Journal Cover Blood
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   ISSN (Print) 0006-4971 - ISSN (Online) 1528-0020
   Published by American Society of Hematology Homepage  [1 journal]
  • Function and dysfunction
    • Authors: Mohandas N.
      Pages: 2179 - 2180
      Keywords: Free Research Articles
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2018-04-840827
      Issue No: Vol. 131, No. 20 (2018)
  • Ezh2 spares KitL from the cutter
    • Authors: Pietras E. M.
      Pages: 2180 - 2181
      Keywords: Free Research Articles
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2018-04-841890
      Issue No: Vol. 131, No. 20 (2018)
  • TKI resistance in Ph-like ALL
    • Authors: Roberts K. G.
      Pages: 2181 - 2182
      Keywords: Free Research Articles
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2018-03-833665
      Issue No: Vol. 131, No. 20 (2018)
  • Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate
           Kinase Deficiency Natural History Study
    • Authors: Grace, R. F; Bianchi, P, van Beers, E. J, Eber, S. W, Glader, B, Yaish, H. M, Despotovic, J. M, Rothman, J. A, Sharma, M, McNaull, M. M, Fermo, E, Lezon-Geyda, K, Morton, D. H, Neufeld, E. J, Chonat, S, Kollmar, N, Knoll, C. M, Kuo, K, Kwiatkowski, J. L, Pospisilova, D, Pastore, Y. D, Thompson, A. A, Newburger, P. E, Ravindranath, Y, Wang, W. C, Wlodarski, M. W, Wang, H, Holzhauer, S, Breakey, V. R, Kunz, J, Sheth, S, Rose, M. J, Bradeen, H. A, Neu, N, Guo, D, Al-Sayegh, H, London, W. B, Gallagher, P. G, Zanella, A, Barcellini, W.
      Pages: 2183 - 2192
      Abstract: An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at as #NCT02053480.
      Keywords: Plenary Papers, Red Cells, Iron, and Erythropoiesis, Clinical Trials and Observations
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2017-10-810796
      Issue No: Vol. 131, No. 20 (2018)
  • Biomarkers for posttransplantation outcomes
    • Authors: Paczesny S.
      Pages: 2193 - 2204
      Abstract: During the last decade, the development of biomarkers for the complications seen after allogeneic hematopoietic stem cell transplantation has expanded tremendously, with the most progress having been made for acute graft-versus-host disease (aGVHD), a common and often fatal complication. Although many factors are known to determine transplant outcome (including the age of the recipient, comorbidity, conditioning intensity, donor source, donor-recipient HLA compatibility, conditioning regimen, posttransplant GVHD prophylaxis), they are incomplete guides for predicting outcomes. Thanks to the advances in genomics, transcriptomics, proteomics, and cytomics technologies, blood biomarkers have been identified and validated for us in promising diagnostic tests, prognostic tests stratifying for future occurrence of aGVHD, and predictive tests for responsiveness to GVHD therapy and nonrelapse mortality. These biomarkers may facilitate timely and selective therapeutic intervention. However, such blood tests are not yet available for routine clinical care. This article provides an overview of the candidate biomarkers for clinical evaluation and outlines a path from biomarker discovery to first clinical correlation, to validation in independent cohorts, to a biomarker-based clinical trial, and finally to general clinical application. This article focuses on biomarkers discovered with a large-scale proteomics platform and validated with the same reproducible assay in at least 2 independent cohorts with sufficient sample size according to the 2014 National Institutes of Health consensus on biomarker criteria, as well as on biomarkers as tests for risk stratification of outcomes, but not on their pathophysiologic contributions, which have been reviewed recently.
      Keywords: Perspectives, Immunobiology and Immunotherapy, Transplantation, Clinical Trials and Observations
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2018-02-791509
      Issue No: Vol. 131, No. 20 (2018)
  • Tolerogenic properties of the Fc portion of IgG and its relevance to the
           treatment and management of hemophilia
    • Authors: Blumberg, R. S; Lillicrap, D, the IgG Fc Immune Tolerance Group
      Pages: 2205 - 2214
      Abstract: Hemophilia, or inherited genetic deficiencies in coagulation factors, results in uncontrolled bleeding requiring replacement therapy with recombinant proteins given preventively or on demand. However, a major problem with these approaches is the potential for development of immune responses to the administered proteins due to the underlying genetic deficiency of the factor(s) throughout life. As such, there is great interest in developing strategies that avoid immunogenicity and induce immune tolerance. Recently, recombinant factor VIII (rFVIII) and rFIX fused to the crystallizable fragment (Fc) domain of immunoglobulin G (IgG) have been developed as therapeutic agents for hemophilia A and B, respectively. Although it is well known that the possession of an Fc domain confers IgG’s longer-lasting circulating half-life, it is not generally appreciated that the Fc domain also confers immunoregulatory properties that are associated with the induction of tolerance. Here, we review some of the latest advances in our understanding of the tolerogenic abilities of IgG Fc and the impact of Fc-fusion proteins of rFVIII on the treatment of hemophilia.
      Keywords: Immunobiology and Immunotherapy, Thrombosis and Hemostasis, Review Articles
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2017-12-822908
      Issue No: Vol. 131, No. 20 (2018)
  • How I treat the postthrombotic syndrome
    • Authors: Rabinovich, A; Kahn, S. R.
      Pages: 2215 - 2222
      Abstract: The postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT) that imposes significant morbidity, reduces quality of life, and is costly. After DVT, 20% to 50% of patients will develop PTS, and up to 5% will develop severe PTS. The principal risk factors for PTS are anatomically extensive DVT, recurrent ipsilateral DVT, obesity, and older age. By preventing the initial DVT and DVT recurrence, primary and secondary prophylaxis of DVT will reduce occurrence of PTS. The effectiveness of elastic compression stockings (ECSs) for PTS prevention is controversial. Catheter-directed thrombolysis is not effective to prevent PTS overall but may prevent more severe forms of PTS and should be reserved for select patients with extensive thrombosis, recent symptoms onset, and low bleeding risk. For patients with established PTS, the cornerstone of management is ECS, exercise, and lifestyle modifications. Surgical or endovascular interventions may be considered in refractory cases. Because of a lack of effective therapies, new approaches to preventing and treating PTS are needed. This article uses a case-based approach to discuss risk factors for PTS after DVT, how to diagnose PTS, and available means to prevent and treat PTS, with a focus on new information in the field.
      Keywords: How I Treat, Free Research Articles, Thrombosis and Hemostasis
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2018-01-785956
      Issue No: Vol. 131, No. 20 (2018)
  • Cell-extrinsic hematopoietic impact of Ezh2 inactivation in fetal liver
           endothelial cells
    • Authors: Neo, W. H; Booth, C. A. G, Azzoni, E, Chi, L, Delgado-Olguin, P, de Bruijn, M. F. T. R, Jacobsen, S. E. W, Mead, A. J.
      Pages: 2223 - 2234
      Abstract: Despite the well-established cell-intrinsic role of epigenetic factors in normal and malignant hematopoiesis, their cell-extrinsic role remains largely unexplored. Herein we investigated the hematopoietic impact of inactivating Ezh2, a key component of polycomb repressive complex 2 (PRC2), in the fetal liver (FL) vascular niche. Hematopoietic specific (Vav-iCre) Ezh2 inactivation enhanced FL hematopoietic stem cell (HSC) expansion with normal FL erythropoiesis. In contrast, endothelium (Tie2-Cre) targeted Ezh2 inactivation resulted in embryonic lethality with severe anemia at embryonic day 13.5 despite normal emergence of functional HSCs. Ezh2-deficient FL endothelium overexpressed Mmp9, which cell-extrinsically depleted the membrane-bound form of Kit ligand (mKitL), an essential hematopoietic cytokine, in FL. Furthermore, Mmp9 inhibition in vitro restored mKitL expression along with the erythropoiesis supporting capacity of FL endothelial cells. These data establish that Ezh2 is intrinsically dispensable for FL HSCs and provides proof of principle that modulation of epigenetic regulators in niche components can exert a marked cell-extrinsic impact.
      Keywords: Hematopoiesis and Stem Cells, Red Cells, Iron, and Erythropoiesis
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2017-10-811455
      Issue No: Vol. 131, No. 20 (2018)
  • The tumor suppressive TGF-{beta}/SMAD1/S1PR2 signaling axis is recurrently
           inactivated in diffuse large B-cell lymphoma
    • Authors: Stelling, A; Hashwah, H, Bertram, K, Manz, M. G, Tzankov, A, Müller, A.
      Pages: 2235 - 2246
      Abstract: The sphingosine-1-phosphate receptor S1PR2 and its downstream signaling pathway are commonly silenced in diffuse large B-cell lymphoma (DLBCL), either by mutational inactivation or through negative regulation by the oncogenic transcription factor FOXP1. In this study, we examined the upstream regulators of S1PR2 expression and have newly identified the transforming growth factor-β (TGF-β)/TGF-βR2/SMAD1 axis as critically involved in S1PR2 transcriptional activation. Phosphorylated SMAD1 directly binds to regulatory elements in the S1PR2 locus as assessed by chromatin immunoprecipitation, and the CRISPR-mediated genomic editing of S1PR2, SMAD1, or TGFBR2 in DLBCL cell lines renders cells unresponsive to TGF-β–induced apoptosis. DLBCL clones lacking any 1 of the 3 factors have a clear growth advantage in vitro, as well as in subcutaneous xenotransplantation models, and in a novel model of orthotopic growth of DLBCL cells in the spleens and bone marrow of MISTRG mice expressing various human cytokines. The loss of S1pr2 induces hyperproliferation of the germinal center (GC) B-cell compartment of immunized mice and accelerates MYC-driven lymphomagenesis in spontaneous and serial transplantation models. The specific loss of Tgfbr2 in murine GC B-cell phenocopies the effects of S1pr2 loss on GC B-cell hyperproliferation. Finally, we show that SMAD1 expression is aberrantly downregulated in >85% of analyzed DLBCL patients. The combined results uncover an important novel tumor suppressive function of the TGF-β/TGF-βR2/SMAD1/S1PR2 axis in DLBCL, and show that DLBCL cells have evolved to inactivate the pathway at the level of SMAD1 expression.
      Keywords: Immunobiology and Immunotherapy, Lymphoid Neoplasia
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2017-10-810630
      Issue No: Vol. 131, No. 20 (2018)
  • SOX11 augments BCR signaling to drive MCL-like tumor development
    • Authors: Kuo, P.-Y; Jatiani, S. S, Rahman, A. H, Edwards, D, Jiang, Z, Ahr, K, Perumal, D, Leshchenko, V. V, Brody, J, Shaknovich, R, Ye, B. H, Parekh, S.
      Pages: 2247 - 2255
      Abstract: Mantle cell lymphoma (MCL) is characterized by increased B-cell receptor (BCR) signaling, and BTK inhibition is an effective therapeutic intervention in MCL patients. The mechanisms leading to increased BCR signaling in MCL are poorly understood, as mutations in upstream regulators of BCR signaling such as CD79A, commonly observed in other lymphomas, are rare in MCL. The transcription factor SOX11 is overexpressed in the majority (78% to 93%) of MCL patients and is considered an MCL-specific oncogene. So far, attempts to understand SOX11 function in vivo have been hampered by the lack of appropriate animal models, because germline deletion of SOX11 is embryonically lethal. We have developed a transgenic mouse model (Eμ-SOX11-EGFP) in the C57BL/6 background expressing murine SOX11 and EGFP under the control of a B-cell–specific IgH-Eμ enhancer. The overexpression of SOX11 exclusively in B cells exhibits oligoclonal B-cell hyperplasia in the spleen, bone marrow, and peripheral blood, with an immunophenotype (CD5+CD19+CD23–) identical to human MCL. Furthermore, phosphocytometric time-of-flight analysis of the splenocytes from these mice shows hyperactivation of pBTK and other molecules in the BCR signaling pathway, and serial bone marrow transplant from transgenic donors produces lethality with decreasing latency. We report here that overexpression of SOX11 in B cells promotes BCR signaling and a disease phenotype that mimics human MCL.
      Keywords: Lymphoid Neoplasia
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2018-02-832535
      Issue No: Vol. 131, No. 20 (2018)
  • PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute
           lymphoblastic leukemia
    • Authors: Zhang, Y; Gao, Y, Zhang, H, Zhang, J, He, F, Hnizda, A, Qian, M, Liu, X, Gocho, Y, Pui, C.-H, Cheng, T, Wang, Q, Yang, J. J, Zhu, X, Liu, X.
      Pages: 2256 - 2261
      Abstract: Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ~10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, PDGFRBC843G, which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB-mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment.
      Keywords: Free Research Articles, Lymphoid Neoplasia, CME article, Brief Reports
      PubDate: 2018-05-17T09:05:03-07:00
      DOI: 10.1182/blood-2017-11-817510
      Issue No: Vol. 131, No. 20 (2018)
  • Recurrent STAT3-JAK2 fusions in indolent T-cell lymphoproliferative
           disorder of the gastrointestinal tract
    • Authors: Sharma, A; Oishi, N, Boddicker, R. L, Hu, G, Benson, H. K, Ketterling, R. P, Greipp, P. T, Knutson, D. L, Kloft-Nelson, S. M, He, R, Eckloff, B. W, Jen, J, Nair, A. A, Davila, J. I, Dasari, S, Lazaridis, K. N, Bennani, N. N, Wu, T.-T, Nowakowski, G. S, Murray, J. A, Feldman, A. L.
      Pages: 2262 - 2266
      Keywords: Lymphoid Neoplasia
      PubDate: 2018-05-17T09:05:04-07:00
      DOI: 10.1182/blood-2018-01-830968
      Issue No: Vol. 131, No. 20 (2018)
  • RUNX1 mutations in pediatric acute myeloid leukemia are associated with
           distinct genetic features and an inferior prognosis
    • Authors: Yamato, G; Shiba, N, Yoshida, K, Hara, Y, Shiraishi, Y, Ohki, K, Okubo, J, Park, M.-j, Sotomatsu, M, Arakawa, H, Kiyokawa, N, Tomizawa, D, Adachi, S, Taga, T, Horibe, K, Miyano, S, Ogawa, S, Hayashi, Y.
      Pages: 2266 - 2270
      Keywords: Pediatric Hematology, Myeloid Neoplasia
      PubDate: 2018-05-17T09:05:04-07:00
      DOI: 10.1182/blood-2017-11-814442
      Issue No: Vol. 131, No. 20 (2018)
  • 25-Hydroxyvitamin D3-1{alpha}-hydroxylase- and multiple cytokine-producing
           diffuse large B-cell lymphoma
    • Authors: Nakayama, S; Matsuda, M.
      Pages: 2271 - 2271
      Keywords: Free Research Articles, BloodWork, Myeloid Neoplasia, Lymphoid Neoplasia
      PubDate: 2018-05-17T09:05:04-07:00
      DOI: 10.1182/blood-2018-02-832568
      Issue No: Vol. 131, No. 20 (2018)
  • Pallasch CP, Schulz A, Kutsch N, et al. Overexpression of TOSO in CLL is
           triggered by B-cell receptor signaling and associated with progressive
           disease. Blood. 2008;112(10):4213-4219.
    • Pages: 2272 - 2272
      Keywords: Free Research Articles
      PubDate: 2018-05-17T09:05:04-07:00
      DOI: 10.1182/blood-2018-04-843490
      Issue No: Vol. 131, No. 20 (2018)
  • Kruse-Jarres R, Johnsen JM. How I treat type 2B von Willebrand disease.
           Blood. 2018;131(12):1292-1300.
    • Pages: 2272 - 2272
      Keywords: Free Research Articles
      PubDate: 2018-05-17T09:05:04-07:00
      DOI: 10.1182/blood-2018-04-844357
      Issue No: Vol. 131, No. 20 (2018)
  • A novel PDGFRB mutation in TKI-resistant Ph-like ALL
    • Pages: 2273 - 2273
      Keywords: Free Research Articles, CME article
      PubDate: 2018-05-17T09:05:04-07:00
      DOI: 10.1182/blood-2018-04-843516
      Issue No: Vol. 131, No. 20 (2018)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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Fax: +00 44 (0)131 4513327
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