited in extracellular tissues and organs, resulting in impairment of vital organ

    更新日期:2017-09-15
  • Exuberant nodal proliferation of mature plasmacytoid dendritic cells in a patient with chronic myelomonocytic leukemia
    Blood (IF 13.164) Pub Date : 2017-09-14
    Huan-You Wang; Andrew L. Feldman

    ![Figure][1] A 71-year-old man presented with an enlarged axillary lymph node 7 months after a diagnosis of chronic myelomonocytic leukemia 1 (CMML-1). Microscopically, the nodal architecture was nearly effaced by diffuse proliferation with scattered residual lymphoid aggregates (panel A;

    更新日期:2017-09-15
  • Cyclin D1–negative mantle cell lymphoma with aberrant CD3 expression
    Blood (IF 13.164) Pub Date : 2017-09-14
    Anita Malek; Govind Bhagat

    ![Figure][1] A 57-year-old man presented with generalized lymphadenopathy. Lymph node biopsy showed a vaguely nodular infiltrate of pleomorphic intermediate-sized lymphocytes (panels A and B, original magnification ×20 and ×500, respectively; hematoxylin and eosin [H&E]–stained lymph node

    更新日期:2017-09-15
  • A recombinant human ADAMTS-13: first-in-human study evaluating pharmacokinetics, safety and tolerability in cTTP patients
    Blood (IF 13.164) Pub Date : 2017-01-01
    Marie Scully; Paul Knöbl; Karim Kentouche; Lawrence Rice; Jerzy Windyga; Reinhard Schneppenheim; Johanna A. Kremer Hovinga; Michiko Kajiwara; Yoshihiro Fujimura; Caterina Maggiore; Jennifer Doralt; Christopher Hibbard; Leah Martell; Bruce Ewenstein

    Safety, tolerability and pharmacokinetics of recombinant ADAMTS-13 (rADAMTS-13; BAX 930; SHP655) were investigated in 15 patients diagnosed with severe congenital ADAMTS-13 deficiency (plasma ADAMTS-13 activity < 6%) in a prospective phase 1, first-in-human, multicenter dose escalation study. BAX 930 was well tolerated, no serious adverse events occurred, and no anti-ADAMTS-13 antibodies were observed. Following single dose administration of BAX 930 at 5, 20, or 40 U/kg body weight to adolescents and adults, there was approximate dose proportionality with respect to Cmax and AUC. Dose related increases of individual ADAMTS-13:Ag and activity were observed and reached a maximum within 1 hour. With escalating BAX 930 doses administered, a dose-dependent persistence of ADAMTS-13 mediated VWF cleavage products and reduced VWF multimeric size were observed. This study demonstrated that pharmacokinetic parameters of BAX 930 were comparable to those estimated in previous plasma infusion studies and provided evidence of pharmacodynamic activity. The study was registered on www.clinicaltrials.gov under the number NCT02216084.

    更新日期:2017-09-14
  • A dual role for the class III PI3K, Vps34, in platelet production and thrombus growth
    Blood (IF 13.164) Pub Date : 2017-01-01
    Colin Valet; Marie Levade; Gaëtan Chicanne; Benoit Bilanges; Cendrine Cabou; Julien Viaud; Marie-Pierre Gratacap; Frédérique Gaits-Iacovoni; Bart Vanhaesebroeck; Bernard Payrastre; Sonia Severin

    To uncover the role of Vps34, the sole class III phosphoinositide 3-kinase, in megakaryocytes (MKs) and platelets, we created a mouse model with Vps34 deletion in the MK/platelet lineage (Pf4-Cre/Vps34lox/lox). Deletion of Vps34 in MKs led to the loss of its regulator protein Vps15, and was associated with microthrombocytopenia and platelet granule abnormalities. While Vps34 deficiency did not impact on MK polyploidisation or proplatelet formation, it dampened MK granule biogenesis and directional migration towards an SDF1α gradient, leading to ectopic platelet release within the bone marrow. In MKs, the level of phosphatidylinositol 3-monophosphate (PI3P) was significantly reduced by Vps34 deletion resulting in endocytic/trafficking defects. In platelets, the basal level of PI3P was only slightly affected by Vps34 loss while the stimulation-dependent pool of PI3P was significantly decreased. Accordingly, a significant increase in the specific activity of Vps34 lipid kinase was observed following acute platelet stimulation. Similar as in Vps34-deficient platelets, ex vivo treatment of WT mouse or human platelets with Vps34 specific inhibitors, SAR405 and VPS34-IN1, induced abnormal secretion and affected thrombus growth at arterial shear rate, indicating a role for Vps34 kinase activity in platelet activation, independently from its role in MKs. In vivo, Vps34 deficiency had no impact on tail bleeding time but significantly reduced platelet prothrombotic capacity following carotid injury. This study uncovers a dual role for Vps34 as a regulator of platelet production by MKs and as an unexpected regulator of platelet activation and arterial thrombus formation dynamics.

    更新日期:2017-09-14
  • Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies
    Blood (IF 13.164) Pub Date : 2017-01-01
    Maureen C. Ryan; Maria Corinna Palanca-Wessels; Brian Schimpf; Kristine A. Gordon; Heather Kostner; Brad Meyer; Changpu Yu; Heather Van Epps; Dennis Benjamin

    Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia (B-ALL) have a poor prognosis. Despite measurable clinical activity with new targeted therapies, many patients do not achieve a complete or durable response suggesting an opportunity to improve upon existing therapies. Here we describe SGN-CD19B, a pyrrolobenzodiazepine (PBD)-based anti-CD19 antibody drug conjugate (ADC) being investigated for treatment of B-cell malignancies, which has improved potency compared to other ADCs. CD19-expressing tumor cells rapidly internalize SGN-CD19B and the released PBD drug induces DNA damage, resulting in G2-M cell cycle arrest and cell death. SGN-CD19B demonstrated activity against a broad panel of malignant B-cell lines and induced durable regressions in mice bearing xenografts derived from these B-cell malignancies. A single dose of SGN-CD19B induced durable regressions at 300 mcg/kg (3 mcg/kg drug equivalents); combination with rituximab decreased the curative dose to 100 mcg/kg (1 mcg/kg drug equivalents). These doses are significantly lower than the level of drug required with other ADC payloads. In cynomolgus monkeys, SGN-CD19B effectively depleted CD20+ B-lymphocytes in peripheral blood and lymphoid tissues confirming that SGN-CD19B is pharmacodynamically active at well-tolerated doses. In summary, preclinical studies show SGN-CD19B is a highly active ADC, which releases a DNA-crosslinking agent rather than a microtubule-inhibitor. The distinct mechanism of action, broad potency and potential to combine with rituximab suggest that SGN-CD19B may offer unique clinical opportunities in B-cell malignancies. A Phase 1 clinical trial is in progress to investigate the therapeutic potential of SGN-CD19B in relapsed/refractory B-NHL [NCT02702141].

    更新日期:2017-09-14
  • Non-classical FCGR2C haplotype is associated with protection from red blood cell allo-immunization in sickle cell disease
    Blood (IF 13.164) Pub Date : 2017-01-01
    Sanne M. Meinderts; Joep W.R. Sins; Karin Fijnvandraat; Sietse Q. Nagelkerke; Judy Geissler; Michael W. Tanck; Christine Bruggeman; Bart J. Biemond; Anita W. Rijneveld; Jean-Louis H. Kerkhoffs; Sadaf Pakdaman; Anoosha Habibi; Robin van Bruggen; Taco W. Kuijpers; France Pirenne; Timo K. van den Berg

    Red blood cell (RBC) transfusions are of vital importance in patients with sickle cell disease (SCD). However, a major complication of transfusion therapy is allo-immunization. The low-affinity Fc gamma receptors (FcγRs), expressed on immune cells, are important regulators of antibody responses. Genetic variation in FCGR genes has been associated with various auto- and allo-immune diseases. The aim of this study was to evaluate the association between genetic variation of FCGR and RBC allo-immunization in SCD. In this case-control study, DNA samples from 2 cohorts of transfused SCD patients were combined (France and the Netherlands). Cases had a positive history of allo-immunization, having received ≥1 RBC unit. Controls had a negative history of allo-immunization, having received ≥20 RBC units. Single nucleotide polymorphisms and copy number variation of the FCGR2/3 gene cluster were studied in a FCGR-specific multiplex ligation-dependent probe amplification assay. Frequencies were compared using logistic regression. Two-hundred-seventy-two patients were included (130 controls, 142 cases). The non-classical open reading frame in the FCGR2C gene (FCGR2C.nc-ORF) was strongly associated with a decreased allo-immunization risk (OR 0.26, 95% CI 0.11-0.64). This association persisted when only including controls with exposure to ≥100 units (OR 0.30, CI 0.11-0.85), and appeared even stronger when excluding cases with Rh or K antibodies only (OR 0.19, CI 0.06-0.59). In conclusion, SCD patients with the FCGR2C.nc-ORF polymorphism have over a threefold lower risk for RBC allo-immunization compared to patients without this mutation. This protective effect was strongest for exposure to antigens other than the immunogenic Rh or K antigens.

    更新日期:2017-09-12
  • The potential for chemotherapy-free strategies in mantle cell lymphoma
    Blood (IF 13.164) Pub Date : 2017-01-01
    Peter Martin; Jia Ruan; John P. Leonard

    Mantle cell lymphoma (MCL) may be one of the few cancers where multiple chemotherapy and non-chemotherapy regimens are considered as standard. Despite the significant activity of chemotherapy in the first-line setting and beyond, its limitations are reflected in the relatively poor ultimate outcomes of patients with MCL treated in the real world. Highly proliferative MCL and those with TP53 mutations tend to respond poorly despite intensive cytotoxic therapies. Patients with co-morbidities and those that are geographically isolated may not have access to the regimens that may appear most promising in clinical trials. Thoughtfully directed, non-chemotherapy agents might overcome some of the factors associated with a poor prognosis, such at TP53 mutation, and might resolve some of the challenges related to the toxicity and deliverability of standard chemotherapy regimens. Several clinical trials have already demonstrated that combinations of non-chemotherapy plus chemotherapy drugs can impact outcomes, while data with non-chemotherapy agents alone or in combination have suggested that some patients might be well suited to treatment without chemotherapy at all. However, challenges including chronic or unexpected toxicities, the rational versus practical development of combinations, and the financial acceptability of new strategies abound. The non-chemotherapy era is here, how it unfolds will depend on how we meet these challenges.

    更新日期:2017-09-12
  • Identification of extant vertebrate Myxine glutinosa vWF: evolutionary conservation of primary hemostasis
    Blood (IF 13.164) Pub Date : 2017-01-01
    Marianne A. Grant; David L. Beeler; Katherine C. Spokes; Junmei Chen; Harita Dharaneeswaran; Tracey E. Sciuto; Ann M. Dvorak; Gianluca Interlandi; José A. Lopez; William C. Aird

    Hemostasis in vertebrates involves both a cellular and protein component. Previous studies in jawless vertebrates (cyclostomes) suggest that the protein response, which involves thrombin-catalyzed conversion of a soluble plasma protein, fibrinogen, into a polymeric fibrin clot, is conserved in all vertebrates. However, similar data are lacking for the cellular response, which in gnathostomes, is regulated by von Willebrand factor (VWF), a glycoprotein that mediates the adhesion of platelets to the subendothelial matrix of injured blood vessels. To gain evolutionary insights into the cellular phase of coagulation, we asked whether a functional vwf gene is present in the Atlantic hagfish, Myxine glutinosa. We found a single vwf transcript that encodes a simpler protein compared to higher vertebrates, the most striking difference being the absence of an A3 domain, which otherwise binds collagen under high flow conditions. Immunohisto-chemical analyses of hagfish tissues and blood revealed Vwf expression in endothelial cells and thrombocytes. Electron microscopic studies of hagfish tissues demonstrated the presence of Weibel-Palade bodies (WPB) in the endothelium. Hagfish Vwf formed high molecular weight multimers in hagfish plasma and in stably transfected CHO cells. In functional assays, botrocetin promoted VWF-dependent thrombocyte aggregation. A search for vwf sequences in the genome of sea squirts, the closest invertebrate relatives of hagfish, failed to reveal evidence of an intact vwf gene. Together, our findings suggest that VWF evolved in the ancestral vertebrate following the divergence of the urochordates some 500 million years ago and that it acquired increasing complexity though sequential insertion of functional modules.

    更新日期:2017-09-12
  • Topological analysis reveals a PD-L1 associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma
    Blood (IF 13.164) Pub Date : 2017-01-01
    Christopher D. Carey; Daniel Gusenleitner; Mikel Lipschitz; Margaretha G.M. Roemer; Edward C. Stack; Evisa Gjini; Xihao Hu; Robert Redd; Gordon J. Freeman; Donna Neuberg; F. Stephen Hodi; Xiaole Shirley Liu; Margaret A. Shipp; Scott J. Rodig

    Signaling between programmed cell death protein 1 (PD-1) and the programmed cell death -1 ligands (PD-1 ligands, PD-L1, PD-L2) is essential for malignant Hodgkin Reed-Sternberg (HRS) cells to evade anti-tumor immunity in classical Hodgkin lymphoma (cHL). Copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) contribute to robust PD-L1 and PD-L2 expression by HRS cells. PD-L1 is also expressed by non-malignant tumor-associated macrophages (TAMs) but the relationships between PD-L1+ HRS cells, PD-L1+ TAMs, and PD-1+ T-cells remain undefined. We used multiplex immunofluorescence and digital image analysis to examine the topography of PD-L1+ and PD-1+ cells in the tumor microenvironment (TME) of cHL. We find that the majority of PD-L1 in the TME is expressed by the abundant PD-L1+ TAMs which physically co-localize with PD-L1+ HRS cells in a microenvironmental niche. PD-L1+ TAMs are enriched for contacts with T-cells and PD-L1+ HRS cells are enriched for contacts with CD4+ T-cells, a subset of which are PD-1+. Our data define a unique topology of cHL in which PD-L1+ TAMs surround HRS cells and implicate CD4+ T-cells as a target of PD-1 blockade.

    更新日期:2017-09-11
  • At least 20% donor myeloid chimerism is necessary to reverse the sickle phenotype after allogeneic HSCT
    Blood (IF 13.164) Pub Date : 2017-01-01
    Courtney D. Fitzhugh; Stefan Cordes; Tiffani Taylor; Wynona Coles; Katherine Roskom; Mary Link; Matthew M. Hsieh; John F. Tisdale

    Novel curative therapies employing genetic transfer of normal globin-producing genes into autologous hematopoietic stem cells (HSCs) are in clinical trials for patients with sickle cell disease (SCD). The percentage of transferred globin necessary to cure SCD is currently not known. In the setting of allogeneic nonmyeloablative hematopoietic stem cell transplants (HSCT), stable mixed chimerism is sufficient to reverse the disease. We regularly monitored 67 patients after HSCT. After initially robust engraftment, three of these patients experienced declining donor myeloid chimerism (DMC) levels with eventual return of disease. From this we discovered that 20% DMC is necessary to reverse the sickle phenotype. We subsequently developed a mathematical model to test the hypothesis that the percentage of DMC necessary is determined solely by differences between donor and recipient red blood cell (RBC) survival times. In our model, the required 20% DMC can be entirely explained by the large differences between donor and recipient RBC survival times. Our model predicts that the requisite DMC and therefore necessary level of transferred globin is lowest in patients with the highest reticulocyte counts and concomitantly shortened RBC lifespans.

    更新日期:2017-09-08
  • Cytoprotective activated protein C averts Nlrp3 inflammasome induced ischemia reperfusion injury via mTORC1 inhibition
    Blood (IF 13.164) Pub Date : 2017-01-01
    Sumra Nazir; Ihsan Gadi; Moh'd Mohanad Al-Dabet; Ahmed Elwakiel; Shrey Kohli; Sanchita Ghosh; Jayakumar Manoharan; Satish Ranjan; Fabian Bock; Ruediger C. Braun-Dullaeus; Charles T. Esmon; Tobias B. Huber; Eric Camerer; Chris Dockendorff; John H. Griffin; Berend Isermann; Khurrum Shahzad

    Cytoprotection by activated protein C (aPC) following ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation and hence conceptually cell-death forms disjunct from immunologically silent apoptosis are more likely to be relevant. As pyroptosis, cell death resulting from inflammasome activation, is typically observed in IRI we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRI. aPC treatment before or after myocardial IRI reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that Nlrp3 inflammasome activation preceded myocardial injury and apoptosis, corroborating a pathogenic role of the Nlrp3 inflammasome. The constitutively active Nlrp3A350V mutant abolished aPC's protective effect, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation in macrophages, cardiomyocytes, and cardiac fibroblasts via PAR-1 and mTORC1 signaling. Accordingly, inhibiting PAR-1 signaling, but not aPC's anticoagulant properties, abolished aPC's ability to restrict Nlrp3 inflammasome activity and tissue damage in myocardial IRI. Targeting biased PAR-1 signaling via parmodulin-2 restricted mTORC1 and Nlrp3 inflammasome activation and limited myocardial IRI as efficient as aPC. The relevance of aPC-mediated Nlrp3 inflammasome suppression following IRI was corroborated in renal IRI, where aPC's tissue protective effect was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1 dependent inflammasome activation and that mimicking biased aPC-PAR1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI.

    更新日期:2017-09-07
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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