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  • SETD1A protects HSCs from activation-induced functional decline in vivo
    Blood (IF 13.164) Pub Date : 2018-01-01
    Kathrin Arndt; Andrea Kranz; Juliane Fohgrub; Adrien Jolly; Anita S. Bledau; Michela Di Virgilio; Mathias Lesche; Andreas Dahl; Thomas Höfer; A. Francis Stewart; Claudia Waskow

    The regenerative capacity of hematopoietic stem cells (HSCs) is limited by the accumulation of DNA damage. Conditional mutagenesis of the histone 3 lysine 4 (H3K4) methyltransferase, Setd1a, revealed that it is required for the expression of DNA damage recognition and repair pathways in HSCs. Specific deletion of Setd1a in adult long-term (LT)-HSCs is compatible with adult life and has little effect on the maintenance of phenotypic LT-HSCs in the bone marrow. However, SETD1A-deficient LT-HSCs lose their transcriptional cellular identity accompanied by loss of their proliferative capacity and stem cell function under replicative stress in situ and after transplantation. In response to inflammatory stimulation in vivo SETD1A protects HSCs and progenitors from activation-induced attrition. The comprehensive regulation of DNA damage responses by SETD1A in HSCs is clearly distinct from the key roles played by other epigenetic regulators including the major leukemogenic H3K4 methyltransferase, MLL1, or MLL5, indicating that HSC identity and function is supported by co-operative specificities within an epigenetic framework.

    更新日期:2018-01-19
  • Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation
    Blood (IF 13.164) Pub Date : 2018-01-01
    Heike Pfeifer; Katharina Raum; Sandra Markovic; Verena Nowak; Stephanie Fey; Julia Obländer; Jovita Pressler; Verena Böhm; Monika Brüggemann; Lydia Wunderle; Andreas Hüttmann; Ralph Wäsch; Joachim Beck; Matthias Stelljes; Andreas Viardot; Fabian Lang; Dieter Hoelzer; Wolf-Karsten Hofmann; Hubert Serve; Christel Weiss; Nicola Goekbuget; Oliver G. Ottmann; Daniel Nowak

    We investigated the role of copy number alterations to refine risk stratification in adult Philadelphia chromosome positive (Ph)+ ALL treated with tyrosine kinase inhibitors (TKI) and allogeneic stem cell transplantation (aSCT). 97 Ph+ ALL patients (median age 41 years, range 18-64 years) within the prospective multicenter GMALL studies 06/99 (n=8) and 07/2003 (n=89) were analysed. All patients received TKI and aSCT in first complete remission (CR1). Copy number analysis was performed with SNP arrays and validated by multiplex ligation-dependent probe amplification (MLPA). The frequencies of recurrently deleted genes were: IKZF1, 76%, CDKN2A/2B, 45%, PAX5, 43%, BTG1, 18%, EBF1, 13%, ETV6, 5%, RB, 14%. In univariate analyses, the presence of CDKN2A/2B deletions had a negative impact on all endpoints: overall survival (p=0.023), disease free survival (p=0.012) and remission duration (p=0.036). The negative predictive value of CDKN2A/2B deletions was retained in multivariable analysis along with other factors such as timing of TKI therapy, intensity of conditioning, achieving remission after induction phase I and BTG1 deletions. We therefore conclude that acquired genomic CDKN2A/2B deletions identify a subgroup of Ph+ ALL patients, who have an inferior prognosis despite aSCT in CR1. Their poor outcome was attributable primarily to a high relapse rate after aSCT.

    更新日期:2018-01-19
  • Pevonedistat, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, combined with azacitidine, in patients with AML
    Blood (IF 13.164) Pub Date : 2018-01-01
    Ronan T. Swords; Steven Coutre; Michael B. Maris; Joshua F. Zeidner; James M. Foran; Jose Cruz; Harry P. Erba; Jesus G. Berdeja; Wayne Tam; Saran Vardhanabhuti; Iwona Pawlikowska-Dobler; Hélène M. Faessel; Ajeeta B. Dash; Farhad Sedarati; Bruce J. Dezube; Douglas V. Faller; Michael R. Savona

    Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study (NCT01814826) of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naïve AML, unfit for standard induction therapy, received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5, combined with fixed-dose AZA (75 mg/m2 IV/SC) on days 1-5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in AST and ALT were dose limiting. The recommended phase 2 dose of PEV in this combination is 20 mg/m2. PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an ITT analysis was 50% (20 CR, 5 CRi, 7 PR), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR.

    更新日期:2018-01-19
  • Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients
    Blood (IF 13.164) Pub Date : 2018-01-01
    Jing Du; Ryan Flynn; Katelyn Paz; Hong-Gang Ren; Yuko Ogata; Qing Zhang; Philip R. Gafken; Barry E. Storer; Nathan H. Roy; Janis K. Burkhardt; Wendy Mathews; Jakub Tolar; Stephanie J. Lee; Bruce R. Blazar; Sophie Paczesny

    Improved diagnostic and treatment methods are needed for chronic graft-versus-host disease (cGVHD), the leading cause of late non-relapse mortality (NRM) in long-term survivors of allogenic hematopoietic cell transplantation (allo-HCT). Validated biomarkers that facilitate disease diagnosis, and classification generally are lacking in cGVHD. Here, we conducted whole serum proteomics analysis of a well-established murine multi-organ system cGVHD model. We discovered 4 up-regulated proteins during cGVHD that are targetable by genetic ablation or blocking antibodies, including the RAS and JUN kinase activator, CRKL, and CXCL7, CCL8 and CCL9 chemokines. Donor T cells lacking CRK/CRKL prevented the generation of cGVHD, germinal center reactions and macrophage infiltration seen with wild-type T cells. Whereas antibody blockade of CCL8 or CXCL7 was ineffective in treating cGVHD, CCL9 blockade reversed cGVHD clinical manifestations, histopathological changes and immunopathological hallmarks. Mechanistically, elevated CCL9 expression was present predominantly in vascular smooth muscle cells and uniquely seen in cGVHD mice. Plasma concentrations of CCL15, the human homologue of mouse CCL9, were elevated in a previously published cohort of 211 cGVHD patients compared to controls and associated with NRM. In a cohort of 792 patients, CCL15 measured at day +100 could not predict cGVHD occurring within the next 3 months with clinically relevant sensitivity/specificity. Our findings demonstrate for the first time the utility of preclinical proteomics screening to identify potential new targets for cGVHD and specifically CCL15 as a diagnosis marker for cGVHD. These data warrant prospective biomarker validation studies.

    更新日期:2018-01-19
  • Refining genetic stratification in T-ALL
    Blood (IF 13.164) Pub Date : 2018-01-18
    David O’Connor

    In this issue of Blood , [Petit et al][1] demonstrate the clinical utility of a genetic classifier combined with end of induction minimal residual disease (MRD) assessment and presenting white blood cell (WBC) count in the effective risk stratification of pediatric patients with T-cell acute

    更新日期:2018-01-19
  • Editing gene engineering to enhance function
    Blood (IF 13.164) Pub Date : 2018-01-18
    Emma C. Morris

    In this issue of Blood , [Legut et al][1] have tackled a major scientific challenge relating to T-cell engineering, with an unexpected outcome. They have demonstrated that CRISPR-mediated knockout of the native T-cell receptor (TCR) β chain dramatically improves the expression of inserted

    更新日期:2018-01-19
  • ASXL1 mutations gain a function
    Blood (IF 13.164) Pub Date : 2018-01-18
    Toshio Kitamura

    Whether additional Sex Combs-Like 1 ( ASXL1 ) mutations are loss-of-function, dominant-negative, or gain-of-function mutations remains a point of considerable controversy. In this issue of Blood , [Yang et al][1] present clear evidence of a new “gain-of-function” role for an ASXL1 mutation.[1][2

    更新日期:2018-01-19
  • Prochemerin processing by factor XIa
    Blood (IF 13.164) Pub Date : 2018-01-18
    Joost C. M. Meijers

    In this issue of Blood , [Ge et al][1] demonstrate a novel link between coagulation and inflammation by showing that factor XIa (FXIa) can generate the active chemoattractant and adipokine chemerin from its inactive precursor prochemerin.[1][2] ![Figure][3] Processing of prochemerin by FXIa

    更新日期:2018-01-19
  • Platelets and vascular integrity: how platelets prevent bleeding in inflammation
    Blood (IF 13.164) Pub Date : 2018-01-18
    Benoit Ho-Tin-Noé; Yacine Boulaftali; Eric Camerer

    Platelets play a central role in primary hemostasis by forming aggregates that plug holes in injured vessels. Half a century ago, detailed studies of the microvasculature by electron microscopy revealed that under inflammatory conditions that do not induce major disruption to vascular structure, individual platelets are mobilized to the vessel wall, where they interact with leukocytes and appear to seal gaps that arise between endothelial cells. Recent developments in genetic engineering and intravital microscopy have allowed further molecular and temporal characterization of these events. Surprisingly, it turns out that platelets support the recruitment of leukocytes to sites of inflammation. In parallel, however, they exercise their hemostatic function by securing the integrity of inflamed blood vessels to prevent bleeding from sites of leukocyte infiltration. It thus appears that platelets not only serve in concert as building blocks of the hemostatic plug but also act individually as gatekeepers of the vascular wall to help preserve vascular integrity while coordinating host defense. Variants of this recently appreciated hemostatic function of platelets that we refer to as “inflammation-associated hemostasis” are engaged in different contexts in which the endothelium is challenged or dysfunctional. Although the distinguishing characteristics of these variants and the underlying mechanisms of inflammation-associated hemostasis remain to be fully elucidated, they can differ notably from those supporting thrombosis, thus presenting therapeutic opportunities.

    更新日期:2018-01-19
  • Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia
    Blood (IF 13.164) Pub Date : 2018-01-18
    Arnaud Petit; Amélie Trinquand; Sylvie Chevret; Paola Ballerini; Jean-Michel Cayuela; Nathalie Grardel; Aurore Touzart; Benoit Brethon; Hélène Lapillonne; Claudine Schmitt; Sandrine Thouvenin; Gerard Michel; Claude Preudhomme; Jean Soulier; Judith Landman-Parker; Guy Leverger; Elizabeth Macintyre; André Baruchel; Vahid Asnafi

    Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 (N/F) mutations and RAS/PTEN (R/P) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10−4, 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 109/L, gHiR classifier, and MRD ≥10−4 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 109/L, gLoR classifier, and MRD <10−4 had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the N/F/R/P mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 109/L, it identifies a significant subgroup of patients with a low risk of relapse.

    更新日期:2018-01-19
  • Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma
    Blood (IF 13.164) Pub Date : 2018-01-18
    Thierry Facon; Meletios A. Dimopoulos; Angela Dispenzieri; John V. Catalano; Andrew Belch; Michele Cavo; Antonello Pinto; Katja Weisel; Heinz Ludwig; Nizar J. Bahlis; Anne Banos; Mourad Tiab; Michel Delforge; Jamie D. Cavenagh; Catarina Geraldes; Je-Jung Lee; Christine Chen; Albert Oriol; Javier De La Rubia; Darrell White; Daniel Binder; Jin Lu; Kenneth C. Anderson; Philippe Moreau; Michel Attal; Aurore Perrot; Bertrand Arnulf; Lugui Qiu; Murielle Roussel; Eileen Boyle; Salomon Manier; Mohamad Mohty; Herve Avet-Loiseau; Xavier Leleu; Annette Ervin-Haynes; Guang Chen; Vanessa Houck; Lotfi Benboubker; Cyrille Hulin

    This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ≥60 months’ follow-up). Patients were randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an ≈30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39.

    更新日期:2018-01-19
  • CRISPR-mediated TCR replacement generates superior anticancer transgenic T cells
    Blood (IF 13.164) Pub Date : 2018-01-18
    Mateusz Legut; Garry Dolton; Afsar Ali Mian; Oliver G. Ottmann; Andrew K. Sewell

    Adoptive transfer of T cells genetically modified to express a cancer-specific T-cell receptor (TCR) has shown significant therapeutic potential for both hematological and solid tumors. However, a major issue of transducing T cells with a transgenic TCR is the preexisting expression of TCRs in the recipient cells. These endogenous TCRs compete with the transgenic TCR for surface expression and allow mixed dimer formation. Mixed dimers, formed by mispairing between the endogenous and transgenic TCRs, may harbor autoreactive specificities. To circumvent these problems, we designed a system where the endogenous TCR-β is knocked out from the recipient cells using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) technology, simultaneously with transduction with a cancer-reactive receptor of choice. This TCR replacement strategy resulted in markedly increased surface expression of transgenic αβ and γδ TCRs, which in turn translated to a stronger, and more polyfunctional, response of engineered T cells to their target cancer cell lines. Additionally, the TCR-plus-CRISPR–modified T cells were up to a thousandfold more sensitive to antigen than standard TCR-transduced T cells or conventional model proxy systems used for studying TCR activity. Finally, transduction with a pan-cancer–reactive γδ TCR used in conjunction with CRISPR/Cas9 knockout of the endogenous αβ TCR resulted in more efficient redirection of CD4+ and CD8+ T cells against a panel of established blood cancers and primary, patient-derived B-cell acute lymphoblastic leukemia blasts compared with standard TCR transfer. Our results suggest that TCR transfer combined with genome editing could lead to new, improved generations of cancer immunotherapies.

    更新日期:2018-01-19
  • Smoothened signaling in the mouse osteoblastoid lineage is required for efficient B lymphopoiesis
    Blood (IF 13.164) Pub Date : 2018-01-18
    Wenyan Lu; Dominic Dordai; David Huso; Stephen Desiderio

    The stromal signals that promote B lymphopoiesis remain poorly understood. Hedgehog (Hh) signaling promotes B lymphopoiesis in a non–cell-autonomous fashion in vitro, and depletion of the Hh effector Smoothened (Smo) from stromal cells is associated with the loss of osteoblastoid markers. These observations suggested that Hh signaling in the osteoblastoid lineage promotes B lymphopoiesis in vivo. To test this, we employed a mouse model for conditional ablation of Smo in the osteoblastoid lineage. Depletion of Smo from osteoblastoid cells is associated with profound and selective reductions in the number and proportion of bone marrow B-lymphoid progenitors. Upon partial bone marrow ablation, mutant animals exhibit delayed repopulation of the B-lymphoid compartment after the early lymphoid progenitor stage. Primary osteoblasts from mutant mice are defective in supporting B lymphopoiesis in vitro, whereas hematopoietic progenitors from mutant mice exhibit normal differentiation. We conclude that efficient B lymphopoiesis in vivo is dependent on the maintenance of Hh signaling in the osteoblastoid lineage.

    更新日期:2018-01-19
  • Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies
    Blood (IF 13.164) Pub Date : 2018-01-18
    Hui Yang; Stefan Kurtenbach; Ying Guo; Ines Lohse; Michael A. Durante; Jianping Li; Zhaomin Li; Hassan Al-Ali; Lingxiao Li; Zizhen Chen; Matthew G. Field; Peng Zhang; Shi Chen; Shohei Yamamoto; Zhuo Li; Yuan Zhou; Stephen D. Nimer; J. William Harbour; Claes Wahlestedt; Mingjiang Xu; Feng-Chun Yang

    Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter-driven Flag-Asxl1Y588X transgenic mouse model, Asxl1Y588XTg, to express a truncated FLAG-ASXL1aa1-587 protein in the hematopoietic system. The Asxl1Y588XTg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations. ATAC- and RNA-sequencing analyses revealed that the ASXL1aa1-587 truncating protein expression results in more open chromatin in cKit+ cells compared with wild-type cells, accompanied by dysregulated expression of genes critical for HSC self-renewal and differentiation. Liquid chromatography–tandem mass spectrometry and coimmunoprecipitation experiments showed that ASXL1aa1-587 acquired an interaction with BRD4. An epigenetic drug screening demonstrated a hypersensitivity of Asxl1Y588XTg bone marrow cells to BET bromodomain inhibitors. This study demonstrates that ASXL1aa1-587 plays a gain-of-function role in promoting myeloid malignancies. Our model provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies.

    更新日期:2018-01-19
  • Ferritin is secreted via 2 distinct nonclassical vesicular pathways
    Blood (IF 13.164) Pub Date : 2018-01-18
    Marianna Truman-Rosentsvit; Dina Berenbaum; Lior Spektor; Lyora A. Cohen; Shirly Belizowsky-Moshe; Lena Lifshitz; Jing Ma; Wei Li; Ellina Kesselman; Inbal Abutbul-Ionita; Dganit Danino; Lucia Gutierrez; Huihui Li; Kuanyu Li; Huifang Lou; Maria Regoni; Maura Poli; Fabian Glaser; Tracey A. Rouault; Esther G. Meyron-Holtz

    Ferritin turnover plays a major role in tissue iron homeostasis, and ferritin malfunction is associated with impaired iron homeostasis and neurodegenerative diseases. In most eukaryotes, ferritin is considered an intracellular protein that stores iron in a nontoxic and bioavailable form. In insects, ferritin is a classically secreted protein and plays a major role in systemic iron distribution. Mammalian ferritin lacks the signal peptide for classical endoplasmic reticulum–Golgi secretion but is found in serum and is secreted via a nonclassical lysosomal secretion pathway. This study applied bioinformatics and biochemical tools, alongside a protein trafficking mouse models, to characterize the mechanisms of ferritin secretion. Ferritin trafficking via the classical secretion pathway was ruled out, and a 2:1 distribution of intracellular ferritin between membrane-bound compartments and the cytosol was observed, suggesting a role for ferritin in the vesicular compartments of the cell. Focusing on nonclassical secretion, we analyzed mouse models of impaired endolysosomal trafficking and found that ferritin secretion was decreased by a BLOC-1 mutation but increased by BLOC-2, BLOC-3, and Rab27A mutations of the cellular trafficking machinery, suggesting multiple export routes. A 13-amino-acid motif unique to ferritins that lack the secretion signal peptide was identified on the BC-loop of both subunits and plays a role in the regulation of ferritin secretion. Finally, we provide evidence that secretion of iron-rich ferritin was mediated via the multivesicular body–exosome pathway. These results enhance our understanding of the mechanism of ferritin secretion, which is an important piece in the puzzle of tissue iron homeostasis.

    更新日期:2018-01-19
  • Prochemerin cleavage by factor XIa links coagulation and inflammation
    Blood (IF 13.164) Pub Date : 2018-01-18
    Xiaomei Ge; Yasuto Yamaguchi; Lei Zhao; Loredana Bury; Paolo Gresele; Caroline Berube; Lawrence L. Leung; John Morser

    Chemerin is a chemoattractant and adipokine that circulates in blood as inactive prochemerin (chem163S). Chem163S is activated by a series of C-terminal proteolytic cleavages resulting in diverse chemerin forms with different levels of activity. We screened a panel of proteases in the coagulation, fibrinolytic, and inflammatory cascades to identify those that process prochemerin in plasma. Factor XIa (FXIa) cleaved chem163S, generating a novel chemerin form, chem162R, as an intermediate product, and chem158K, as the final product. Processing at Arg162 was not required for cleavage at Lys158 or regulation of chemerin bioactivity. Contact phase activation of human platelet-poor plasma by kaolin led to cleavage of chem163S, which was undetectable in FXI-depleted plasma and markedly enhanced in platelet-rich plasma (PRP). Contact phase activation by polyphosphate in PRP resulted in 75% cleavage of chem163S. This cleavage was partially inhibited by hirudin, which blocks thrombin activation of FXI. After activation of plasma, levels of the most potent form of chemerin, chem157S, as well as inactive chem155A, increased. Plasma levels of chem163S in FXI-deficient patients were significantly higher compared with a matched control group (91 ± 10 ng/mL vs 58 ± 3 ng/mL, n = 8; P < .01) and inversely correlated with the plasma FXI levels. Thus FXIa, generated on contact phase activation, cleaves chem163S to generate chem158K, which can be further processed to the most active chemerin form, providing a molecular link between coagulation and inflammation.

    更新日期:2018-01-19
  • Chronic lymphocytic leukemia international prognostic index: a systematic review and meta-analysis
    Blood (IF 13.164) Pub Date : 2018-01-18
    Stefano Molica; Diana Giannarelli; Rosanna Mirabelli; Luciano Levato; Neil E. Kay; Tait D. Shanafelt

    To the editor: The chronic lymphocytic leukemia international prognostic index (CLL-IPI), which combines 5 parameters (age, clinical stage, TP53 status [normal vs del(17p) and/or TP53 mutation], IGHV mutational status, and serum β2-microglobulin) to predict clinical outcome in chronic lymphocytic

    更新日期:2018-01-19
  • First report of ibrutinib in IgM-related amyloidosis: few responses, poor tolerability, and short survival
    Blood (IF 13.164) Pub Date : 2018-01-18
    Tomas Pika; Ute Hegenbart; Pavla Flodrova; Bettina Maier; Christoph Kimmich; Stefan O. Schönland

    TO THE EDITOR: Light-chain amyloidosis (AL) is a rare systemic protein deposition disorder that belongs to the group of plasma cell dyscrasias. Approximately 10% to 22% of cases are associated with symptomatic multiple myeloma or Waldenström macroglobulinemia (WM). The disease is characterized by

    更新日期:2018-01-19
  • Composite morphologically and immunohistochemically distinct classical and pleomorphic mantle cell lymphomas
    Blood (IF 13.164) Pub Date : 2018-01-18
    Huan-You Wang; Richard L. Wong

    ![Figure][1] The patient is a 76-year-old woman with right-axillary lymphadenopathy. Hematoxylin-and-eosin staining of core biopsies shows nodules composed of small- to medium-sized atypical lymphoid cells (panels A-C; original magnification: ×20 [A], ×40 [B], ×400 [C]). Interestingly, at

    更新日期:2018-01-19
  • Sood R, Kamikubo Y, Liu P. Role of RUNX1 in hematological malignancies. Blood. 2017;129(15):2070-2082.
    Blood (IF 13.164) Pub Date : 2018-01-18
    American Society of Hematology

    On pages 2070 and 2071 in the 13 April 2017 issue, there are errors in the text. In the third sentence under “Genomic organization and functional domains of RUNX1 ” on page 2070, “distal promoter P1” should read “proximal promoter P2.” In the next sentence, “proximal promoter P2”

    更新日期:2018-01-19
  • NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBPα and inflammatory signaling
    Blood (IF 13.164) Pub Date : 2018-01-01
    Pablo R. Freire; Orla M. Conneely

    Members of the NR4A subfamily of nuclear receptors have complex, overlapping roles during hematopoietic cell development and also function as tumor suppressors of hematological malignancies. We previously identified NR4A1 and NR4A3 as functionally redundant suppressors of AML development. However, their role in hematopoietic stem cell (HSC) homeostasis remains to be disclosed. Using a conditional Nr4a1/Nr4a3 knockout mouse (CDKO), we show that codepletion of NR4A1/3 promotes acute changes in HSC homeostasis including loss of HSC quiescence, accumulation of oxidative stress and DNA damage while maintaining stem cell regenerative and differentiation capacity. Molecular profiling of CDKO HSCs revealed widespread up-regulation of genetic programs governing cell cycle and inflammation and an aberrant activation of the interferon and NF-κB signaling pathways in the absence of stimuli. Mechanistically, we demonstrate that NR4A1/3 restrict HSC proliferation in part through activation of a C/EBPα-driven anti-proliferative network by directly binding to a hematopoietic-specific Cebpa enhancer and activating Cebpa transcription. Additionally, NR4A1/3 occupy the regulatory regions of NF-κB-regulated inflammatory cytokines, antagonizing the activation of NF-κB signaling. Taken together, our results reveal a novel coordinate control of HSC quiescence by NR4A1/3 through direct activation of C/EBPα and suppression of activation of NF-κB- driven proliferative inflammatory responses.

    更新日期:2018-01-18
  • PAR1 Biased Signaling is Required for Activated Protein C In Vivo Benefits in Sepsis and Stroke
    Blood (IF 13.164) Pub Date : 2018-01-01
    Ranjeet K. Sinha; Yaoming Wang; Zhen Zhao; Xiao Xu; Laurent Burnier; Naveen Gupta; José A. Fernandez; Greg Martin; Sergey Kupriyanov; Laurent O. Mosnier; Berislav V. Zlokovic; John H. Griffin

    Activated Protein C (APC) cleaves protease activated receptor (PAR)1 in vitro at R46 to initiate beneficial cell signaling; however, thrombin and APC can cleave at R41. To elucidate PAR1-dependent aspects of pharmacologic APC's in vivo mechanisms, we generated C57BL/6 mouse strains carrying QQ41 or QQ46 point mutations in PAR1 (F2r gene). Using these strains, we determined whether or not recombinant murine signaling-selective APC mutants would reduce septic death or provide neuroprotection against ischemic stroke when mice carried PAR1 homozygous mutations that prevent cleavage at either R41 or R46. Intercrossing PAR1+/R46Q mice generated expected numbers of PAR1+/+, PAR1+/R46Q and R46Q/R46Q offspring whereas intercrossing PAR1+/R41Q mice gave decreased R41Q/R41Q homozygotes (resembling intercrossing PAR1+/PAR1-knockout mice). QQ41-PAR1 and QQ46-PAR1 brain endothelial cells showed the predicted retention or loss of cellular responses to thrombin receptor activating peptide, thrombin or APC for each PAR1 mutation. In sepsis studies, exogenous APC reduced mortality from 50% to 10% in E. coli-induced pneumonia for wildtype-PAR1 and QQ41-PAR1 mice (p<0.01) but had no benefit for QQ46-PAR1 mice. In transient distal middle cerebral artery occlusion stroke studies, exogenous APC significantly reduced infarct size, edema and neuronal apoptosis for wildtype mice and QQ41-PAR1 mice but had no detectable benefits for mice carrying QQ46-PAR1. In functional studies of forelimb asymmetry and foot fault tests at 24 h after stroke induction, signaling-selective APC was beneficial for wildtype and QQ41-PAR1 mice but not QQ46-PAR1 mice. These results support the concept that APC-induced, PAR1-dependent biased signaling following R46 cleavage is central to APC's in vivo benefits.

    更新日期:2018-01-18
  • Hif-1α and Hif-2α regulate hemogenic endothelium and hematopoietic stem cell formation in zebrafish
    Blood (IF 13.164) Pub Date : 2018-01-01
    Claudia Gerri; Michele Marass; Andrea Rossi; Didier Y.R. Stainier

    During development, hematopoietic stem cells (HSCs) derive from specialized endothelial cells (ECs), called hemogenic endothelium (HE), via a process called endothelial-to-hematopoietic transition (EHT). While hypoxia inducible factor-1α (HIF-1α) has been reported to positively modulate EHT in vivo, current data indicate the existence of other regulators of this process. Here we show that in zebrafish Hif-2α also positively modulates HSC formation. Specifically, HSC marker gene expression is strongly decreased in hif-1aa;hif-1ab (hif-1α) and in hif-2aa;hif-2ab (hif-2α) zebrafish mutants and morphants. Moreover, live imaging studies reveal a positive role for hif-1α and hif-2α in regulating HE specification. Knockdown of hif-2α in hif-1α mutants leads to a greater decrease in HSC formation, indicating that hif-1α and hif-2α have partially overlapping roles in EHT. Furthermore, hypoxic conditions, which strongly stimulate HSC formation in wild-type animals, have little effect in the combined absence of Hif-1α and Hif-2α function. In addition, we present evidence for Hif and Notch working in the same pathway upstream of EHT. notch1a and notch1b mutants display impaired EHT, which can not be rescued by hypoxia. However, overexpression of the Notch intracellular domain in ECs is sufficient to rescue the hif-1α and hif-2α morphant EHT phenotype, suggesting that Notch signaling functions downstream of the Hif pathway during HSC formation. Altogether, our data provide genetic evidence that Hif-1α and Hif-2α both regulate EHT upstream of Notch signaling.

    更新日期:2018-01-17
  • A phase 1 study of azacitidine combined with chemotherapy in childhood leukemia: a report from TACL consortium
    Blood (IF 13.164) Pub Date : 2018-01-01
    Weili Sun; Timothy Triche; Jemily Malvar; Paul Gaynon; Richard Sposto; Xiaojing Yang; Henrique Bittencourt; Andrew E. Place; Yoav Messinger; Chris Fraser; Luciano Dalla-Pozza; Bodour Salhia; Peter Jones; Alan S. Wayne; Lia Gore; Todd M. Cooper; Gangning Liang

    Growing evidence indicates that aberrant DNA hypermethylation is associated with leukemogenesis, chemotherapy resistance, and relapse. DNA methyltransferase inhibitors such as azacitidine and decitabine have been shown to reverse drug resistance and prime leukemia cells to cytotoxic agents in vitro. Here we report the first pediatric phase 1 study using azacitidine in sequence with chemotherapy in patients with relapsed/refractory leukemia. Fourteen patients were enrolled, twelve with acute myeloid leukemia (AML) and two with acute lymphoblastic leukemia (ALL). All patients received azacitidine 75mg/m2/day subcutaneously for 5 days, followed by fludarabine 30mg/m2/day and cytarabine 2gm/m2/day intravenously for 5 days. The median number of prior regimens was 2 (range 1-5). Toxicities were typical of intensive chemotherapy. Febrile neutropenia and infection were the most common non-hematologic toxicities. No patients experienced dose-limiting toxicity. Seven of twelve AML patients achieved complete response after the first cycle. Illumina HumanMethylation450 BeadChip arrays identified a single region at gene body of farnesyldiphosphate farnesyl-transferase 1 gene (FDFT1) that showed methylome-wide significant differential methylation between patients who achieved response and those who did not (p = 0.002). The prognostic significance of this region was further analyzed in a separate data set from a phase II study of decitabine with combination chemotherapy in children with de novo AML. Our study indicates azacitidine plus fludarabine and cytarabine is well tolerated and active in children with relapsed leukemia and warrants further testing. The prognostic significance of the methylation biomarker merits further evaluation. This study was registered at http://www.clinicaltrials.gov (NCT01861002).

    更新日期:2018-01-17
  • Canonical Notch signaling is dispensible for adult steady-state and stress myelo-erythropoiesis
    Blood (IF 13.164) Pub Date : 2018-01-01
    Sara Duarte; Petter S. Woll; Natalija Buza-Vidas; Desmond Wai Loon Chin; Hanane Boukarabila; Tiago C. Luís; Laura Stenson; Tiphaine Bouriez-Jones; Helen Ferry; Adam J. Mead; Deborah Atkinson; Shaobo Jin; Sally-Ann Clark; Bishan Wu; Emmanouela Repapi; Nicki Gray; Stephen Taylor; Anders P. Mutvei; Yat Long Tsoi; Claus Nerlov; Urban Lendahl; Sten Eirik W. Jacobsen

    While an essential role for canonical Notch signaling in generation of hematopoietic stem cells in the embryo and in thymic T cell development is well established, its role in adult bone marrow (BM) myelopoiesis remains unclear. Some studies, analyzing myeloid progenitors in adult mice with inhibited Notch signaling, implicated distinct roles of canonical Notch signaling in regulation of progenitors for the megakaryocyte, erythroid and granulocyte-macrophage cell lineages. However, these studies might also have targeted other pathways. Therefore, we specifically deleted, in adult BM, the transcription factor recombination signal-binding protein J kappa (Rbpj), which canonical signaling through all Notch receptors converges. Notably, detailed progenitor staging established that canonical Notch signaling is fully dispensable for all investigated stages of megakaryocyte, erythroid and myeloid progenitors, in steady state unperturbed hematopoiesis, following competitive BM transplantation and in stress-induced erythropoiesis. Moreover, expression of key regulators of these hematopoietic lineages and Notch target genes were unaffected by Rbpj-deficiency in BM progenitor cells.

    更新日期:2018-01-17
  • Minimal/measurable residual disease in AML: consensus document from ELN MRD Working Party
    Blood (IF 13.164) Pub Date : 2018-01-01
    Gerrit J. Schuurhuis; Michael Heuser; Sylvie Freeman; Marie-Christine Béné; Francesco Buccisano; Jacqueline Cloos; David Grimwade; Torsten Haferlach; Robert K. Hills; Christopher S. Hourigan; Jeffrey L. Jorgensen; Wolfgang Kern; Francis Lacombe; Luca Maurillo; Claude Preudhomme; Bert A. van der Reijden; Christian Thiede; Adriano Venditti; Paresh Vyas; Brent L. Wood; Roland B. Walter; Konstanze Döhner; Gail J. Roboz; Gert J. Ossenkoppele

    Measurable residual disease (MRD, previously termed minimal residual disease) is an independent, post-diagnosis, prognostic indicator in acute myeloid leukemia (AML) that is important for risk stratification and treatment planning, in conjunction with other well-established clinical, cytogenetic, and molecular data assessed at diagnosis. MRD can be evaluated using a variety of multi-parameter flow cytometry (MFC) and molecular protocols but, to date, these approaches have not been qualitatively or quantitatively standardized, making their use in clinical practice challenging. The objective of this work was to identify key clinical and scientific issues in the measurement and application of MRD in AML, to achieve consensus on these issues, and to provide guidelines for the current and future use of MRD in clinical practice. The work was accomplished over two years, during four meetings by a specially designated MRD working party of the European LeukemiaNet (ELN). The group included 24 faculty with expertise in AML hematopathology, molecular diagnostics, clinical trials, and clinical medicine, from 19 institutions in Europe and the USA. The manuscript is dedicated to the memory of our esteemed colleague David Grimwade, a pioneer in the field of MRD in AML, and an active participant in the present work.

    更新日期:2018-01-12
  • Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome
    Blood (IF 13.164) Pub Date : 2018-01-01
    Eric S. Weiss; Charlotte Girard-Guyonvarc'h; Dirk Holzinger; Adriana A. de Jesus; Zeshan Tariq; Jennifer Picarsic; Eduardo J. Schiffrin; Dirk Foell; Alexei A. Grom; Sandra Ammann; Stephan Ehl; Tomoaki Hoshino; Raphaela Goldbach-Mansky; Cem Gabay; Scott W. Canna

    Hemophagocytic Lymphohistiocytosis (HLH) and Macrophage Activation Syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Though profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of Interleukin (IL)-18. We tested this association in hyperferritinemic and autoinflammatory patients, and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 Binding Protein, or Free IL-18. In a mouse engineered to carry a disease-causing germline NLRC4T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of Interferon-γ-induced genes. Assessing cellular and tissue expression, classical inflammasome components like Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18-driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.

    更新日期:2018-01-12
  • Limited-stage DLBCL: it’s patient selection
    Blood (IF 13.164) Pub Date : 2018-01-11
    Daniel O. Persky

    In this issue of Blood , [Lamy et al][1] present the results of the LYSA/GOELAMS trial 02-03, where patients with limited-stage diffuse large B-cell lymphoma (DLBCL) received either 4 or 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) based on risk

    更新日期:2018-01-12
  • Choosing ibrutinib wisely
    Blood (IF 13.164) Pub Date : 2018-01-11
    Farrukh T. Awan

    In this issue of Blood , [Bartlett et al][1] share their experience with the use of ibrutinib in patients with relapsed or refractory follicular lymphoma (FL).[1][2] This study was part of a multicenter, international, phase 2 consortium trial that enrolled 40 patients with recurrent FL, who were

    更新日期:2018-01-12
  • NOTCHing down a win for megakaryocytes
    Blood (IF 13.164) Pub Date : 2018-01-11
    Samir Taoudi

    By exploiting a congenic pair of induced pluripotent stem cell (iPSC) lines derived from a familial platelet disorder (FPD) patient, 1 harboring a monoallelic mutation in RUNX1 and the other a corrected allele, in this issue of Blood , [Li et al][1] have discovered that negative regulation of NOTCH4

    更新日期:2018-01-12
  • Clinicogenetic risk modeling in ATL
    Blood (IF 13.164) Pub Date : 2018-01-11
    Noriaki Yoshida; David M. Weinstock

    In this issue of Blood , [Kataoka et al][1][1][2] leverage their landscape of adult T-cell leukemia/lymphoma (ATL) to define associations between outcome and specific genetic alterations.[2][3] They identify gene alterations in both high-grade and low-grade disease that correlate with outcome.

    更新日期:2018-01-12
  • NK cell destiny after haploSCT with PT-Cy
    Blood (IF 13.164) Pub Date : 2018-01-11
    Amnon Peled; Arnon Nagler

    In this issue of Blood , [Russo et al][1] provide important insights on the effect of posttransplantation cyclophosphamide (PT-Cy) on natural killer (NK) cell recovery and function after haploidentical allogeneic stem cell transplantation (haploSCT).[1][2] Allogeneic hematopoietic stem cell

    更新日期:2018-01-12
  • How I manage monoclonal gammopathy of undetermined significance
    Blood (IF 13.164) Pub Date : 2018-01-11
    Ronald S. Go; S. Vincent Rajkumar

    Monoclonal gammopathy of undetermined significance (MGUS) is, in many ways, a unique hematologic entity. Unlike most hematologic conditions in which the diagnosis is intentional and credited to hematologists, the discovery of MGUS is most often incidental and made by nonhematologists. MGUS is considered an obligate precursor to several lymphoplasmacytic malignancies, including immunoglobulin light-chain amyloidosis, multiple myeloma, and Waldenström macroglobulinemia. Therefore, long-term follow-up is generally recommended. Despite its high prevalence, there is surprisingly limited evidence to inform best clinical practice both at the time of diagnosis and during follow-up. We present 7 vignettes to illustrate common clinical management questions that arise during the course of MGUS. Where evidence is present, we provide a concise summary of the literature and clear recommendations on management. Where evidence is lacking, we describe how we practice and provide a rationale for our approach. We also discuss the potential harms associated with MGUS diagnosis, a topic that is rarely, if ever, broached between patients and providers, or even considered in academic debate.

    更新日期:2018-01-12
  • R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma
    Blood (IF 13.164) Pub Date : 2018-01-11
    Thierry Lamy; Gandhi Damaj; Pierre Soubeyran; Emmanuel Gyan; Guillaume Cartron; Krimo Bouabdallah; Rémy Gressin; Jérôme Cornillon; Anne Banos; Katell Le Du; Mohamed Benchalal; Marie-Pierre Moles; Steven Le Gouill; Joel Fleury; Pascal Godmer; Hervé Maisonneuve; Eric Deconinck; Roch Houot; Kamel Laribi; Jean Pierre Marolleau; Olivier Tournilhac; Bernard Branger; Anne Devillers; Jean Philippe Vuillez; Thierry Fest; Philippe Colombat; Valérie Costes; Vanessa Szablewski; Marie C. Béné; Vincent Delwail

    The benefit of radiotherapy (RT) after chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. We conducted a randomized trial in patients with nonbulky limited-stage DLBCL to evaluate the benefit of RT after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients were stratified according to the modified International Prognostic Index, including lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, age, and disease stage. The patients received 4 or 6 consecutive cycles of R-CHOP delivered once every 2 weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last R-CHOP cycle. All patients were evaluated by fluorodeoxyglucose-positron emission tomography scans performed at baseline, after 4 cycles of R-CHOP, and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. The trial randomly assigned 165 patients in the R-CHOP arm and 169 in the R-CHOP plus RT arm. In an intent-to-treat analysis with a median follow-up of 64 months, 5-year EFS was not statistically significantly different between the 2 arms, with 89% ± 2.9% in the R-CHOP arm vs 92% ± 2.4% in the R-CHOP plus RT arm (hazard ratio, 0.61; 95% confidence interval [CI], 0.3-1.2; P = .18). Overall survival was also not different at 92% (95% CI, 89.5%-94.5%) for patients assigned to R-CHOP alone and 96% (95% CI, 94.3%-97.7%) for those assigned to R-CHOP plus RT (P = not significant). R-CHOP alone is not inferior to R-CHOP followed by RT in patients with nonbulky limited-stage DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT00841945.

    更新日期:2018-01-12
  • Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial
    Blood (IF 13.164) Pub Date : 2018-01-11
    Nancy L. Bartlett; Brian A. Costello; Betsy R. LaPlant; Stephen M. Ansell; John G. Kuruvilla; Craig B. Reeder; Lim S. Thye; Daniel M. Anderson; Kilannin Krysiak; Cody Ramirez; Jing Qi; Barry A. Siegel; Malachi Griffith; Obi L. Griffith; Felicia Gomez; Todd A. Fehniger

    Most patients with follicular lymphoma (FL) experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of several B-cell malignancies, showed promising activity in FL in a phase 1 study. We report the results of a phase 2 trial evaluating ibrutinib in recurrent FL. Forty patients with recurrent FL were treated with ibrutinib 560 mg/d until progression or intolerance. The primary end point was overall response rate (ORR). Exploratory analyses included correlations of outcome with recurrent mutations identified in a cancer gene panel that used next-generation sequencing in pretreatment biopsies from 31 patients and results of early interim positron emission tomography/computed tomography scans in 20 patients. ORR was 37.5% with a complete response rate of 12.5%, median progression-free survival (PFS) of 14 months, and 2-year PFS of 20.4%. Response rates were significantly higher among patients whose disease was sensitive to rituximab (52.6%) compared with those who were rituximab refractory (16.7%) (P = .04). CARD11 mutations were present in 16% of patients (5 of 31) and predicted resistance to ibrutinib with only wild-type patients responding (P = .002). Maximum standardized uptake value at cycle 1 day 8 correlated with response and PFS. Ibrutinib was well-tolerated with a toxicity profile similar to labeled indications. Ibrutinib is a well-tolerated treatment with modest activity in relapsed FL. Evaluation of BTK inhibitors in earlier lines of therapy may be warranted on the basis of improved response rates in rituximab-sensitive disease. Somatic mutations such as CARD11 may have an impact on response to ibrutinib, may inform clinical decisions, and should be evaluated in larger data sets. This trial was registered at www.clinicaltrials.gov as #NCT01849263.

    更新日期:2018-01-12
  • Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation
    Blood (IF 13.164) Pub Date : 2018-01-11
    Yueying Li; Chen Jin; Hao Bai; Yongxing Gao; Shu Sun; Lei Chen; Lei Qin; Paul P. Liu; Linzhao Cheng; Qian-Fei Wang

    Megakaryocytes (MKs) in adult marrow produce platelets that play important roles in blood coagulation and hemostasis. Monoallelic mutations of the master transcription factor gene RUNX1 lead to familial platelet disorder (FPD) characterized by defective MK and platelet development. However, the molecular mechanisms of FPD remain unclear. Previously, we generated human induced pluripotent stem cells (iPSCs) from patients with FPD containing a RUNX1 nonsense mutation. Production of MKs from the FPD-iPSCs was reduced, and targeted correction of the RUNX1 mutation restored MK production. In this study, we used isogenic pairs of FPD-iPSCs and the MK differentiation system to identify RUNX1 target genes. Using integrative genomic analysis of hematopoietic progenitor cells generated from FPD-iPSCs, and mutation-corrected isogenic controls, we identified 2 gene sets the transcription of which is either up- or downregulated by RUNX1 in mutation-corrected iPSCs. Notably, NOTCH4 expression was negatively controlled by RUNX1 via a novel regulatory DNA element within the locus, and we examined its involvement in MK generation. Specific inactivation of NOTCH4 by an improved CRISPR-Cas9 system in human iPSCs enhanced megakaryopoiesis. Moreover, small molecules known to inhibit Notch signaling promoted MK generation from both normal human iPSCs and postnatal CD34+ hematopoietic stem and progenitor cells. Our study newly identified NOTCH4 as a RUNX1 target gene and revealed a previously unappreciated role of NOTCH4 signaling in promoting human megakaryopoiesis. Our work suggests that human iPSCs with monogenic mutations have the potential to serve as an invaluable resource for discovery of novel druggable targets.

    更新日期:2018-01-12
  • Decitabine enhances targeting of AML cells by CD34+ progenitor-derived NK cells in NOD/SCID/IL2Rgnull mice
    Blood (IF 13.164) Pub Date : 2018-01-11
    Jeannette Cany; Mieke W. H. Roeven; Janneke S. Hoogstad-van Evert; Willemijn Hobo; Frans Maas; Rosalia Franco Fernandez; Nicole M. A. Blijlevens; Walter J. van der Velden; Gerwin Huls; Joop H. Jansen; Nicolaas P. M. Schaap; Harry Dolstra

    Combining natural killer (NK) cell adoptive transfer with hypomethylating agents (HMAs) is an attractive therapeutic approach for patients with acute myeloid leukemia (AML). However, data regarding the impact of HMAs on NK cell functionality are mostly derived from in vitro studies with high nonclinical relevant drug concentrations. In the present study, we report a comparative study of azacitidine (AZA) and decitabine (DAC) in combination with allogeneic NK cells generated from CD34+ hematopoietic stem and progenitor cells (HSPC-NK cells) in in vitro and in vivo AML models. In vitro, low-dose HMAs did not impair viability of HSPC-NK cells. Furthermore, low-dose DAC preserved HSPC-NK killing, proliferation, and interferon gamma production capacity, whereas AZA diminished their proliferation and reactivity. Importantly, we showed HMAs and HSPC-NK cells could potently work together to target AML cell lines and patient AML blasts. In vivo, both agents exerted a significant delay in AML progression in NOD/SCID/IL2Rgnull mice, but the persistence of adoptively transferred HSPC-NK cells was not affected. Infused NK cells showed sustained expression of most activating receptors, upregulated NKp44 expression, and remarkable killer cell immunoglobulin-like receptor acquisition. Most importantly, only DAC potentiated HSPC-NK cell anti-leukemic activity in vivo. Besides upregulation of NKG2D- and DNAM-1–activating ligands on AML cells, DAC enhanced messenger RNA expression of inflammatory cytokines, perforin, and TRAIL by HSPC-NK cells. In addition, treatment resulted in increased numbers of HSPC-NK cells in the bone marrow compartment, suggesting that DAC could positively modulate NK cell activity, trafficking, and tumor targeting. These data provide a rationale to explore combination therapy of adoptive HSPC-NK cells and DAC in patients with AML.

    更新日期:2018-01-12
  • Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma
    Blood (IF 13.164) Pub Date : 2018-01-11
    Keisuke Kataoka; Masako Iwanaga; Jun-ichirou Yasunaga; Yasunobu Nagata; Akira Kitanaka; Takuro Kameda; Makoto Yoshimitsu; Yuichi Shiraishi; Aiko Sato-Otsubo; Masashi Sanada; Kenichi Chiba; Hiroko Tanaka; Yotaro Ochi; Kosuke Aoki; Hiromichi Suzuki; Yusuke Shiozawa; Tetsuichi Yoshizato; Yusuke Sato; Kenichi Yoshida; Kisato Nosaka; Masakatsu Hishizawa; Hidehiro Itonaga; Yoshitaka Imaizumi; Wataru Munakata; Kotaro Shide; Yoko Kubuki; Tomonori Hidaka; Tsuyoshi Nakamaki; Ken Ishiyama; Shuichi Miyawaki; Ryohei Ishii; Osamu Nureki; Kensei Tobinai; Yasushi Miyazaki; Akifumi Takaori-Kondo; Tatsuhiro Shibata; Satoru Miyano; Kenji Ishitsuka; Atae Utsunomiya; Kazuya Shimoda; Masao Matsuoka; Toshiki Watanabe; Seishi Ogawa

    Adult T-cell leukemia/lymphoma (ATL) is a heterogeneous group of peripheral T-cell malignancies characterized by human T-cell leukemia virus type-1 infection, whose genetic profile has recently been fully investigated. However, it is still poorly understood how these alterations affect clinical features and prognosis. We investigated the effects of genetic alterations commonly found in ATL on disease phenotypes and clinical outcomes, based on genotyping data obtained from 414 and 463 ATL patients using targeted-capture sequencing and single nucleotide polymorphism array karyotyping, respectively. Aggressive (acute/lymphoma) subtypes were associated with an increased burden of genetic and epigenetic alterations, higher frequencies of TP53 and IRF4 mutations, and many copy number alterations (CNAs), including PD-L1 amplifications and CDKN2A deletions, compared with indolent (chronic/smoldering) subtypes. By contrast, STAT3 mutations were more characteristic of indolent ATL. Higher numbers of somatic mutations and CNAs significantly correlated with worse survival. In a multivariate analysis incorporating both clinical factors and genetic alterations, the Japan Clinical Oncology Group prognostic index high-risk, older age, PRKCB mutations, and PD-L1 amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions were significantly associated with shorter survival, although the chronic subtype with unfavorable clinical factors was only marginally significant. Thus, somatic alterations characterizing aggressive diseases predict worse prognosis in indolent ATL, among which PD-L1 amplifications are a strong genetic predictor in both aggressive and indolent ATL. ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic profiling might contribute to improved prognostication and management of ATL patients.

    更新日期:2018-01-12
  • FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab and chemotherapy
    Blood (IF 13.164) Pub Date : 2018-01-11
    Anja Mottok; Vindi Jurinovic; Pedro Farinha; Andreas Rosenwald; Ellen Leich; German Ott; Heike Horn; Wolfram Klapper; Michael Boesl; Wolfgang Hiddemann; Christian Steidl; Joseph M. Connors; Laurie H. Sehn; Randy D. Gascoyne; Eva Hoster; Oliver Weigert; Robert Kridel

    Follicular lymphoma (FL) is a clinically and molecularly highly heterogeneous disease, yet prognostication relies predominantly on clinical tools. We recently demonstrated that integration of mutation status of 7 genes, including EZH2 and MEF2B, improves risk stratification. We mined gene expression data to uncover genes that are differentially expressed in EZH2- and MEF2B-mutated cases. We focused on FOXP1 and assessed its protein expression by immunohistochemistry (IHC) in 763 tissue biopsies. For outcome correlation, a population-based training cohort of 142 patients with FL treated with rituximab, cyclophosphamide, vincristine, and prednisone, and a clinical trial validation cohort comprising 395 patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) ± rituximab were used. We found FOXP1 to be significantly downregulated in both EZH2- and MEF2B-mutated cases. By IHC, 76 specimens in the training cohort (54%) had high FOXP1 expression (>10%), which was associated with reduced 5-year failure-free survival (FFS) rates (55% vs 70%). In the validation cohort, high FOXP1 expression status was observed in 248 patients (63%) and correlated with significantly shorter FFS in patients treated with R-CHOP (hazard ratio [HR], 1.95; P = .017) but not in patients treated with CHOP (HR, 1.15; P = .44). The impact of high FOXP1 expression on FFS in immunochemotherapy-treated patients was additional to the Follicular Lymphoma International Prognostic Index. High FOXP1 expression was associated with distinct molecular features such as TP53 mutations, expression of IRF4, and gene expression signatures reminiscent of dark zone germinal center or activated B cells. In summary, FOXP1 is a downstream phenotypic commonality of gene mutations and predicts outcome following rituximab-containing regimens.

    更新日期:2018-01-12
  • Inhibition of heme oxygenase ameliorates anemia and reduces iron overload in a β-thalassemia mouse model
    Blood (IF 13.164) Pub Date : 2018-01-11
    Daniel Garcia-Santos; Amel Hamdi; Zuzana Saxova; Carine Fillebeen; Kostas Pantopoulos; Monika Horvathova; Prem Ponka

    Thalassemias are a heterogeneous group of red blood cell disorders, considered a major cause of morbidity and mortality among genetic diseases. However, there is still no universally available cure for thalassemias. The underlying basis of thalassemia pathology is the premature apoptotic destruction of erythroblasts causing ineffective erythropoiesis. In β-thalassemia, β-globin synthesis is reduced causing α-globin accumulation. Unpaired globin chains, with heme attached to them, accumulate in thalassemic erythroblasts causing oxidative stress and the premature cell death. We hypothesize that in β-thalassemia heme oxygenase (HO) 1 could play a pathogenic role in the development of anemia and ineffective erythropoiesis. To test this hypothesis, we exploited a mouse model of β-thalassemia intermedia, Th3/+. We observed that HO inhibition using tin protoporphyrin IX (SnPP) decreased heme-iron recycling in the liver and ameliorated anemia in the Th3/+ mice. SnPP administration led to a decrease in erythropoietin and increase in hepcidin serum levels, changes that were accompanied by an alleviation of ineffective erythropoiesis in Th3/+ mice. Additionally, the bone marrow from Th3/+ mice treated with SnPP exhibited decreased heme catabolism and diminished iron release as well as reduced apoptosis. Our results indicate that the iron released from heme because of HO activity contributes to the pathophysiology of thalassemia. Therefore, new therapies that suppress heme catabolism may be beneficial in ameliorating the anemia and ineffective erythropoiesis in thalassemias.

    更新日期:2018-01-12
  • NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications
    Blood (IF 13.164) Pub Date : 2018-01-11
    Antonio Russo; Giacomo Oliveira; Sofia Berglund; Raffaella Greco; Valentina Gambacorta; Nicoletta Cieri; Cristina Toffalori; Laura Zito; Francesca Lorentino; Simona Piemontese; Mara Morelli; Fabio Giglio; Andrea Assanelli; Maria Teresa Lupo Stanghellini; Chiara Bonini; Jacopo Peccatori; Fabio Ciceri; Leo Luznik; Luca Vago

    The use of posttransplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis has revolutionized haploidentical hematopoietic stem cell transplantation (HSCT), allowing safe infusion of unmanipulated T cell–replete grafts. PT-Cy selectively eliminates proliferating alloreactive T cells, but whether and how it affects natural killer (NK) cells and their alloreactivity is largely unknown. Here we characterized NK cell dynamics in 17 patients who received unmanipulated haploidentical grafts, containing high numbers of mature NK cells, according to PT-Cy–based protocols in 2 independent centers. In both series, we documented robust proliferation of donor-derived NK cells immediately after HSCT. After infusion of Cy, a marked reduction of proliferating NK cells was evident, suggesting selective purging of dividing cells. Supporting this hypothesis, proliferating NK cells did not express aldehyde dehydrogenase and were killed by Cy in vitro. After ablation of mature NK cells, starting from day 15 after HSCT and favored by the high levels of interleukin-15 present in patients' sera, immature NK cells (CD62L+NKG2A+KIR−) became highly prevalent, possibly directly stemming from infused hematopoietic stem cells. Importantly, also putatively alloreactive single KIR+ NK cells were eliminated by PT-Cy and were thus decreased in numbers and antileukemic potential at day 30 after HSCT. As a consequence, in an extended series of 99 haplo-HSCT with PT-Cy, we found no significant difference in progression-free survival between patients with or without predicted NK alloreactivity (42% vs 52% at 1 year, P = NS). Our data suggest that the majority of mature NK cells infused with unmanipulated grafts are lost upon PT-Cy administration, blunting NK cell alloreactivity in this transplantation setting.

    更新日期:2018-01-12
  • Efficacy and safety of ruxolitinib in regularly transfused patients with thalassemia: results from a phase 2a study
    Blood (IF 13.164) Pub Date : 2018-01-11
    Ali T. Taher; Zeynep Karakas; Elena Cassinerio; Noppadol Siritanaratkul; Antonis Kattamis; Aurelio Maggio; Stefano Rivella; Norbert Hollaender; Bruyère Mahuzier; Brian Gadbaw; Yesim Aydinok

    To the editor: Ineffective erythropoiesis is a key pathological feature in thalassemia and is the major perpetrator of profound anemia and hypoxia seen in these patients.[1][1][⇓][2]-[3][3] The inadequate tissue oxygenation in thalassemia sets up several compensatory mechanisms, including an

    更新日期:2018-01-12
  • Histiocytic sarcoma: a population-based analysis of incidence, demographic disparities, and long-term outcomes
    Blood (IF 13.164) Pub Date : 2018-01-11
    Anuhya Kommalapati; Sri Harsha Tella; Martin Durkin; Ronald S. Go; Gaurav Goyal

    TO THE EDITOR: Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from non-Langerhans histiocytic cells of the monocyte/macrophage system that is diagnosed using immunohistochemistry markers, such as CD68, lysozyme, CD4, and CD163, on the tissue biopsies.[1][1] HS can occur in

    更新日期:2018-01-12
  • Talaromyces marneffei and dysplastic neutrophils on blood smear in newly diagnosed HIV
    Blood (IF 13.164) Pub Date : 2018-01-11
    Jad Othman; Christina M. Brown

    ![Figure][1] A 23-year-old Thai man presented with lethargy, arthralgia, diarrhea, fevers, and a papular rash. Past medical history was unremarkable. White cell count was 4.5 × 109/L (neutrophils 2.6 × 109/L, lymphocytes 0.1 × 109/L), hemoglobin 10 g/dL with mean corpuscular volume of 59

    更新日期:2018-01-12
  • When a marginal zone–type lymphocytosis mimics large granular lymphocytes
    Blood (IF 13.164) Pub Date : 2018-01-11
    Coralie Derrieux; Emilie Klein

    ![Figure][1] A 72-year-old man presented with a persistent lymphocytosis. Physical examination was unremarkable, with no evidence of lymphadenopathy or organomegaly. A marked lymphocytosis (11.4 × 109/L) and slight anemia (12.0 g/dL) were observed. The peripheral blood smear showed 70%

    更新日期:2018-01-12
  • Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency
    Blood (IF 13.164) Pub Date : 2018-01-01
    Amy D. Shapiro; Charles Nakar; Joseph M. Parker; Gary R. Albert; John E. Moran; Karen Thibaudeau; Neelam Thukral; Brandon M. Hardesty; Pierre Laurin; Per Morten Sandset

    Congenital plasminogen deficiency is caused by mutation(s) in PLG, the gene coding for production of the zymogen plasminogen, and is an ultra-rare disorder associated with abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes, such as the conjunctiva, gingiva, and linings of the airways and genitourinary tract. Left untreated, these lesions may impair normal tissue and organ function, and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the clinical manifestations of congenital plasminogen deficiency. An open-label phase 2/3 study of human Glu-plasminogen administered intravenously at 6.6 mg/kg every 2-4 days in 15 patients with congenital plasminogen deficiency is ongoing. Reported here are data on 14 patients who completed at least 12 weeks of treatment. The primary endpoint was an increase in trough plasminogen activity levels by at least an absolute 10% above baseline. The secondary endpoint was clinical success, defined as ≥50% improvement in lesion number/size or functionality impact from baseline. All patients achieved at least an absolute 10% increase in trough plasminogen activity above baseline. Overall clinical success was observed in all patients with clinically visible (conjunctiva and gingiva), non-visible (nasopharynx, bronchus, colon, kidney, cervix, and vagina), and wound-healing manifestations of the disease. Therapeutic effects were rapid as all but 2 lesions resolved or improved after 4 weeks of treatment. Human Glu plasminogen was well tolerated in both children and adults. This study provides critical first evidence of the clinical utility of ongoing replacement therapy with human Glu-plasminogen for the treatment of children and adults with congenital plasminogen deficiency. This trial was registered at www.clinicaltrials.gov as #NCT02690714.

    更新日期:2018-01-11
  • Casein Kinase 1 is a Therapeutic Target in Chronic Lymphocytic Leukemia
    Blood (IF 13.164) Pub Date : 2018-01-01
    Pavlina Janovska; Jan Verner; Jiri Kohoutek; Lenka Bryjova; Michaela Gregorova; Marta Dzimkova; Hana Skabrahova; Tomasz Radaszkiewicz; Petra Ovesna; Olga Vondalova Blanarova; Tereza Nemcova; Zuzana Hoferova; Katerina Vasickova; Lucie Smyckova; Alexander Egle; Sarka Pavlova; Lucie Poppova; Karla Plevova; Sarka Pospisilova; Vitezslav Bryja

    Casein kinase (CK) 1δ/ε is a key component of non-canonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study we investigated thoroughly the effects of CK1δ/ε inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using two murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resemble closely the human CLL. We can demonstrate that CK1δ/ε inhibitor PF-670462 significantly blocks microenvironmental interactions – chemotaxis, invasion and communication with stromal cells in primary CLL cells in all major subtypes of CLL. In the mouse models, CK1 inhibition slows down accumulation of leukemic cells in the peripheral blood and spleen, and prevents onset of anemia. As a consequence, PF-670462 treatment results in a significantly longer overall survival. Importantly, CK1 inhibition has synergistic effect to the BCR inhibitors such as ibrutinib in vitro and significantly improves ibrutinib effects in vivo. Mice treated by combination of PF-670462 and ibrutinib show the slowest progression of the disease and survive significantly longer compared to ibrutinib-only treatment when the therapy is discontinued. In summary, this preclinical testing of CK1δ/ε inhibitor PF-670462 demonstrates that CK1 may serve as a novel therapeutic target in CLL, acting in synergy with BCR inhibitors. Our work provides evidence that targeting CK1 can represent an alternative or addition to the therapeutic strategies based on B-cell receptor (BCR) signaling and anti-apoptotic signaling (BCL-2) inhibition.

    更新日期:2018-01-10
  • Targeting anticoagulant protein S to improve hemostasis in hemophilia
    Blood (IF 13.164) Pub Date : 2018-01-01
    Raja Prince; Luca Bologna; Mirko Manetti; Daniela Melchiorre; Irene Rosa; Natacha Dewarrat; Silvia Suardi; Poorya Amini; José A. Fernández; Laurent Burnier; Claudia Quarroz; Maria Desiré Reina Caro; Yasuhiro Matsumura; Johanna A. Kremer Hovinga; John H. Griffin; Hans-Uwe Simon; Lidia Ibba-Manneschi; François Saller; Sara Calzavarini; Anne Angelillo-Scherrer

    Improved treatments are needed for hemophilia A and B, bleeding disorders affecting 400,000 people worldwide. We investigated whether targeting protein S could promote hemostasis in hemophilia by re-balancing coagulation. Protein S is an anticoagulant acting as cofactor for activated protein C and tissue factor pathway inhibitor (TFPI). This dual role makes PS a key regulator of thrombin generation. Here, we report that targeting protein S rebalances coagulation in hemophilia. Protein S gene targeting in hemophilic mice protected them against bleeding, especially when intra-articular. Mechanistically, these mice displayed increased thrombin generation, resistance to activated protein C and TFPI, and improved fibrin network. Blocking protein S in plasma of hemophilia patients normalized in vitro thrombin generation. Both protein S and TFPIα were detected in hemophilic mice joints. Protein S and TFPI expression was stronger in joints of hemophilia A than hemophilia B patients when receiving on demand therapy, e.g., during a bleeding episode. In contrast, protein S and TFPI expression was decreased in hemophilia A patients receiving prophylaxis with coagulation factor concentrates, and comparable to osteoarthritis patients. These results establish protein S inhibition as both controller of coagulation and potential therapeutic target in hemophilia. The murine protein S silencing RNA approach that we successfully used in hemophilic mice might constitute a new therapeutic concept for hemophilic patients.

    更新日期:2018-01-10
  • Early detection and evolution of pre-leukemic clones in therapy-related myeloid neoplasms following autologous SCT
    Blood (IF 13.164) Pub Date : 2018-01-01
    Gerbrig Berger; Leonie I. Kroeze; Theresia N. Koorenhof-Scheele; Aniek O. de Graaf; Kenichi Yoshida; Hiroo Ueno; Yuichi Shiraishi; Satoru Miyano; Eva van den Berg; Hein Schepers; Bert A. van der Reijden; Seishi Ogawa; Edo Vellenga; Joop H. Jansen

    Therapy-related myeloid neoplasms (tMNs) are severe adverse events that can occur following treatment with autologous hematopoietic stem cell transplantation (ASCT). This study aimed to investigate the development of tMN following ASCT at the molecular level by whole exome sequencing (WES) and targeted deep sequencing (TDS) in sequential (pre-) tMN samples. WES identified a significantly higher number of mutations in tMN as compared to de novo MDS (median 27 vs 12, p=0.001). The mutations found in tMN did not carry a clear ageing-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism. In some patients, tMN mutations were identified in both myeloid and T-cells, suggesting that tMNs may originate from early hematopoietic stem cells (HSCs). However, the mutational spectra of tMN and the preceding malignancies did not overlap, excluding common ancestry for these malignancies. Using TDS, tMN mutations were identified at low variant allele frequencies (VAFs) in transplant material in 70% of the tMN cases. Reconstruction of clonal patterns based on VAFs, revealed that pre-malignant clones can be present more than seven years preceding tMN diagnosis, a finding that was confirmed by immunohistochemistry on bone marrow biopsies. Our results indicate that tMN development following ASCT originates in HSCs bearing tMN mutations that are present years before disease onset and that post-ASCT treatment can influence the selection of these clones. Early detection of pre-malignant clones and monitoring their evolutionary trajectory may help to predict the development of tMN and guide early intervention in the future.

    更新日期:2018-01-09
  • Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia (T-ALL)
    Blood (IF 13.164) Pub Date : 2018-01-01
    Karen L. Bride; Tiffaney L. Vincent; Soo-Yeon Im; Richard Aplenc; David M. Barrett; William L. Carroll; Robin Carson; Yunfeng Dai; Meenakshi Devidas; Kimberly P. Dunsmore; Tori Fuller; Tina Glisovic-Aplenc; Terzah M. Horton; Stephen P. Hunger; Mignon L. Loh; Shannon L. Maude; Elizabeth A. Raetz; Stuart S. Winter; Stephan A. Grupp; Michelle L. Hermiston; Brent L. Wood; David T. Teachey

    As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-ALL, however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multi-agent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of non-hematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human IgG1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma (MM). We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.

    更新日期:2018-01-05
  • Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy
    Blood (IF 13.164) Pub Date : 2018-01-01
    Steven Coutre; Michael Choi; Richard R. Furman; Herbert Eradat; Leonard Heffner; Jeffrey A. Jones; Brenda Chyla; Lang Zhou; Suresh Agarwal; Tina Waskiewicz; Maria Verdugo; Rod A. Humerickhouse; Jalaja Potluri; William G. Wierda; Matthew S. Davids

    B-cell receptor pathway inhibitors (BCRi) have transformed treatment for chronic lymphocytic leukemia (CLL); however, efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRi is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi prior to enrollment. Venetoclax was initiated at 20mg daily followed by intra-patient ramp up to 400mg daily. Primary objectives included efficacy (objective response rate [ORR]) and safety of venetoclax. The study enrolled 36 patients who previously received idelalisib, with ORR of 67% (24/36); two patients achieved complete remission and one had complete remission with incomplete bone marrow recovery. Median progression-free survival (PFS) has not yet been reached and estimated 12-month PFS was 79%. The most common AEs (all grades) were neutropenia (56%), diarrhea (42%), upper respiratory tract infection (39%), thrombocytopenia (36%), nausea (31%), fatigue (28%), cough (22%), rash (22%), and anemia (22%). Grade 3 or 4 AEs were primarily hematologic (neutropenia [50%], thrombocytopenia [25%], and anemia [17%]). No patients experienced tumor lysis syndrome. Venetoclax demonstrated promising clinical activity and favorable tolerability in patients with CLL whose disease progressed during or after idelalisib therapy. Trial registration: clinicaltrials.gov #NCT02141282.

    更新日期:2018-01-05
  • Copper-64-labeled daratumumab as a PET/CT imaging tracer for multiple myeloma
    Blood (IF 13.164) Pub Date : 2018-01-01
    Enrico Caserta; Junie Chea; Megan Minnix; Domenico Viola; Steven Vonderfecht; Paul Yazaki; Desiree Crow; Jihane Khalife; James F. Sanchez; Joycelynne M. Palmer; Susanta Hui; Nadia Carlesso; Jonathan Keats; Young Kim; Ralf Buettner; Guido Marcucci; Steven Rosen; John Shively; David Colcher; Amrita Krishnan; Flavia Pichiorri

    As a growing number of patients with multiple myeloma (MM) respond to upfront therapies while eventually relapsing in a time frame that is often non-predictable, attention has increasingly focused on developing novel diagnostic criteria to also account for disease dissemination. Positron emission tomography/computed tomography (PET/CT) is often used as a non-invasive monitoring strategy to assess cancer cell dissemination, but because the uptake of the currently used radiotracer 18fluoro-deoxyglucose (18F-FDG) is a function of the metabolic activity of both malignant and non-malignant cells, results frequently lack sufficient specificity. Radiolabeled antibodies targeting MM tissue may detect disease irrespective of cell metabolism. Hence, we conjugated the clinically significant CD38-directed human antibody daratumumab (Darzalex™ [Dara]) to the DOTA chelator and labeled with the positron-emitting radionuclide Copper-64 (64Cu-DOTA-Dara). Here, we show that 64Cu-DOTA-Dara can efficiently bind CD38 on the surface of MM cells and was mainly detected in the bones associated with tumor in a MM murine model. We also show that PET/CT based on 64Cu-DOTA-Dara displays a higher resolution and specificity to detect MM cell dissemination compared to 18F-FDG PET/CT and was even more sensitive than bioluminescence signals. We therefore have supporting evidence to use 64Cu-DOTA-Dara as a novel imaging agent for MM.

    更新日期:2018-01-05
  • Maintenance of murine platelet homeostasis by the kinase Csk and the phosphatase CD148
    Blood (IF 13.164) Pub Date : 2018-01-01
    Jun Mori; Zoltan Nagy; Giada Di Nunzio; Christopher W. Smith; Mitchell J. Geer; Rashid Al Ghaithi; Johanna P. van Geffen; Silke Heising; Luke Boothman; Bibian M. E. Tullemans; Joao N. Correia; Louise Tee; Marijke J. E. Kuijpers; Paul Harrison; Johan W. M. Heemskerk; Gavin E. Jarvis; Alexander Tarakhovsky; Arthur Weiss; Alexandra Mazharian; Yotis A. Senis

    Src family kinases (SFKs) coordinate the initiating and propagating activation signals in platelets, however it remains unclear how they are regulated. Here we show that ablation of C-terminal Src kinase (Csk) and receptor-like protein tyrosine-phosphatase CD148 in mice results in a dramatic increase in platelet SFK activity, demonstrating that these proteins are essential regulators of platelet reactivity. Paradoxically, Csk/CD148-deficient mice exhibit reduced in vivo and ex vivo thrombus formation and increased bleeding following injury, rather than a prothrombotic phenotype. This is a consequence of multiple negative feedback mechanisms, including downregulation of the immunoreceptor tyrosine-based activation motif (ITAM)- and hemi-ITAM-containing receptors GPVI-FcR γ-chain and CLEC-2, respectively and upregulation of the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B and its interaction with the tyrosine phosphatases Shp1 and Shp2. Results from an analogue-sensitive Csk mouse model demonstrate the unconventional role of SFKs in activating ITIM signaling. This study establishes Csk and CD148 as critical molecular switches controlling the thrombotic and hemostatic capacity of platelets, and reveals cell-intrinsic mechanisms that prevent pathological thrombosis from occurring.

    更新日期:2018-01-05
  • Introduction to a review series on therapeutic antibodies
    Blood (IF 13.164) Pub Date : 2018-01-04
    Freda K. Stevenson; Catherine M. Bollard

    The success of antibodies in fighting infection is clear, but directing this power against cancer cells has been a challenge. For cancer, antibodies are usually made externally and injected into patients, where they act against established or residual tumors. The initial goal of this form of cancer

    更新日期:2018-01-05
  • Baseline PET as prognostic marker for Hodgkin?
    Blood (IF 13.164) Pub Date : 2018-01-04
    Josée M. Zijlstra; Ronald Boellaard

    In this issue of Blood , [Akhtari et al][1] present a retrospective analysis of baseline positron emission tomography-computed tomography (PET-CT) in Hodgkin lymphoma (HL) in relation to the prognostic significance of the metabolic tumor volume (MTV) in risk classification of early-stage HL.[1][2]

    更新日期:2018-01-05
  • LEDGF: a leukemia-specific target
    Blood (IF 13.164) Pub Date : 2018-01-04
    Thomas A. Milne

    In this issue of Blood , [El Ashkar et al][1][1][2] reveal that the lens epithelium-derived growth factor (LEDGF) protein is a key therapeutic target by showing that it is essential for leukemia, but not normal hematopoiesis. Such context-dependent information is important for the development of new

    更新日期:2018-01-05
  • Off-the-shelf TCR for graft-versus-leukemia without GVHD
    Blood (IF 13.164) Pub Date : 2018-01-04
    Frederick L. Locke; Claudio Anasetti

    In this issue of Blood , [Dossa et al][1] report the engineering of T-cell receptor (TCR) transgenic T cells against the human minor histocompatibility antigen HA-1 for the prevention or treatment of leukemia relapse after allogeneic stem cell transplantation.[1][2] With the recent US Food and Drug

    更新日期:2018-01-05
  • CD19 CAR-T therapy and sepsis: dancing with the devil
    Blood (IF 13.164) Pub Date : 2018-01-04
    Lihua E. Budde; John A. Zaia

    In this issue of Blood , [Hill and colleagues][1] characterized infectious complications in patients with relapsed or refractory B-cell malignancies after treatment with CD19-targeted chimeric antigen receptor–modified T (CAR-T) cells in a phase 1/2 study.[1][2] This is the first study that

    更新日期:2018-01-05
  • AML: exposed and exploited?
    Blood (IF 13.164) Pub Date : 2018-01-04
    Jeffery J. Auletta

    In this issue of Blood , [Gillissen and colleagues][1] characterize donor-derived cytotoxic antibodies, isolated from allogeneic hematopoietic cell transplant (HSCT) patients with acute myelogenous leukemia (AML) in sustained remission, that targeted the spliceosome U5 snRNP200 complex expressed on

    更新日期:2018-01-05
  • The delectability of platelets to a phagocyte
    Blood (IF 13.164) Pub Date : 2018-01-04
    Thomas S. Kickler

    In this issue of Blood , [Saris et al][1] show that some HLA antigens, namely, B8, B12, and B35, vary in expression on the platelets of some individuals and that this is a constant variant in these people.[1][2] In this study, a unique opsonification assay is used to support the authors' hypothesis

    更新日期:2018-01-05
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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