Journal Cover
Blood
Journal Prestige (SJR): 6.434
Citation Impact (citeScore): 7
Number of Followers: 264  
 
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ISSN (Print) 0006-4971 - ISSN (Online) 1528-0020
Published by American Society of Hematology Homepage  [2 journals]
  • CASIN the joint: immune aging at the stem cell level
    • Authors: Pawelec; G. P.
      Pages: 553 - 554
      Keywords: Free Research Articles
      PubDate: 2018-08-09T09:00:28-07:00
      DOI: 10.1182/blood-2018-06-858696
      Issue No: Vol. 132, No. 6 (2018)
       
  • Detailing the genomic landscape of myeloma
    • Authors: Bergsagel, P. L; Kuehl, W. M.
      Pages: 554 - 555
      Keywords: Free Research Articles
      PubDate: 2018-08-09T09:00:28-07:00
      DOI: 10.1182/blood-2018-06-857508
      Issue No: Vol. 132, No. 6 (2018)
       
  • TPO-logy accepted
    • Authors: Hoffmeister; K. M.
      Pages: 555 - 557
      Keywords: Free Research Articles
      PubDate: 2018-08-09T09:00:28-07:00
      DOI: 10.1182/blood-2018-06-854935
      Issue No: Vol. 132, No. 6 (2018)
       
  • Endosome trafficking: blood and more
    • Authors: Kupfer; G. M.
      Pages: 557 - 558
      Keywords: Free Research Articles
      PubDate: 2018-08-09T09:00:28-07:00
      DOI: 10.1182/blood-2018-06-854968
      Issue No: Vol. 132, No. 6 (2018)
       
  • Hematopoiesis and the bacterial microbiome
    • Authors: Yan, H; Baldridge, M. T, King, K. Y.
      Pages: 559 - 564
      Abstract: Recent studies have revealed that the intestinal bacterial microbiome plays an important role in the regulation of hematopoiesis. A correlation between adverse hematologic effects and imbalance of the intestinal microbiome, or dysbiosis, is evident in several human conditions, such as inflammatory bowel disease, obesity, and, critically, in the setting of antibiotic exposure. Here we review the effects of gut dysbiosis on the hematological compartment and our current understanding of the mechanisms through which changes in the bacterial microbiome affect hematopoiesis.
      Keywords: Hematopoiesis and Stem Cells, Blood Spotlight
      PubDate: 2018-08-09T09:00:28-07:00
      DOI: 10.1182/blood-2018-02-832519
      Issue No: Vol. 132, No. 6 (2018)
       
  • Aged murine hematopoietic stem cells drive aging-associated immune
           remodeling
    • Authors: Leins, H; Mulaw, M, Eiwen, K, Sakk, V, Liang, Y, Denkinger, M, Geiger, H, Schirmbeck, R.
      Pages: 565 - 576
      Abstract: Aging-associated remodeling of the immune system impairs its functional integrity and contributes to increased morbidity and mortality in the elderly. Aging of hematopoietic stem cells (HSCs), from which all cells of the adaptive immune system ultimately originate, might play a crucial role in the remodeling of the aged immune system. We recently reported that aging of HSCs is, in part, driven by elevated activity of the small RhoGTPase Cdc42 and that aged HSCs can be rejuvenated in vitro by inhibition of the elevated Cdc42 activity in aged HSCs with the pharmacological compound CASIN. To study the quality of immune systems stemming selectively from young or aged HSCs, we established a HSC transplantation model in T- and B-cell-deficient young RAG1–/– hosts. We report that both phenotypic and functional changes in the immune system on aging are primarily a consequence of changes in the function of HSCs on aging and, to a large extent, independent of the thymus, as young and aged HSCs reconstituted distinct T- and B-cell subsets in RAG1–/– hosts that mirrored young and aged immune systems. Importantly, aged HSCs treated with CASIN reestablished an immune system similar to that of young animals, and thus capable of mounting a strong immune response to vaccination. Our studies further imply that epigenetic signatures already imprinted in aged HSCs determine the transcriptional profile and function of HSC-derived T and B cells.
      Keywords: Hematopoiesis and Stem Cells, Immunobiology and Immunotherapy
      PubDate: 2018-08-09T09:00:28-07:00
      DOI: 10.1182/blood-2018-02-831065
      Issue No: Vol. 132, No. 6 (2018)
       
  • CK1{alpha} and IRF4 are essential and independent effectors of
           immunomodulatory drugs in primary effusion lymphoma
    • Authors: Patil, A; Manzano, M, Gottwein, E.
      Pages: 577 - 586
      Abstract: Primary effusion lymphoma (PEL) is an aggressive cancer with few treatment options. The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide have recently been shown to kill PEL cell lines, and lenalidomide is in clinical trials against PEL. IMiDs bind to the CRL4CRBN E3 ubiquitin ligase complex, leading to the acquisition of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), casein kinase 1 α (CK1α), and zinc finger protein 91 (ZFP91) as neosubstrates. IMiDs are effective against multiple myeloma because of degradation of IKZF1 and IKZF3 and the consequent loss of interferon regulatory factor 4 (IRF4) and MYC expression. Lenalidomide is also effective in chromosome 5q deletion–associated myelodysplastic syndrome as a result of degradation of CK1α. An essential IKZF1-IRF4-MYC axis has recently been proposed to underlie the toxicity of IMiDs in PEL. Here, we further investigate IMiD effectors in PEL cell lines, based on genome-wide CRISPR/Cas9 screens for essential human genes. These screens and extensive validation experiments show that, of the 4 neosubstrates, only CK1α is essential for the survival of PEL cell lines. In contrast, IKZF1 and IKZF3 are dispensable, individually or in combination. IRF4 was critical in all 8 PEL cell lines tested, and surprisingly, IMiDs triggered downregulation of IRF4 expression independently of both IKZF1 and IKZF3. Reexpression of CK1α and/or IRF4 partially rescued PEL cell lines from IMiD-mediated toxicity. In conclusion, IMiD toxicity in PEL cell lines is independent of IKZF1 and IKZF3 but proceeds through degradation of the neosubstrate CK1α and downregulation of IRF4.
      Keywords: Immunobiology and Immunotherapy, Lymphoid Neoplasia
      PubDate: 2018-08-09T09:00:28-07:00
      DOI: 10.1182/blood-2018-01-828418
      Issue No: Vol. 132, No. 6 (2018)
       
  • Identification of novel mutational drivers reveals oncogene dependencies
           in multiple myeloma
    • Authors: Walker, B. A; Mavrommatis, K, Wardell, C. P, Ashby, T. C, Bauer, M, Davies, F. E, Rosenthal, A, Wang, H, Qu, P, Hoering, A, Samur, M, Towfic, F, Ortiz, M, Flynt, E, Yu, Z, Yang, Z, Rozelle, D, Obenauer, J, Trotter, M, Auclair, D, Keats, J, Bolli, N, Fulciniti, M, Szalat, R, Moreau, P, Durie, B, Stewart, A. K, Goldschmidt, H, Raab, M. S, Einsele, H, Sonneveld, P, San Miguel, J, Lonial, S, Jackson, G. H, Anderson, K. C, Avet-Loiseau, H, Munshi, N, Thakurta, A, Morgan, G. J.
      Pages: 587 - 597
      Abstract: Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including IDH1, IDH2, HUWE1, KLHL6, and PTPN11. Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more driver gene abnormalities are associated with worse outcomes, as are identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in FGFR3, DIS3, and PRKD2; t(11;14) with mutations in CCND1 and IRF4; t(14;16) with mutations in MAF, BRAF, DIS3, and ATM; and hyperdiploidy with gain 11q, mutations in FAM46C, and MYC rearrangements. These associations indicate that the genomic landscape of myeloma is predetermined by the primary events upon which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens.
      Keywords: Lymphoid Neoplasia
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2018-03-840132
      Issue No: Vol. 132, No. 6 (2018)
       
  • Phase 2b study of 2 dosing regimens of quizartinib monotherapy in
           FLT3-ITD-mutated, relapsed or refractory AML
    • Authors: Cortes, J. E; Tallman, M. S, Schiller, G. J, Trone, D, Gammon, G, Goldberg, S. L, Perl, A. E, Marie, J.-P, Martinelli, G, Kantarjian, H. M, Levis, M. J.
      Pages: 598 - 607
      Abstract: This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal tandem duplication (ITD)–mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD–mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia’s formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.
      Keywords: Myeloid Neoplasia, Clinical Trials and Observations
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2018-01-821629
      Issue No: Vol. 132, No. 6 (2018)
       
  • Srsf2P95H initiates myeloid bias and myelodysplastic/myeloproliferative
           syndrome from hemopoietic stem cells
    • Authors: Smeets, M. F; Tan, S. Y, Xu, J. J, Anande, G, Unnikrishnan, A, Chalk, A. M, Taylor, S. R, Pimanda, J. E, Wall, M, Purton, L. E, Walkley, C. R.
      Pages: 608 - 621
      Abstract: Mutations in SRSF2 occur in myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPN). SRSF2 mutations cluster at proline 95, with the most frequent mutation being a histidine (P95H) substitution. They undergo positive selection, arise early in the course of disease, and have been identified in age-related clonal hemopoiesis. It is not clear how mutation of SRSF2 modifies hemopoiesis or contributes to the development of myeloid bias or MDS/MPN. Two prior mouse models of Srsf2P95H mutation have been reported; however, these models do not recapitulate many of the clinical features of SRSF2-mutant disease and relied on bone marrow (BM) transplantation stress to elicit the reported phenotypes. We describe a new conditional murine Srsf2P95H mutation model, where the P95H mutation is expressed physiologically and heterozygously from its endogenous locus after Cre activation. Using multiple Cre lines, we demonstrate that during native hemopoiesis (ie, no BM transplantation), the Srsf2P95H mutation needs to occur within the hemopoietic stem-cell–containing populations to promote myelomonocytic bias and expansion with corresponding transcriptional and RNA splicing changes. With age, nontransplanted Srsf2P95H animals developed a progressive, transplantable disease characterized by myeloid bias, morphological dysplasia, and monocytosis, hallmarks of MDS/MPN in humans. Analysis of cooccurring mutations within the BM demonstrated the acquisition of additional mutations that are recurrent in humans with SRSF2 mutations. The tractable Srsf2P95H/+ knock-in model we have generated is highly relevant to human disease and will serve to elucidate the effect of SRSF2 mutations on initiation and maintenance of MDS/MPN.
      Keywords: Hematopoiesis and Stem Cells, Myeloid Neoplasia
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2018-04-845602
      Issue No: Vol. 132, No. 6 (2018)
       
  • GPIb{alpha} is required for platelet-mediated hepatic thrombopoietin
           generation
    • Authors: Xu, M; Li, J, Neves, M. A. D, Zhu, G, Carrim, N, Yu, R, Gupta, S, Marshall, J, Rotstein, O, Peng, J, Hou, M, Kunishima, S, Ware, J, Branch, D. R, Lazarus, A. H, Ruggeri, Z. M, Freedman, J, Ni, H.
      Pages: 622 - 634
      Abstract: Thrombopoietin (TPO), a hematopoietic growth factor produced predominantly by the liver, is essential for thrombopoiesis. Prevailing theory posits that circulating TPO levels are maintained through its clearance by platelets and megakaryocytes via surface c-Mpl receptor internalization. Interestingly, we found a two- to threefold decrease in circulating TPO in GPIbα–/– mice compared with wild-type (WT) controls, which was consistent in GPIbα-deficient human Bernard-Soulier syndrome (BSS) patients. We showed that lower TPO levels in GPIbα-deficient conditions were not due to increased TPO clearance by GPIbα–/– platelets but rather to decreased hepatic TPO mRNA transcription and production. We found that WT, but not GPIbα–/–, platelet transfusions rescued hepatic TPO mRNA and circulating TPO levels in GPIbα–/– mice. In vitro hepatocyte cocultures with platelets or GPIbα-coupled beads further confirm the disruption of platelet-mediated hepatic TPO generation in the absence of GPIbα. Treatment of GPIbα–/– platelets with neuraminidase caused significant desialylation; however, strikingly, desialylated GPIbα–/– platelets could not rescue impaired hepatic TPO production in vivo or in vitro, suggesting that GPIbα, independent of platelet desialylation, is a prerequisite for hepatic TPO generation. Additionally, impaired hepatic TPO production was recapitulated in interleukin-4/GPIbα–transgenic mice, as well as with antibodies targeting the extracellular portion of GPIbα, demonstrating that the N terminus of GPIbα is required for platelet-mediated hepatic TPO generation. These findings reveal a novel nonredundant regulatory role for platelets in hepatic TPO homeostasis, which improves our understanding of constitutive TPO regulation and has important implications in diseases related to GPIbα, such as BSS and auto- and alloimmune-mediated thrombocytopenias.
      Keywords: Platelets and Thrombopoiesis, Thrombosis and Hemostasis
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2017-12-820779
      Issue No: Vol. 132, No. 6 (2018)
       
  • ADAP deficiency impairs megakaryocyte polarization with ectopic
           proplatelet release and causes microthrombocytopenia
    • Authors: Spindler, M; van Eeuwijk, J. M. M, Schurr, Y, Nurden, P, Nieswandt, B, Stegner, D, Reinhold, A, Bender, M.
      Pages: 635 - 646
      Abstract: Bone marrow (BM) megakaryocytes (MKs) produce platelets by extending proplatelets into sinusoidal blood vessels. Defects in thrombopoiesis can lead to thrombocytopenia associated with increased bleeding tendency. Recently, the platelet disorder congenital autosomal-recessive small-platelet thrombocytopenia (CARST) was described; it is caused by mutations in the adhesion and degranulation-promoting adaptor protein (ADAP; synonym: FYB, SLAP130/120) gene, and characterized by microthrombocytopenia and bleeding symptoms. In this study, we used constitutive ADAP-deficient mice (Adap–/–) as a model to investigate mechanisms underlying the microthrombocytopenia in CARST. We show that Adap–/– mice display several characteristics of human CARST, with moderate thrombocytopenia and smaller-sized platelets. Adap–/– platelets had a shorter life span than control platelets, and macrophage depletion, but not splenectomy, increased platelet counts in mutant mice to control levels. Whole-sternum 3-dimensional confocal imaging and intravital 2-photon microscopy revealed altered morphology of ADAP-deficient MKs with signs of fragmentation and ectopic release of (pro)platelet-like particles into the BM compartment. In addition, cultured BM-derived MKs lacking ADAP showed reduced spreading on extracellular matrix proteins as well as activation of β1 integrins, impaired podosome formation, and displayed defective polarization of the demarcation membrane system in vitro. MK-/platelet-specific ADAP-deficient mice (PF4-cre) also produced fewer and smaller-sized platelets and released platelets ectopically. These data demonstrate that the abnormal platelet production in the mutant mice is an MK-intrinsic defect. Taken together, these results point to an as-yet-unidentified role of ADAP in the process of MK polarization and platelet biogenesis.
      Keywords: Thrombocytopenia, Platelets and Thrombopoiesis
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2018-01-829259
      Issue No: Vol. 132, No. 6 (2018)
       
  • Warfarin and vitamin K epoxide reductase: a molecular accounting for
           observed inhibition
    • Authors: Wu, S; Chen, X, Jin, D.-Y, Stafford, D. W, Pedersen, L. G, Tie, J.-K.
      Pages: 647 - 657
      Abstract: Vitamin K epoxide reductase (VKOR), an endoplasmic reticulum membrane protein, is the key enzyme for vitamin K–dependent carboxylation, a posttranslational modification that is essential for the biological functions of coagulation factors. VKOR is the target of the most widely prescribed oral anticoagulant, warfarin. However, the topological structure of VKOR and the mechanism of warfarin’s inhibition of VKOR remain elusive. Additionally, it is not clear why warfarin-resistant VKOR mutations identified in patients significantly decrease warfarin’s binding affinity, but have only a minor effect on vitamin K binding. Here, we used immunofluorescence confocal imaging of VKOR in live mammalian cells and PEGylation of VKOR’s endogenous cytoplasmic-accessible cysteines in intact microsomes to probe the membrane topology of human VKOR. Our results show that the disputed loop sequence between the first and second transmembrane (TM) domain of VKOR is located in the cytoplasm, supporting a 3-TM topological structure of human VKOR. Using molecular dynamics (MD) simulations, a T-shaped stacking interaction between warfarin and tyrosine residue 139, within the proposed TY139A warfarin-binding motif, was observed. Furthermore, a reversible dynamic warfarin-binding pocket opening and conformational changes were observed when warfarin binds to VKOR. Several residues (Y25, A26, and Y139) were found essential for warfarin binding to VKOR by MD simulations, and these were confirmed by the functional study of VKOR and its mutants in their native milieu using a cell-based assay. Our findings provide new insights into the dynamics of the binding of warfarin to VKOR, as well as into warfarin’s mechanism of anticoagulation.
      Keywords: Thrombosis and Hemostasis
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2018-01-830901
      Issue No: Vol. 132, No. 6 (2018)
       
  • Syndromic congenital myelofibrosis associated with a loss-of-function
           variant in RBSN
    • Authors: Magoulas, P. L; Shchelochkov, O. A, Bainbridge, M. N, Ben-Shachar, S, Yatsenko, S, Potocki, L, Lewis, R. A, Searby, C, Marcogliese, A. N, Elghetany, M. T, Zapata, G, Hernandez, P. P, Gadkari, M, Einhaus, D, Muzny, D. M, Gibbs, R. A, Bertuch, A. A, Scott, D. A, Corvera, S, Franco, L. M.
      Pages: 658 - 662
      Keywords: Hematopoiesis and Stem Cells, Phagocytes, Granulocytes, and Myelopoiesis, Clinical Trials and Observations
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2017-12-824433
      Issue No: Vol. 132, No. 6 (2018)
       
  • Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to
           intravenous administration in rhesus macaques
    • Authors: Nellan, A; McCully, C. M. L, Cruz Garcia, R, Jayaprakash, N, Widemann, B. C, Lee, D. W, Warren, K. E.
      Pages: 662 - 666
      Keywords: Immunobiology and Immunotherapy
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2018-05-846428
      Issue No: Vol. 132, No. 6 (2018)
       
  • Rituximab monotherapy in splenic marginal zone lymphoma: prolonged
           responses and potential benefit from maintenance
    • Authors: Kalpadakis, C; Pangalis, G. A, Sachanas, S, Tsirkinidis, P, Kontopidou, F. N, Moschogiannis, M, Yiakoumis, X, Koulieris, E, Dimopoulou, M. N, Kokkoris, S. I, Kyrtsonis, M.-C, Siakantaris, M. P, Tsourouflis, G, Korkolopoulou, P, Rontogianni, D, Tsaftaridis, P, Plata, E, Papadaki, H. A, Panagiotidis, P, Angelopoulou, M. K, Vassilakopoulos, T. P.
      Pages: 666 - 670
      Keywords: Lymphoid Neoplasia
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2018-02-833608
      Issue No: Vol. 132, No. 6 (2018)
       
  • A universal solution for eliminating false positives in myeloma due to
           therapeutic monoclonal antibody interference
    • Authors: Mills, J. R; Kohlhagen, M. C, Willrich, M. A. V, Kourelis, T, Dispenzieri, A, Murray, D. L.
      Pages: 670 - 672
      Keywords: Multiple Myeloma, Lymphoid Neoplasia
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2018-05-848986
      Issue No: Vol. 132, No. 6 (2018)
       
  • Rasburicase-induced hemolytic anemia in previously undiagnosed G6PD
           deficiency
    • Authors: Ferguson, D; Kovach, A. E.
      Pages: 673 - 673
      Keywords: Transfusion Medicine, Free Research Articles, BloodWork, Red Cells, Iron, and Erythropoiesis
      PubDate: 2018-08-09T09:00:29-07:00
      DOI: 10.1182/blood-2018-04-842724
      Issue No: Vol. 132, No. 6 (2018)
       
 
 
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