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  • The Immune Landscape and Response to Immune Checkpoint Blockade Therapy in Lymphoma.
    Blood (IF 16.562) Pub Date : null
    Justin Kline,James Godfrey,Stephen M Ansell

    The clinical development of effective cancer immunotherapies, along with advances in genomic analysis, has led to the identification of tumor environmental features that predict for sensitivity to immune checkpoint blockade therapy (CBT). Early-phase clinical trial results have demonstrated the remarkable effectiveness of CBT in specific lymphoma subtypes, including classical Hodgkin lymphoma (cHL) and primary mediastinal B cell lymphoma (PMBL). Conversely, CBT has been relatively disappointing in follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL). These clinical observations, coupled with important scientific discoveries, have uncovered salient features of the lymphoma microenvironment that correlate with immunotherapy response in patients. For example, cHL is characterized by an inflammatory environment, genetic alterations that facilitate escape from immune attack, and sensitivity to PD-1 blockade therapy. On the other hand, for lymphomas in which measures of immune surveillance are lacking, including FL and most DLBCLs, anti-PD-1 therapy has been less effective. An improved understanding of the immune landscapes of these lymphomas is needed to define subsets that might benefit from CBT. In this article, we describe the immune environments associated with major B cell lymphomas with an emphasis on the immune escape pathways orchestrated by these diseases. We also discuss how oncogenic alterations in lymphoma cells may affect the cellular composition of the immune environment and ultimately, vulnerability to CBT. Finally, we highlight key areas for future investigation, including the need for the development of biomarkers that predict for sensitivity to CBT in lymphoma patients.

    更新日期:2019-11-01
  • Paraneoplastic thrombocytosis: the secrets of tumor self-promotion.
    Blood (IF 16.562) Pub Date : 2014-05-29
    Richard J Lin,Vahid Afshar-Kharghan,Andrew I Schafer

    Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival. Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation. Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis. Taken together, these findings provide exciting new potential targets for therapeutic intervention.

    更新日期:2019-11-01
  • From Budd-Chiari syndrome to acquired von Willebrand syndrome: thrombosis and bleeding complications in the myeloproliferative neoplasms.
    Blood (IF 16.562) Pub Date : null
    Brady L Stein,Karlyn Martin

    Thrombotic and hemorrhagic complications are prevalent in patients with essential thrombocythemia, polycythemia vera, and myelofibrosis. Given the impact on morbidity and mortality, reducing the risk of thrombosis and/or hemorrhage is a major therapeutic goal. Historically, patients have been risk stratified on the basis of traditional factors, such as advanced age and thrombosis history. However, multiple factors contribute to the thrombotic tendency, including gender, mutational profile, inflammatory stress, and abnormal cell adhesion. Management includes cardiovascular risk reduction and use of antiplatelet therapy, depending on myeloproliferative neoplasm subtype and mutational status. Anticoagulation is a mainstay of therapy for those with venous thrombosis, but practice patterns remain heterogeneous. Cytoreduction is indicated for higher-risk patients, but efficacy may depend on the involved vascular bed. Management of special situations, such as unusual site thrombosis, bleeding, the perioperative period, and pregnancy, are especially challenging. In this article, risk factors and treatment strategies for myeloproliferative neoplasm thrombosis and bleeding, including special situations, are reviewed. Insights gained from recent studies may lead to the development of a more precise risk classification and tailored therapy.

    更新日期:2019-11-01
  • Platelets and cancer-associated thrombosis: focusing on the platelet activation receptor CLEC-2 and podoplanin.
    Blood (IF 16.562) Pub Date : null
    Katsue Suzuki-Inoue

    Patients with cancer have an increased risk of thromboembolism, which is the second leading cause of death in these patients. Several mechanisms of the prothrombotic state in these patients have been proposed. Among them are a platelet activation receptor, C-type lectin-like receptor 2 (CLEC-2), and its endogenous ligand podoplanin, which are the focus of this review. CLEC-2 is almost specifically expressed in platelets/megakaryocytes in humans. A membrane protein, podoplanin is expressed in certain types of cancer cells, including squamous cell carcinoma, brain tumor, and osteosarcoma, in addition to several normal tissues, including kidney podocytes and lymphatic endothelial cells but not vascular endothelial cells. In the bloodstream, podoplanin induces platelet activation by binding to CLEC-2 and facilitates hematogenous cancer metastasis and cancer-associated thrombosis. In an experimental lung metastasis model, the pharmacological depletion of CLEC-2 from platelets in mice resulted in a marked reduction of lung metastasis of podoplanin-expressing B16F10 cells. Control mice with B16F10 orthotopically inoculated in the back skin showed massive thrombus formation in the lungs, but the cancer-associated thrombus formation in CLEC-2-depleted mice was significantly inhibited, suggesting that CLEC-2-podoplanin interaction stimulates cancer-associated thrombosis. Thromboinflammation induced ectopic podoplanin expression in vascular endothelial cells or macrophages, which may also contribute to cancer-associated thrombosis. CLEC-2 depletion in cancer-bearing mice resulted in not only reduced cancer-associated thrombosis but also reduced levels of plasma inflammatory cytokines, anemia, and sarcopenia, suggesting that cancer-associated thrombosis may cause thromboinflammation and cancer cachexia. Blocking CLEC-2-podoplanin interaction may be a novel therapeutic strategy in patients with podoplanin-expressing cancer.

    更新日期:2019-11-01
  • Infectious mononucleosis affecting sinonasal mucosa.
    Blood (IF 16.562) Pub Date : null
    Elham Vali Betts,Regina Gandour-Edwards

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Engraftment in utero: it's all in the delivery.
    Blood (IF 16.562) Pub Date : null
    Allistair A Abraham,Dana Block-Abraham

    更新日期:2019-11-01
  • Platelet alloantibody detection: moving ahead.
    Blood (IF 16.562) Pub Date : null
    Adrian R Wilkie,Joseph E Italiano

    更新日期:2019-11-01
  • Killing the minotaur in its amazing maze.
    Blood (IF 16.562) Pub Date : null
    Daniela S Krause

    更新日期:2019-11-01
  • TFPI blockade: removing coagulation's brakes.
    Blood (IF 16.562) Pub Date : null
    Robert F Sidonio,Karen L Zimowski

    更新日期:2019-11-01
  • CLL: deep dive for residual cells by NGS matters.
    Blood (IF 16.562) Pub Date : null
    Clemens-Martin Wendtner

    更新日期:2019-11-01
  • Cardiovascular adverse events of ibrutinib.
    Blood (IF 16.562) Pub Date : null
    Inhye E Ahn

    更新日期:2019-11-01
  • Bioengineered iPSC-derived megakaryocytes for the detection of platelet-specific patient alloantibodies.
    Blood (IF 16.562) Pub Date : 2019-11-08
    Nanyan Zhang,Sentot Santoso,Richard H Aster,Brian R Curtis,Peter J Newman

    Human platelet membrane glycoprotein polymorphisms can be immunogenic in man and are frequently the cause of clinically important immune reactions responsible for disorders such as neonatal alloimmune thrombocytopenia. Platelets from individuals carrying rare polymorphisms are often difficult to obtain, making diagnostic testing and transfusion of matched platelets challenging. In addition, class I HLA antibodies frequently present in maternal sera interfere with the detection of platelet-reactive alloantibodies. Detection of alloantibodies to human platelet antigen 3 (HPA-3) and HPA-9 is especially challenging, in part because of the presence of cell type-specific glycans situated near the polymorphic amino acid that together form the alloepitope. To overcome these limitations, we generated a series of HLA class I-negative blood group O induced pluripotent stem cell (iPSC) lines that were gene edited to sequentially convert their endogenous HPA-3a alloantigenic epitope to HPA-3b, and HPA-9a to HPA-9b. Subjecting these cell lines, upon differentiation into CD41+/CD42b+ human megakaryocytes (MKs), to flow cytometric detection of suspected anti-HPA-3 and HPA-9 alloantisera revealed that the HPA-3a-positive MKs specifically reacted with HPA-3a patient sera, whereas the HPA-3b MKs lost reactivity with HPA-3a patient sera while acquiring reactivity to HPA-3b patient sera. Importantly, HPA-9b-expressing MKs specifically reacted with anti-HPA-9b-suspected patient samples that had been undetectable using conventional techniques. The provision of specialized iPSC-derived human MKs expressing intact homozygous glycoprotein alloantigens on the cell surface that carry the appropriate endogenous carbohydrate moieties should greatly enhance detection of clinically important and rare HPA-specific alloantibodies that, to date, have resisted detection using current methods.

    更新日期:2019-11-01
  • Epigenetic therapies in acute myeloid leukemia: where to from here?
    Blood (IF 16.562) Pub Date : 2019-11-08
    Katie A Fennell,Charles C Bell,Mark A Dawson

    A hallmark of acute myeloid leukemia (AML) is epigenetic dysregulation, which is initiated by recurrent translocations and/or mutations in transcription factors and chromatin regulators. This manifests as a block in myeloid differentiation and an increase in malignant self-renewal. These common features of AML have led to widespread optimism that epigenetic therapies would dramatically change the natural history of this disease. Although preclinical studies with these drugs fueled this optimism, results from early clinical trials have offered a more sobering message. Here, we provide an overview of epigenetic therapies that are currently approved by therapeutic regulatory authorities across the world and those undergoing early-phase clinical trials. We also discuss the conceptual and molecular factors that may explain some of the disparity between the bench and bedside, as well as emerging avenues for combining the current generation of epigenetic therapies with other classes of agents and the development of novel epigenetic therapies. With further research and development of this exciting class of drugs, we may finally be able to dramatically improve outcomes for patients afflicted with this aggressive and often incurable malignancy.

    更新日期:2019-11-01
  • A role for macrophages in hematopoiesis in the embryonic head.
    Blood (IF 16.562) Pub Date : 2019-11-08
    Zhuan Li,Samanta A Mariani,Carmen Rodriguez-Seoane,Wenyan He,Xiaowei Ning,Bing Liu,Chris S Vink,Elaine Dzierzak

    Along with the aorta-gonad-mesonephros region, the head is a site of hematopoietic stem and progenitor cell (HS/PC) development in the mouse embryo. Macrophages are present in both these embryonic hemogenic sites, and recent studies indicate a functional interaction of macrophages with hematopoietic cells as they are generated in the aorta. Whereas brain macrophages or "microglia" are known to affect neuronal patterning and vascular circuitry in the embryonic brain, it is unknown whether macrophages play a role in head hematopoiesis. Here, we characterize head macrophages and examine whether they affect the HS/PC output of the hindbrain-branchial arch (HBA) region of the mouse embryo. We show that HBA macrophages are CD45+F4/80+CD11b+Gr1- and express the macrophage-specific Csf1r-GFP reporter. In the HBA of chemokine receptor-deficient (Cx3cr1-/-) embryos, a reduction in erythropoiesis is concomitant with a decrease in HBA macrophage percentages. In cocultures, we show that head macrophages boost hematopoietic progenitor cell numbers from HBA endothelial cells > twofold, and that the proinflammatory factor tumor necrosis factor-α is produced by head macrophages and influences HBA hematopoiesis in vitro. Taken together, head macrophages play a positive role in HBA erythropoiesis and HS/PC expansion and/or maturation, acting as microenvironmental cellular regulators in hematopoietic development.

    更新日期:2019-11-01
  • Hypertension and incident cardiovascular events following ibrutinib initiation.
    Blood (IF 16.562) Pub Date : 2019-10-05
    Tyler Dickerson,Tracy Wiczer,Allyson Waller,Jennifer Philippon,Kyle Porter,Devin Haddad,Avirup Guha,Kerry A Rogers,Seema Bhat,John C Byrd,Jennifer A Woyach,Farrukh Awan,Daniel Addison

    Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, it has been linked with potentially limiting cardiotoxicity, including emerging reports of profound hypertension (HTN). The long-term incidence, severity, and impact of HTN development with ibrutinib are unknown. Therefore, in 562 consecutive patients treated with ibrutinib for B-cell malignancies from 2009 through 2016, we assessed the new/incident or worsened HTN (systolic blood pressure [BP] cutoff, 130 mm Hg). Observed incident HTN rates were compared with Framingham-heart-predicted incident HTN rates. We also evaluated the relationship of HTN to the development of other major adverse cardiovascular events (MACEs), including arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the effects of different antihypertensive classes on ibrutinib-related HTN. Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months. New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months. Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg). In multivariate regression, new or worsened HTN was associated with increased MACEs (hazard ratio [HR], 2.17; 95% confidence interval [CI], 1.08-4.38). No single antihypertensive class was associated with prevention or control of ibrutinib-related HTN. However, antihypertensive initiation was associated with a lower risk of a MACE (HR, 0.40; 95% CI, 0.24-0.66). Collectively, these data suggest that ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.

    更新日期:2019-11-01
  • Donor cell engineering with GSK3 inhibitor-loaded nanoparticles enhances engraftment after in utero transplantation.
    Blood (IF 16.562) Pub Date : 2019-10-02
    Stavros P Loukogeorgakis,Camila G Fachin,Andre I B S Dias,Haiying Li,Li Tang,Aimee G Kim,Jesse D Vrecenak,John D Stratigis,Nicholas J Ahn,Ilana Nissim,Izhtak Nissim,Antonio F Moron,Jose L Martins,William H Peranteau,Paolo De Coppi,Darrell J Irvine,Alan W Flake

    Host cell competition is a major barrier to engraftment after in utero hematopoietic cell transplantation (IUHCT). Here we describe a cell-engineering strategy using glycogen synthase kinase-3 (GSK3) inhibitor-loaded nanoparticles conjugated to the surface of donor hematopoietic cells to enhance their proliferation kinetics and ability to compete against their fetal host equivalents. With this approach, we achieved remarkable levels of stable, long-term hematopoietic engraftment for up to 24 weeks post-IUHCT. We also show that the salutary effects of the nanoparticle-released GSK3 inhibitor are specific to donor progenitor/stem cells and achieved by a pseudoautocrine mechanism. These results establish that IUHCT of hematopoietic cells decorated with GSK3 inhibitor-loaded nanoparticles can produce therapeutic levels of long-term engraftment and could therefore allow single-step prenatal treatment of congenital hematological disorders.

    更新日期:2019-11-01
  • The architecture of the IgG anti-carbohydrate repertoire in primary antibody deficiencies.
    Blood (IF 16.562) Pub Date : 2019-09-21
    Peter Jandus,Kayluz Frias Boligan,David F Smith,Elisabeth de Graauw,Bodo Grimbacher,Camilla Jandus,Mai M Abdelhafez,Alain Despont,Nicolai Bovin,Dagmar Simon,Robert Rieben,Hans-Uwe Simon,Richard D Cummings,Stephan von Gunten

    Immune system failure in primary antibody deficiencies (PADs) has been linked to recurrent infections, autoimmunity, and cancer, yet clinical judgment is often based on the reactivity to a restricted panel of antigens. Previously, we demonstrated that the human repertoire of carbohydrate-specific immunoglobulin G (IgG) exhibits modular organization related to glycan epitope structure. The current study compares the glycan-specific IgG repertoires between different PAD entities. Distinct repertoire profiles with extensive qualitative glycan-recognition defects were observed, which are characterized by the common loss of Galα and GalNAc reactivity and disease-specific recognition of microbial antigens, self-antigens, and tumor-associated carbohydrate antigens. Antibody repertoire analysis may provide a useful tool to elucidate the degree and the clinical implications of immune system failure in individual patients.

    更新日期:2019-11-01
  • Minimal residual disease undetectable by next-generation sequencing predicts improved outcome in CLL after chemoimmunotherapy.
    Blood (IF 16.562) Pub Date : 2019-09-21
    Philip A Thompson,Jaya Srivastava,Christine Peterson,Paolo Strati,Jeffrey L Jorgensen,Tyler Hether,Michael J Keating,Susan M O'Brien,Alessandra Ferrajoli,Jan A Burger,Zeev Estrov,Nitin Jain,William G Wierda

    Patients with chronic lymphocytic leukemia (CLL) who achieve blood or bone marrow (BM) undetectable minimal residual disease (U-MRD) status after first-line fludarabine, cyclophosphamide, and rituximab (FCR) have prolonged progression-free survival (PFS), when assessed by an assay with sensitivity 10-4 (MRD4). Despite reaching U-MRD4, many patients, especially those with unmutated IGHV, subsequently relapse, suggesting residual disease <10-4 threshold and the need for more sensitive MRD evaluation. MRD evaluation by next-generation sequencing (NGS) has a sensitivity of 10-6 (MRD6). To better assess the depth of remission following first-line FCR treatment, we used NGS (Adaptive Biotechnologies Corporation) to assess MRD in 62 patients, all of whom had BM U-MRD by multicolor flow cytometry (sensitivity 10-4) at end-of-FCR treatment. Samples from these patients included 57 BM samples, 29 peripheral blood mononuclear cell (PBMC) samples, and 32 plasma samples. Only 27.4% of the 62 patients had U-MRD by NGS. Rate of U-MRD by NGS was lowest in BM (25%), compared with PBMC (55%) or plasma (75%). No patient with U-MRD by NGS in BM or PBMC was MRD+ in plasma. Patients with mutated IGHV were more likely to have U-MRD by NGS at the end of treatment (EOT; 41% vs 13%, P = .02) than those with unmutated IGHV. Median follow-up was 81.6 months. Patients with U-MRD at EOT had superior PFS vs MRD+ patients, regardless of sample type assessed (BM, P = .02, median not reached [NR] vs 67 months; PBMC, P = .02, median NR vs 74 months). More sensitive MRD6 testing increases prognostic discrimination over MRD4 testing.

    更新日期:2019-11-01
  • A KLF4-DYRK2-mediated pathway regulating self-renewal in CML stem cells.
    Blood (IF 16.562) Pub Date : 2019-09-14
    Chun Shik Park,Andrew H Lewis,Taylor J Chen,Cory S Bridges,Ye Shen,Koramit Suppipat,Monica Puppi,Julie A Tomolonis,Paul D Pang,Toni-Ann Mistretta,Leyuan Ma,Michael R Green,Rachel Rau,H Daniel Lacorazza

    Leukemia stem cells are a rare population with a primitive progenitor phenotype that can initiate, sustain, and recapitulate leukemia through a poorly understood mechanism of self-renewal. Here, we report that Krüppel-like factor 4 (KLF4) promotes disease progression in a murine model of chronic myeloid leukemia (CML)-like myeloproliferative neoplasia by repressing an inhibitory mechanism of preservation in leukemia stem/progenitor cells with leukemia-initiating capacity. Deletion of the Klf4 gene severely abrogated the maintenance of BCR-ABL1(p210)-induced CML by impairing survival and self-renewal in BCR-ABL1+ CD150+ lineage-negative Sca-1+ c-Kit+ leukemic cells. Mechanistically, KLF4 repressed the Dyrk2 gene in leukemic stem/progenitor cells; thus, loss of KLF4 resulted in elevated levels of dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (DYRK2), which were associated with inhibition of survival and self-renewal via depletion of c-Myc protein and p53 activation. In addition to transcriptional regulation, stabilization of DYRK2 protein by inhibiting ubiquitin E3 ligase SIAH2 with vitamin K3 promoted apoptosis and abrogated self-renewal in murine and human CML stem/progenitor cells. Altogether, our results suggest that DYRK2 is a molecular checkpoint controlling p53- and c-Myc-mediated regulation of survival and self-renewal in CML cells with leukemic-initiating capacity that can be targeted with small molecules.

    更新日期:2019-11-01
  • Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results.
    Blood (IF 16.562) Pub Date : 2019-08-25
    Amy D Shapiro,Pantep Angchaisuksiri,Jan Astermark,Gary Benson,Giancarlo Castaman,Pratima Chowdary,Hermann Eichler,Victor Jiménez-Yuste,Kaan Kavakli,Tadashi Matsushita,Lone Hvitfeldt Poulsen,Allison P Wheeler,Guy Young,Silva Zupancic-Salek,Johannes Oldenburg

    Results from the main parts (24 weeks) of 2 concizumab phase 2 trials are presented: explorer4 in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI) and explorer5 in HA. The trials aimed to evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate [ABR] at last dose level), with secondary objectives being safety and immunogenicity (assessed as number of adverse events [AEs] and antidrug antibodies [ADAs]). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if ≥3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic (PK/PD) parameters were assessed. Thirty-six HA, 9 HAwI, and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15 of 17; 88.2%) did not escalate the dose; all patients chose to continue to the extension phase of the trials. Clinical proof of concept for prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs HA: 3.0 (95% confidence interval [CI], 1.7; 5.3) and 5.9 (95% CI, 4.2; 8.5) vs 7.0 (95% CI, 4.6; 10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin fragment 1+2, and d-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very low to medium titer) ADA+ tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297.

    更新日期:2019-11-01
  • JAK2ex13InDel drives oncogenic transformation and is associated with chronic eosinophilic leukemia and polycythemia vera.
    Blood (IF 16.562) Pub Date : 2019-11-08
    Ami B Patel,Anca Franzini,Emilie Leroy,Soo Jin Kim,Anthony D Pomicter,Lidvine Genet,Michael Xiao,Dongqing Yan,Jonathan Ahmann,Archana M Agarwal,Phillip Clair,Juanah Addada,Jonathan Lambert,Matthew Salmon,Gerald J Gleich,Nicholas C P Cross,Stefan Constantinescu,Thomas O'Hare,Josef T Prchal,Michael W Deininger

    The V617F mutation in the JH2 domain of JAK2 is an oncogenic driver in several myeloproliferative neoplasms (MPNs), including essential thrombocythemia, myelofibrosis, and polycythemia vera (PV). Other mutations in JAK2 have been identified in MPNs, most notably exon 12 mutations in PV. Here, we describe a novel recurrent mutation characterized by a common 4-amino acid deletion and variable 1-amino acid insertion (Leu583-Ala586DelInsSer/Gln/Pro) within the JH2 domain of JAK2. All four affected patients had eosinophilia, and both patients with Leu583-Ala586DelInsSer fulfilled diagnostic criteria of both PV and chronic eosinophilic leukemia (CEL). Computational and functional studies revealed that Leu583-Ala586DelInsSer (herein referred to as JAK2ex13InDel) deregulates JAK2 through a mechanism similar to JAK2V617F, activates STAT5 and ERK and transforms parental Ba/F3 cells to growth factor independence. In contrast to JAK2V617F, JAK2ex13InDel does not require an exogenous homodimeric type 1 cytokine receptor to transform Ba/F3 cells, and is capable of activating β common chain family cytokine receptor (IL-3R, IL-5R, granulocyte-macrophage colony stimulating factor receptor) signaling in the absence of ligand, with the maximum effect observed for IL-5R, consistent with the clinical phenotype of eosinophilia. Recognizing this new PV/CEL overlap MPN has significant clinical implications, as both PV and CEL patients are at high risk for thrombosis, and concomitant cytoreduction of red cells, neutrophils and eosinophils may be required for prevention of thromboembolic events. Targeted next-generation sequencing for genes recurrently mutated in myeloid malignancies in patients with unexplained eosinophilia may reveal additional cases of Leu583-Ala586DelInsSer/Gln/Pro, allowing for complete characterization of this unique MPN.

    更新日期:2019-11-01
  • Novel severe hemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and BRCC3 genes.
    Blood (IF 16.562) Pub Date : 2014-06-21
    Szymon Janczar,Anna Fogtman,Marta Koblowska,Dobromila Baranska,Agata Pastorczak,Olga Wegner,Magdalena Kostrzewska,Pawel Laguna,Maciej Borowiec,Wojciech Mlynarski

    更新日期:2019-11-01
  • E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia.
    Blood (IF 16.562) Pub Date : 2003-10-18
    Rebecca J Greenwald,Joseph R Tumang,Anupama Sinha,Nicolas Currier,Robert D Cardiff,Thomas L Rothstein,Douglas V Faller,Gerald V Denis

    Transgenic mice with lymphoid-restricted overexpression of the double bromodomain protein bromodomain-containing 2 (Brd2) develop splenic B-cell lymphoma and, upon transplantation, B-cell leukemia with leukemic infiltrates in liver and lung. Brd2 is a nuclear-localized transcription factor kinase that is most closely related to TATA box binding protein-associated factor, 250 kDa (TAF(II)250) and the Drosophila developmental protein female sterile homeotic. Constitutive expression of BRD2 in the lymphoid compartment increases cyclin A transcription, "priming" transgenic B cells for proliferation. Mice stochastically develop an aggressive B-cell lymphoma with the features of B-1 cells, including CD5 and surface IgM expression. The B-cell lymphoma is monoclonal for immunoglobulin gene rearrangement and is phenotypically stable. The lymphoblasts are very large and express a transcriptome that is similar to human non-Hodgkin lymphomas. Both a wild-type BRD2 transgene and a kinase-null point mutant drive lymphomagenesis; therefore we propose that, rather than kinase activity, Brd2-mediated recruitment of E2 promoter binding factors (E2Fs) and a specific histone acetyltransferase to the cyclin A promoter by both types of transgene is a mechanistic basis for neoplasia. This report is the first to describe a transgenic mouse model for constitutive expression of a protein with more than one bromodomain.

    更新日期:2019-11-01
  • Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL.
    Blood (IF 16.562) Pub Date : null
    Camille Laurent,Alina Nicolae,Cécile Laurent,Fabien Le Bras,Corinne Haioun,Virginie Fataccioli,Nadia Amara,José Adélaïde,Arnaud Guille,Jean-Marc Schiano,Bruno Tesson,Alexandra Traverse-Glehen,Marie-Pierre Chenard,Lénaïg Mescam,Anne Moreau,Catherine Chassagne-Clement,Joan Somja,Fréderic Escudié,Marc André,Nadine Martin,Laetitia Lacroix,François Lemonnier,Anne-Sophie Hamy-Petit,Fabien Reyal,Marie Bannier,Lucie Oberic,Nais Prade,François-Xavier Frénois,Asma Beldi-Ferchiou,Marie-Helene Delfau-Larue,Reda Bouabdallah,Daniel Birnbaum,Pierre Brousset,Luc Xerri,Philippe Gaulard

    The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor, 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole exome sequencing (n=22, with paired tumor/germline DNA) and/or targeted deep sequencing (n=24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%) and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and tri-methylation by immunohistochemistry. Twenty cases (59%) showed mutations in at least one member of the JAK/STAT pathway including STAT3 (38%), JAK1 (18%), STAT5B (3%) and in negative regulators like SOCS3 (6%), SOCS1 (3%) and PTPN1 (3%). These mutations were more frequent in tumor-type than in situ samples (p=0.038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in JAK/STAT pathway. Mutations in EOMES gene (12%) involved in lymphocytes development, PI3K-AKT/mTOR (6%) and loss of function mutations in TP53 (12%) were also identified. Copy number aberration (CNA) analysis identified recurrent alterations including gains on chromosomes 2, 9p, 12p and 21 and losses on 4q, 8p, 15, 16 and 20. Regions of CNA encompassed genes involved in JAK/STAT pathway and epigenetic regulators. Our results show that BI-ALCL genomic landscape is not only characterized by JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.

    更新日期:2019-11-01
  • Structural variants of IFNα preferentially promote antiviral functions.
    Blood (IF 16.562) Pub Date : 2011-07-16
    Nancy Vázquez,Hana Schmeisser,Michael A Dolan,Joseph Bekisz,Kathryn C Zoon,Sharon M Wahl

    IFNα, a cytokine with multiple functions in innate and adaptive immunity and a potent inhibitor of HIV, exerts antiviral activity, in part, by enhancing apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 (APOBEC3) family members. Although IFNα therapy is associated with reduced viral burden, this cytokine also mediates immune dysfunction and toxicities. Through detailed mapping of IFNα receptor binding sites, we generated IFNα hybrids and mutants and determined that structural changes in the C-helix alter the ability of IFN to limit retroviral activity. Selective IFNα constructs differentially block HIV replication and their directional magnitude of inhibition correlates with APOBEC3 levels. Importantly, certain mutants exhibited reduced toxicity as reflected by induced indoleamine 2,3-dioxygenase (IDO), suggesting discreet and shared intracellular signaling pathways. Defining IFN structure and function relative to APOBEC and other antiviral genes may enable design of novel IFN-related molecules preserving beneficial antiviral roles while minimizing negative effects.

    更新日期:2019-11-01
  • Recurrent BRAF mutations in Langerhans cell histiocytosis.
    Blood (IF 16.562) Pub Date : 2010-06-04
    Gayane Badalian-Very,Jo-Anne Vergilio,Barbara A Degar,Laura E MacConaill,Barbara Brandner,Monica L Calicchio,Frank C Kuo,Azra H Ligon,Kristen E Stevenson,Sarah M Kehoe,Levi A Garraway,William C Hahn,Matthew Meyerson,Mark D Fleming,Barrett J Rollins

    Langerhans cell histiocytosis (LCH) has a broad spectrum of clinical behaviors; some cases are self-limited, whereas others involve multiple organs and cause significant mortality. Although Langerhans cells in LCH are clonal, their benign morphology and their lack (to date) of reported recurrent genomic abnormalities have suggested that LCH may not be a neoplasm. Here, using 2 orthogonal technologies for detecting cancer-associated mutations in formalin-fixed, paraffin-embedded material, we identified the oncogenic BRAF V600E mutation in 35 of 61 archived specimens (57%). TP53 and MET mutations were also observed in one sample each. BRAF V600E tended to appear in younger patients but was not associated with disease site or stage. Langerhans cells stained for phospho-mitogen-activated protein kinase kinase (phospho-MEK) and phospho-extracellular signal-regulated kinase (phospho-ERK) regardless of mutation status. High prevalence, recurrent BRAF mutations in LCH indicate that it is a neoplastic disease that may respond to RAF pathway inhibitors.

    更新日期:2019-11-01
  • Interleukin-27 inhibition of HIV-1 involves an intermediate induction of type I interferon.
    Blood (IF 16.562) Pub Date : 2009-06-27
    Teresa Greenwell-Wild,Nancy Vázquez,Wenwen Jin,Zoila Rangel,Peter J Munson,Sharon M Wahl

    Infection of CD4(+) chemokine coreceptor(+) targets by HIV is aided and abetted by the proficiency of HIV in eliminating or neutralizing host cell-derived defensive molecules. Among these innate protective molecules, a family of intracellular apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases, is constitutively expressed but inactivated by HIV viral infectivity factor. The ability of interferon-alpha (IFN-alpha) to augment cytidine deaminases offered the possibility that the balance between virus and target cell might be altered in favor of the host. Further characterization of transcriptional profiles induced by IFN-alpha using microarrays, with the intention to identify and dissociate retroviral countermaneuvers from associated toxicities, revealed multiple molecules with suspected antiviral activity, including IL-27. To establish whether IFN-alpha toxicity might be sidestepped through the use of downstream IL-27 against HIV, we examined whether IL-27 directly regulated cytidine deaminases. Although IL-27 induces APOBECs, it does so in a delayed fashion. Dissecting the underlying regulatory events uncovered an initial IL-27-dependent induction of IFN-alpha and/or IFN-beta, which in turn, induces APOBEC3, inhibited by IFN-alpha/beta receptor blockade. In addition to macrophages, the IL-27-IFN-alpha connection is operative in CD4(+) T cells, consistent with an IFN-alpha-dependent pathway underlying host cell defense to HIV.

    更新日期:2019-11-01
  • SHD1 is a novel cytokine-inducible, negative feedback regulator of STAT5-dependent transcription.
    Blood (IF 16.562) Pub Date : 2008-10-08
    Hideaki Nakajima,Toshiki Tamura,Miyuki Ito,Fumi Shibata,Kana Kuroda,Yumi Fukuchi,Naohide Watanabe,Toshio Kitamura,Yasuo Ikeda,Makoto Handa

    STAT5 is a critical mediator of a variety of cytokine signaling whose transcriptional activity is regulated by associating with various proteins. During a search for STAT5-interacting proteins, we identified SHD1, a mammalian homologue of yeast gene Sac3, as a potential interacter. SHD1 was localized in the nucleus, and induced by cytokines that activate STAT5, such as erythropoietin, interleukin-2 (IL-2), or IL-3. SHD1 interacted specifically with STAT5A and STAT5B, and interestingly, it specifically repressed STAT5-dependent transcription in vitro without affecting the stability or phosphorylation of STAT5 protein. Gene disruption study revealed that T, B, or bone marrow cells from mice lacking SHD1 were hyperresponsive to T-cell-receptor engagement, or stimulation with various STAT5-activating cytokines. These results suggest that SHD1 is a novel cytokine-inducible negative feedback regulator of STAT5.

    更新日期:2019-11-01
  • Myeloid differentiation and susceptibility to HIV-1 are linked to APOBEC3 expression.
    Blood (IF 16.562) Pub Date : 2007-03-21
    Gang Peng,Teresa Greenwell-Wild,Salvador Nares,Wenwen Jin,Ke Jian Lei,Zoila G Rangel,Peter J Munson,Sharon M Wahl

    HIV-1 recognition by, interaction with, and/or infection of CD4(+)CCR5(+) tissue macrophages and dendritic cells (DCs) play important roles in HIV-1 transmission and pathogenesis. By comparison, circulating CD4(+)CCR5(+) monocytes appear relatively resistant to HIV-1, and a fundamental unresolved question involves deciphering restriction factors unique to this precursor population. Not only do monocytes, relative to macrophages, possess higher levels of the innate resistance factor APOBEC3G, but we uncovered APOBEC3A, not previously associated with anti-HIV activity, as being critical in monocyte resistance. Inversely correlated with susceptibility, silencing of APOBEC3A renders monocytes vulnerable to HIV-1. Differences in promiscuity of monocytes, macrophages, and DCs can be defined, at least partly, by disparities in APOBEC expression, with implications for enhancing cellular defenses against HIV-1.

    更新日期:2019-11-01
  • How I treat acute myeloid leukemia in the era of new drugs.
    Blood (IF 16.562) Pub Date : 2019-11-26
    Courtney D DiNardo,Andrew H Wei

    The treatment landscape for acute myeloid leukemia (AML) has changed substantially since 2017. A host of new targeted drugs have emerged onto the scene, including venetoclax to target BCL-2, midostaurin and gilteritinib to target FLT3 and ivosidenib and enasidenib to target mutant IDH1 and IDH2, respectively. Other additions include re-approval of gemtuzumab ozogomycin to target CD33, glasdegib to target the hedgehog pathway and a liposomal formulation of daunorubicin and cytarabine (CPX-351). AML is genomically heterogeneous and has a tendency to evolve, particularly under selective treatment pressure. For decades, treatment decisions have largely centred around chemotherapy drug intensity. Physicians now have access to an increasing number of drugs with novel mechanisms of action and distinctive side-effect profiles. Key issues faced by haematologists in this era of new drugs include 1) the timely identification of actionable mutations, not just at diagnosis but also at relapse, 2) deciding which drug to use when several therapeutic options are available and 3) the need for increased awareness of how to anticipate, mitigate and manage common complications associated with these new agents. This new addition to the How I Treat series will utilize three case presentations to discuss some of the new treatment challenges encountered in the management of AML, with the goal of providing practical guidance to aid the practising physician.

    更新日期:2019-11-01
  • Chromatin occupancy and epigenetic analysis reveal new insights into the function of the GATA1 N terminus in erythropoiesis.
    Blood (IF 16.562) Pub Date : 2019-08-15
    Te Ling,Yehudit Birger,Monika J Stankiewicz,Nissim Ben-Haim,Tomer Kalisky,Avigail Rein,Eitan Kugler,Wei Chen,Chunling Fu,Kevin Zhang,Hiral Patel,Jacek W Sikora,Young Ah Goo,Neil Kelleher,Lihua Zou,Shai Izraeli,John D Crispino

    Mutations in GATA1, which lead to expression of the GATA1s isoform that lacks the GATA1 N terminus, are seen in patients with Diamond-Blackfan anemia (DBA). In our efforts to better understand the connection between GATA1s and DBA, we comprehensively studied erythropoiesis in Gata1s mice. Defects in yolks sac and fetal liver hematopoiesis included impaired terminal maturation and reduced numbers of erythroid progenitors. RNA-sequencing revealed that both erythroid and megakaryocytic gene expression patterns were altered by the loss of the N terminus, including aberrant upregulation of Gata2 and Runx1. Dysregulation of global H3K27 methylation was found in the erythroid progenitors upon loss of N terminus of GATA1. Chromatin-binding assays revealed that, despite similar occupancy of GATA1 and GATA1s, there was a striking reduction of H3K27me3 at regulatory elements of the Gata2 and Runx1 genes. Consistent with the observation that overexpression of GATA2 has been reported to impair erythropoiesis, we found that haploinsufficiency of Gata2 rescued the erythroid defects of Gata1s fetuses. Together, our integrated genomic analysis of transcriptomic and epigenetic signatures reveals that, Gata1 mice provide novel insights into the role of the N terminus of GATA1 in transcriptional regulation and red blood cell maturation which may potentially be useful for DBA patients.

    更新日期:2019-11-01
  • Identifying and Treating Refractory ITP: Difficulty in Diagnosis and Role of Combination Treatment.
    Blood (IF 16.562) Pub Date : 2019-11-23
    Oriana Miltiadous,Ming Hou,James B Bussel

    Immune Thrombocytopenia (ITP) is the commonest acquired thrombocytopenia after chemotherapy-induced thrombocytopenia. Existing guidelines describe the management and treatment of most patients who overall do well, even if they present with chronic disease, and are usually not at high risk of bleeding. However, a small percentage of patients is refractory and difficult to manage. Patients classified as refractory either have a diagnosis that is not really ITP or have disease that is difficult to manage. ITP is a diagnosis of exclusion; no specific tests exist to confirm the diagnosis. Response to treatment is the only affirmative confirmation of diagnosis. However, refractory patients do not respond to front-line or other treatments, and thus, no confirmation of diagnosis exists. This review carefully evaluates the diagnostic considerations in patients with refractory ITP. The second section describes combination treatment for refractory cases of ITP. The reported combinations are divided into the era before thrombopoietin(TPO) and rituximab and the current era. Current therapy appears to have increased effectiveness. However, the definition of refractory, if it includes insufficient response to TPO agents, describes a group with more severe and difficult to treat disease. The biology of refractory ITP is largely unexplored and includes oligoclonality, lymphocyte pumps, and other possibilities. Newer treatments, especially rapamycin, fostamatinib, FcRn and BTK inhibitors, may be useful components of future therapy given their mechanisms of action but TPO agents, notwithstanding failure as monotherapy, appear to be critical components. In summary, refractory ITP is a complicated entity in which precise, specific diagnosis is as important as development of effective combination treatments.

    更新日期:2019-11-01
  • Common variable immune deficiency: case studies.
    Blood (IF 16.562) Pub Date : 2019-11-22
    Charlotte Cunningham-Rundles

    Common variable immune deficiency (CVID) is one of the most common congenital immune defects encountered in clinical practice. The condition occurs equally in males and females, and most commonly in the 20- to 40-year-old age group. The diagnosis is made by documenting reduced serum concentrations of immunoglobulin G (IgG), IgA, and usually IgM, together with loss of protective antibodies. The genetics of this syndrome are complex and are still being unraveled, but the hallmarks for most patients, as with other immune defects, include acute and chronic infections of the sinopulmonary tract. However, other noninfectious autoimmune or inflammatory conditions may also occur in CVID, and indeed these may be the first and only sign that a significant immune defect is present. These manifestations include episodes of immune thrombocytopenia, autoimmune hemolytic anemia, or neutropenia, in addition to splenomegaly, generalized or worrisome lymphadenopathy, and malignancy, especially lymphoma. These issues commonly bring the patient to the attention of hematologists for both evaluation and treatment. This article discusses 3 cases in which patients with CVID had some of these presenting issues and what hematology input was required.

    更新日期:2019-11-01
  • How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide.
    Blood (IF 16.562) Pub Date : 2019-11-22
    Shannon R McCurdy,Leo Luznik

    HLA-haploidentical hematopoietic stem cell transplantation is now one of the most commonly employed alternative donor techniques, with most centers applying T-cell-replete strategies such as that developed by the Baltimore group using high-dose posttransplant cyclophosphamide. HLA-haploidentical hematopoietic stem cell transplantation using posttransplant cyclophosphamide is associated with low rates of severe graft-versus-host disease and nonrelapse mortality and does not require graft manipulation or storage, which results in a low graft acquisition cost. Its remarkable safety when used with reduced-intensity conditioning has been demonstrated in patients up to 75 years old with outcomes similar to those of patients in their 50s. Several large, registry-based retrospective studies have confirmed the efficacy of HLA-haploidentical hematopoietic stem cell transplantation with posttransplant cyclophosphamide, achieving results comparable to those of HLA-matched hematopoietic stem cell transplantation. In this article, we describe our approach to this rapidly available and clinically simple platform and address some of the key clinical questions associated with its use.

    更新日期:2019-11-01
  • Treatment-naive CLL: lessons from phase 2 and phase 3 clinical trials.
    Blood (IF 16.562) Pub Date : 2019-11-22
    Jennifer A Woyach

    The management of chronic lymphocytic leukemia (CLL) has undergone dramatic changes over the previous 2 decades with the introduction of multiple new therapies and new combinations. Management of the newly diagnosed asymptomatic patient has not significantly changed outside of the development of a number of prognostic factors and the CLL International Prognostic Index, which is helpful in discussions regarding prognosis and likelihood of requiring treatment. When therapy is required, initial treatment of most patients now includes either the Bruton tyrosine kinase inhibitor ibrutinib or the B-cell lymphoma 2 inhibitor venetoclax in combination with obinutuzumab. Current frontline trials are focused on the optimal sequencing or combination of targeted therapies. In this review, we will discuss the management of previously untreated CLL with an emphasis on the clinical trials that have formed the standard of care, as well as those newer studies that are likely to form the next generation of therapy.

    更新日期:2019-11-01
  • Genetic characterization of B-PLL.
    Blood (IF 16.562) Pub Date : 2019-11-22

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • AML with inv(16) with numerous Charcot-Leyden crystals.
    Blood (IF 16.562) Pub Date : 2019-11-22
    Denis M Dwyre,Mohamed Osman

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Sugar thieves and addicts: nutrient subversion in JAK2 MPNs.
    Blood (IF 16.562) Pub Date : 2019-11-22
    Charlotte K Brierley,Bethan Psaila

    更新日期:2019-11-01
  • Eosinophils, atherosclerosis, and thrombosis.
    Blood (IF 16.562) Pub Date : 2019-11-22
    Nigel Mackman

    更新日期:2019-11-01
  • B-cell prolymphocytic leukemia has 3 subsets.
    Blood (IF 16.562) Pub Date : 2019-11-22
    Neil E Kay,Curtis A Hanson

    更新日期:2019-11-01
  • Pivotal role of PDK1 in megakaryocyte cytoskeletal dynamics and polarization during platelet biogenesis.
    Blood (IF 16.562) Pub Date : 2019-10-04
    Sascha Geue,Katja Aurbach,Mailin-Christin Manke,Georgi Manukjan,Patrick Münzer,David Stegner,Caroline Brähler,Britta Walker-Allgaier,Melanie Märklin,Carla E Borst,Leticia Quintanilla-Fend,Dominik Rath,Tobias Geisler,Helmut R Salih,Peter Seizer,Florian Lang,Bernhard Nieswandt,Meinrad Gawaz,Harald Schulze,Irina Pleines,Oliver Borst

    During thrombopoiesis, megakaryocytes (MKs) form proplatelets within the bone marrow (BM) and release platelets into BM sinusoids. Phosphoinositide-dependent protein kinase-1 (PDK1) is required for Ca2+-dependent platelet activation, but its role in MK development and regulation of platelet production remained elusive. The present study explored the role of PDK1 in the regulation of MK maturation and polarization during thrombopoiesis using a MK/platelet-specific knockout approach. Pdk1-deficient mice (Pdk1-/-) developed a significant macrothrombocytopenia as compared with wild-type mice (Pdk1fl/fl). Pdk1 deficiency further dramatically increased the number of MKs without sinusoidal contact within the BM hematopoietic compartment, resulting in a pronounced MK hyperplasia and a significantly increased extramedullary thrombopoiesis. Cultured Pdk1-/- BM-MKs showed impaired spreading on collagen, associated with an altered actin cytoskeleton structure with less filamentous actin (F-actin) and diminished podosome formation, whereas the tubulin cytoskeleton remained unaffected. This phenotype was associated with abrogated phosphorylation of p21-activated kinase (PAK) as well as its substrates LIM domain kinase and cofilin, supporting the hypothesis that the defective F-actin assembly results from increased cofilin activity in Pdk1-deficient MKs. Pdk1-/- BM-MKs developed increased ploidy and exhibited an abnormal ultrastructure with disrupted demarcation membrane system (DMS). Strikingly, Pdk1-/- BM-MKs displayed a pronounced defect in DMS polarization and produced significantly less proplatelets, indicating that PDK1 is critically required for proplatelet formation. In human MKs, genetic PDK1 knockdown resulted in increased maturity but reduced platelet-like particles formation. The present observations reveal a pivotal role of PDK1 in the regulation of MK cytoskeletal dynamics and polarization, proplatelet formation, and thrombopoiesis.

    更新日期:2019-11-01
  • Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.
    Blood (IF 16.562) Pub Date : 2019-09-29
    Matthew Lunning,Julie Vose,Loretta Nastoupil,Nathan Fowler,Jan A Burger,William G Wierda,Marshall T Schreeder,Tanya Siddiqi,Christopher R Flowers,Jonathon B Cohen,Peter Sportelli,Hari P Miskin,Michael S Weiss,Susan O'Brien

    Targeting both CD20 and phosphatidylinositol 3-kinase (PI3K), a protein that is critically involved in B-cell maturation, could be an efficacious strategy for treating B-cell malignancies. The safety of the next-generation compounds umbralisib, a PI3K-δ inhibitor, plus ublituximab, an anti-CD20 monoclonal antibody (combination referred to as U2), was evaluated in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL) in this phase 1/1b study. Phase 1 dose escalation was performed with a 3 + 3 design to establish the maximum tolerated dose. In this portion, ublituximab was given intravenously (NHL, 900 mg; CLL, 600 or 900 mg) for 12 cycles. Umbralisib was given orally once daily at 800 or 1200 mg (initial formulation) or 400 to 1200 mg (micronized formulation) in the phase 1 dose escalation portion, and at 800 to 1200 mg in the phase 1b portion until progression, toxicity, or study removal. The maximum tolerated dose was not reached in either the CLL or NHL cohort, and only 1 dose-limiting toxicity was observed. U2 had low instances of grade 3 or higher diarrhea (8%), pneumonia (8%), or hepatic toxicity (4%). Treatment discontinuation due to adverse events occurred in 13% of patients, and umbralisib dose reductions occurred in 15% of patients. The overall response rate for all patients was 46% with 17% complete responses. The median duration of response was 20 months (95% confidence interval, 11.3-not reached). U2 was well tolerated, and no new safety signals were observed over single-agent umbralisib. Preliminary efficacy with this combination is promising and warrants further investigation. This study was registered at www.clinicaltrials.gov as #NCT02006485.

    更新日期:2019-11-01
  • CAR T cell viability release testing and clinical outcomes: is there a lower limit?
    Blood (IF 16.562) Pub Date : 2019-09-27
    Elise A Chong,Bruce L Levine,Stephan A Grupp,Megan M Davis,Don L Siegel,Shannon L Maude,Whitney L Gladney,Noelle V Frey,David L Porter,Wei-Ting Hwang,Emeline R Chong,Carl H June,Stephen J Schuster

    更新日期:2019-11-01
  • Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53.
    Blood (IF 16.562) Pub Date : 2019-09-19
    Elise Chapiro,Elodie Pramil,M'boyba Diop,Damien Roos-Weil,Clémentine Dillard,Clémentine Gabillaud,Karim Maloum,Catherine Settegrana,Lucile Baseggio,Jean-François Lesesve,Mélanie Yon,Ludovic Jondreville,Claude Lesty,Frédéric Davi,Magali Le Garff-Tavernier,Nathalie Droin,Philippe Dessen,Caroline Algrin,Véronique Leblond,Jean Gabarre,Simon Bouzy,Virginie Eclache,Baptiste Gaillard,Evelyne Callet-Bauchu,Marc Muller,Christine Lefebvre,Nathalie Nadal,Antoine Ittel,Stéphanie Struski,Marie-Agnès Collonge-Rame,Benoit Quilichini,Sandra Fert-Ferrer,Nathalie Auger,Isabelle Radford-Weiss,Lena Wagner,Sebastian Scheinost,Thorsten Zenz,Santos A Susin,Olivier A Bernard,Florence Nguyen-Khac

    B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.

    更新日期:2019-11-01
  • JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms.
    Blood (IF 16.562) Pub Date : 2019-09-13
    Tata Nageswara Rao,Nils Hansen,Julian Hilfiker,Shivam Rai,Julia-Magdalena Majewska,Danijela Leković,Deniz Gezer,Nicola Andina,Serena Galli,Teresa Cassel,Florian Geier,Julien Delezie,Ronny Nienhold,Hui Hao-Shen,Christian Beisel,Serena Di Palma,Sarah Dimeloe,Jonel Trebicka,Dominik Wolf,Max Gassmann,Teresa W-M Fan,Andrew N Lane,Christoph Handschin,Stefan Dirnhofer,Nicolaus Kröger,Christoph Hess,Thomas Radimerski,Steffen Koschmieder,Vladan P Čokić,Radek C Skoda

    Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.

    更新日期:2019-11-01
  • Eosinophil-platelet interactions promote atherosclerosis and stabilize thrombosis with eosinophil extracellular traps.
    Blood (IF 16.562) Pub Date : 2019-09-05
    Charlotte Marx,Julia Novotny,Danby Salbeck,Katie R Zellner,Leo Nicolai,Kami Pekayvaz,Badr Kilani,Sven Stockhausen,Niklas Bürgener,Danny Kupka,Thomas J Stocker,Ludwig T Weckbach,Joachim Pircher,Markus Moser,Michael Joner,Walter Desmet,Tom Adriaenssens,Franz-Josef Neumann,Anthony H Gerschlick,Jurrien M Ten Berg,Michael Lorenz,Konstantin Stark

    Clinical observations implicate a role of eosinophils in cardiovascular diseases because markers of eosinophil activation are elevated in atherosclerosis and thrombosis. However, their contribution to atherosclerotic plaque formation and arterial thrombosis remains unclear. In these settings, we investigated how eosinophils are recruited and activated through an interplay with platelets. Here, we provide evidence for a central importance of eosinophil-platelet interactions in atherosclerosis and thrombosis. We show that eosinophils support atherosclerotic plaque formation involving enhanced von Willebrand factor exposure on endothelial cells and augmented platelet adhesion. During arterial thrombosis, eosinophils are quickly recruited in an integrin-dependent manner and engage in interactions with platelets leading to eosinophil activation as we show by intravital calcium imaging. These direct interactions induce the formation of eosinophil extracellular traps (EETs), which are present in human thrombi and constitute a substantial part of extracellular traps in murine thrombi. EETs are decorated with the granule protein major basic protein, which causes platelet activation by eosinophils. Consequently, targeting of EETs diminished thrombus formation in vivo, which identifies this approach as a novel antithrombotic concept. Finally, in our clinical analysis of coronary artery thrombi, we identified female patients with stent thrombosis as the population that might derive the greatest benefit from an eosinophil-inhibiting strategy. In summary, eosinophils contribute to atherosclerotic plaque formation and thrombosis through an interplay with platelets, resulting in mutual activation. Therefore, eosinophils are a promising new target in the prevention and therapy of atherosclerosis and thrombosis.

    更新日期:2019-11-01
  • Predicting success of desensitization after pegaspargase allergy.
    Blood (IF 16.562) Pub Date : null
    Hope D Swanson,John Carl Panetta,Patricia J Barker,Yiwei Liu,Hiroto Inaba,Mary V Relling,Ching-Hon Pui,Seth E Karol

    更新日期:2019-11-01
  • HDAC11 Deficiency or Inhibition Disrupts Oncogene-Induced Stress Hematopoiesis in Myeloproliferative Neoplasms.
    Blood (IF 16.562) Pub Date : null
    Lanzhu Yue,Vasundhara Sharma,Nathan P Horvat,Afua A Akuffo,Matthew S Beatty,Cem Murdun,Christelle Colin,Julia Billington,William E Goodheart,Eva Sahakian,Ling Zhang,John J Powers,Narmin E Amin,Que T Lambert-Showers,Lancia N Darville,Javier Pinilla-Ibarz,Gary Reuther,Kenneth Wright,Chiara Conti,Jennifer Y Lee,Xiaozhang Zheng,Pui Yee Ng,Matthew W Martin,C Gary Marshall,John M Koomen,Ross L Levine,Amit Verma,H Leighton Grimes,Eduardo M Sotomayor,Zonghong Shao,Pearlie K Epling-Burnette

    Protein acetylation is an important contributor to cancer initiation. Histone deacetylase 6 (HDAC6) controls JAK2 translation and protein stability, and has been implicated in JAK2-driven diseases best exemplified by Myeloproliferative Neoplasms (MPNs). Using novel classes of highly selective HDAC inhibitors and genetically deficient mouse models, here we report that HDAC11 rather than HDAC6 is necessary for the proliferation and survival of oncogenic JAK2-driven MPN cells and patient samples. Notably, HDAC11 is variably expressed in primitive stem cells and is expressed largely upon lineage commitment. While dispensable for normal homeostatic hematopoietic stem and progenitor cell differentiation based on chimeric BM reconstitution, Hdac11 deficiency significantly reduced the abnormal megakaryocyte population, improved splenic architecture, reduced fibrosis and increased survival in the MPLW515L-MPN mouse model during primary and secondary transplantation. Therefore, inhibitors of HDAC11 are an attractive therapy for treating MPN patients. While JAK2 inhibitor therapy provides substantial clinical benefit in MPN patients, the identification of alternative therapeutic targets is needed to reverse MPN pathogenesis and control malignant hematopoiesis. This work establishes HDAC11 as a unique type of target molecule having therapeutic potential in MPN.

    更新日期:2019-11-01
  • A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis.
    Blood (IF 16.562) Pub Date : 2017-05-28
    Vaishali Sanchorawala,Giovanni Palladini,Vishal Kukreti,Jeffrey A Zonder,Adam D Cohen,David C Seldin,Angela Dispenzieri,Arnaud Jaccard,Stefan O Schönland,Deborah Berg,Huyuan Yang,Neeraj Gupta,Ai-Min Hui,Raymond L Comenzo,Giampaolo Merlini

    This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902 A phase 3 study is ongoing (#NCT01659658).

    更新日期:2019-11-01
  • Therapeutic regulatory T-cell adoptive transfer ameliorates established murine chronic GVHD in a CXCR5-dependent manner.
    Blood (IF 16.562) Pub Date : 2016-07-08
    Cameron McDonald-Hyman,Ryan Flynn,Angela Panoskaltsis-Mortari,Nicholas Peterson,Kelli P A MacDonald,Geoffrey R Hill,Leo Luznik,Jonathan S Serody,William J Murphy,Ivan Maillard,David H Munn,Laurence A Turka,John Koreth,Corey S Cutler,Robert J Soiffer,Joseph H Antin,Jerome Ritz,Bruce R Blazar

    Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. In cGVHD, alloreactive T cells and germinal center (GC) B cells often participate in GC reactions to produce pathogenic antibodies. Although regulatory T cells (Tregs) can inhibit GC reactions, Treg numbers are reduced in cGVHD, contributing to cGVHD pathogenesis. Here, we explored 2 means to increase Tregs in cGVHD: interleukin-2/monoclonal antibody (IL-2/mAb) complexes and donor Treg infusions. IL-2/mAb complexes given over 1 month were efficacious in expanding Tregs and treating established cGVHD in a multi-organ-system disease mouse model characterized by GC reactions, antibody deposition, and lung dysfunction. In an acute GVHD (aGVHD) model, IL-2/mAb complexes given for only 4 days resulted in rapid mortality, indicating IL-2/mAb complexes can drive conventional T-cell (Tcon)-mediated injury. In contrast, Treg infusions, which uniformly suppress aGVHD, increased Treg frequency and were effective in preventing the onset of, and treating, established cGVHD. Efficacy was dependent upon CXCR5-sufficient Tregs homing to, and inhibiting, GC reactions. These studies indicate that the infusion of Tregs, especially ones enriched for GC homing, may be desirable for cGVHD therapy. Although IL-2/mAb complexes can be efficacious in cGVHD, a cautious approach needs to be taken in settings in which aGVHD elements, and associated Tcon, are present.

    更新日期:2019-11-01
  • Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans.
    Blood (IF 16.562) Pub Date : 2014-05-14
    Ryan Flynn,Jing Du,Rachelle G Veenstra,Dawn K Reichenbach,Angela Panoskaltsis-Mortari,Patricia A Taylor,Gordon J Freeman,Jonathan S Serody,William J Murphy,David H Munn,Stefanie Sarantopoulos,Leo Luznik,Ivan Maillard,John Koreth,Corey Cutler,Robert J Soiffer,Joseph H Antin,Jerome Ritz,Jason A Dubovsky,John C Byrd,Kelli P MacDonald,Geoff R Hill,Bruce R Blazar

    Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Having shown that germinal center (GC) formation and immunoglobulin deposition are required for multiorgan system cGVHD and associated bronchiolitis obliterans syndrome (BOS) in a murine model, we hypothesized that T follicular helper (Tfh) cells are necessary for cGVHD by supporting GC formation and maintenance. We show that increased frequency of Tfh cells correlated with increased GC B cells, cGVHD, and BOS. Although administering a highly depletionary anti-CD20 monoclonal antibody (mAb) to mice with established cGVHD resulted in peripheral B-cell depletion, B cells remained in the lung, and BOS was not reversed. BOS could be treated by eliminating production of interleukin-21 (IL-21) by donor T cells or IL-21 receptor (IL-21R) signaling of donor B cells. Development of BOS was dependent upon T cells expressing the chemokine receptor CXCR5 to facilitate T-cell trafficking to secondary lymphoid organ follicles. Blocking mAbs for IL-21/IL-21R, inducible T-cell costimulator (ICOS)/ICOS ligand, and CD40L/CD40 hindered GC formation and cGVHD. These data provide novel insights into cGVHD pathogenesis, indicate a role for Tfh cells in these processes, and suggest a new line of therapy using mAbs targeting Tfh cells to reverse cGVHD.

    更新日期:2019-11-01
  • Naive B-cell trafficking is shaped by local chemokine availability and LFA-1-independent stromal interactions.
    Blood (IF 16.562) Pub Date : 2013-04-06
    Fernanda M Coelho,Daniela Natale,Silvia F Soriano,Miroslav Hons,Jim Swoger,Jürgen Mayer,Renzo Danuser,Elke Scandella,Markus Pieczyk,Hans-Günter Zerwes,Tobias Junt,Andreas W Sailer,Burkhard Ludewig,James Sharpe,Marc Thilo Figge,Jens V Stein

    It is not known how naive B cells compute divergent chemoattractant signals of the T-cell area and B-cell follicles during in vivo migration. Here, we used two-photon microscopy of peripheral lymph nodes (PLNs) to analyze the prototype G-protein-coupled receptors (GPCRs) CXCR4, CXCR5, and CCR7 during B-cell migration, as well as the integrin LFA-1 for stromal guidance. CXCR4 and CCR7 did not influence parenchymal B-cell motility and distribution, despite their role during B-cell arrest in venules. In contrast, CXCR5 played a nonredundant role in B-cell motility in follicles and in the T-cell area. B-cell migration in the T-cell area followed a random guided walk model, arguing against directed migration in vivo. LFA-1, but not α4 integrins, contributed to B-cell motility in PLNs. However, stromal network guidance was LFA-1 independent, uncoupling integrin-dependent migration from stromal attachment. Finally, we observed that despite a 20-fold reduction of chemokine expression in virus-challenged PLNs, CXCR5 remained essential for B-cell screening of antigen-presenting cells. Our data provide an overview of the contribution of prototype GPCRs and integrins during naive B-cell migration and shed light on the local chemokine availability that these cells compute.

    更新日期:2019-11-01
  • CXCL13/CXCR5 signaling enhances BCR-triggered B-cell activation by shaping cell dynamics.
    Blood (IF 16.562) Pub Date : 2011-06-11
    Julia Sáez de Guinoa,Laura Barrio,Mario Mellado,Yolanda R Carrasco

    Continuous migration of B cells at the follicle contrasts with their stable arrest after encounter with antigen. Two main ligand/receptor pairs are involved in these cell behaviors: the chemokine CXCL13/chemokine receptor CXCR5 and antigen/BCR. Little is known regarding the interplay between CXCR5 and BCR signaling in the modulation of B-cell dynamics and its effect on B-cell activation. We used a 2-dimensional model to study B-cell migration and antigen recognition in real time, and found that BCR signaling strength alters CXCL13-mediated migration, leading to a heterogeneous B-cell behavior pattern. In addition, we demonstrate that CXCL13/CXCR5 signaling does not impair BCR-triggered immune synapse formation and that CXCR5 is excluded from the central antigen cluster. CXCL13/CXCR5 signaling enhances BCR-mediated B-cell activation in at least 2 ways: (1) it assists antigen gathering at the synapse by promoting membrane ruffling and lymphocyte function-associated antigen 1 (LFA-1)-supported adhesion, and (2) it allows BCR signaling integration in motile B cells through establishment of LFA-1-supported migratory junctions. Both processes require functional actin cytoskeleton and non-muscle myosin II motor protein. Therefore, the CXCL13/CXCR5 signaling effect on shaping B-cell dynamics is an effective mechanism that enhances antigen encounter and BCR-triggered B-cell activation.

    更新日期:2019-11-01
  • Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities.
    Blood (IF 16.562) Pub Date : 2008-11-21
    Fouad Eddahri,Sébastien Denanglaire,Fabrice Bureau,Rosanne Spolski,Warren J Leonard,Oberdan Leo,Fabienne Andris

    The conditions leading to the activation/differentiation of T-helper (Th) cells dedicated for B-cell antibody production are still poorly characterized. We now demonstrate that interleukin-6 (IL-6) promotes the differentiation of naive T lymphocytes into helper cells able to promote B-cell activation and antibody secretion. IL-6-driven acquisition of B-cell help capacity requires expression of the signal transducer and activator of transcription 3 (STAT3), but not STAT4 or STAT6 transcription factors, suggesting that the ability to provide help to B cells is not restricted to a well-defined Th1 or Th2 effector population. T cell-specific STAT3-deficient mice displayed reduced humoral responses in vivo that could not be related to an altered expansion of CXCR5-expressing helper T cells. IL-6 was shown to promote IL-21 secretion, a cytokine that was similarly found to promote the differentiation of naive T cells into potent B-cell helper cells. Collectively, these data indicate that the ability to provide B-cell help is regulated by IL-6/IL-21 through STAT3 activation, independently of Th1, Th2, Th17, or follicular helper T cell (T(FH)) differentiation.

    更新日期:2019-11-01
  • The peritoneal micromilieu commits B cells to home to body cavities and the small intestine.
    Blood (IF 16.562) Pub Date : 2007-02-10
    Simon Berberich,Reinhold Förster,Oliver Pabst

    The distinct combination of homing receptors such as selectins, chemokine receptors, and integrins directs the migration of lymphocytes throughout the body. Upon activation lymphocytes irreversibly switch their set of homing receptors, now guiding them to entirely different destinations. Here we report that exposure of naive B cells to the microenvironment of the peritoneal cavity modulates their migration propensities in the absence of antigenic stimulation. B1 and B2 cells isolated from the peritoneal cavity reenter this compartment more efficiently compared with splenic follicular B cells. Moreover, when kept in the peritoneal cavity splenic follicular B cells gain such increased capability to reenter this compartment. These altered migratory capacities are reflected by an up-regulation of the chemokine receptors CXCR4 and CXCR5 and beta7 integrin by the peritoneum-experienced splenic B cells, among which CXCR5 is instrumental in directing B cells into the peritoneal cavity. Moreover, intraperitoneal transfer of plasma blasts favors their migration into the small intestine presumably before class switch recombination occurs, demonstrating that a reconfigured transient migration pattern is not restricted to naive cells. In conclusion, these data demonstrate a hitherto unrecognized role for tissue-specific cues, altering the migratory capacity of B1, naive B2, as well as antigen-experienced B2 cells.

    更新日期:2019-11-01
  • Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help.
    Blood (IF 16.562) Pub Date : 2005-05-19
    Svenja Hardtke,Lars Ohl,Reinhold Förster

    The production of high-affinity antibodies to T-dependent antigens requires the interaction of B cells and T helper cells expressing receptors specific for the same antigen. Although several mechanisms have been elucidated that regulate B-cell trafficking within lymphoid organs, less is known about molecular cues that guide the small subpopulation of CD4+ follicular T helper cells to B-cell follicles. Using adoptive transfer of transgenic T cells in mice, we demonstrate that antigen-induced activation leads to a finely tuned positioning of T cells either to the T-cell area or the B-cell follicle. We show that expression of CXCR5 is indispensable for T cells to enter B-cell follicles, whereas expression of CCR7 provides a counteracting signal to retain activated T cells in the T-cell area. Although only few T cells transiently migrate from the T-cell area to the B-cell follicle of peripheral lymph nodes following antigenic challenge, this step is essential to provide the help B cells require to produce antibodies efficiently. Thus, we demonstrate that the balanced expression of CCR7 and CXCR5 determines the positioning and proper function of follicular T helper cells.

    更新日期:2019-11-01
  • Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a.
    Blood (IF 16.562) Pub Date : 2005-04-30
    Bin Zhang,John Groffen,Nora Heisterkamp

    Resistance to cytotoxic drugs frequently emerges during treatment of leukemia with conventional chemotherapy. New classes of anticancer drugs, such as the farnesyltransferase inhibitors (FTIs), show therapeutic promise, but whether cells will easily develop resistance against them is not known. Here, we grew breakpoint cluster region/Abelson murine leukemia (Bcr/Abl) P190 lymphoblasts on stroma and made them resistant to the FTI SCH66336/lonafarnib to model emerging drug resistance in a patient. These cells exhibited greatly increased (> 100-fold) expression levels of a novel ATP (adenosine triphosphate)-binding cassette (ABC) transporter-homologous gene, ATP11A. We showed that overexpression of this gene provided protection against the effects of SCH66336, whereas knockdown of endogenous ATP11a using small interfering RNA (siRNA) made cells more sensitive to this drug. The lymphoblasts that were resistant to this FTI were also more resistant to FTI-276 and to GGTI-298, 2 other structurally similar inhibitors. Surprisingly, the cells were also able to survive higher concentrations of imatinib mesylate, the Bcr/Abl tyrosine kinase inhibitor. However, the cells remained sensitive to vincristine. Our results show that elevated levels of ATP11a can protect malignant lymphoblastic leukemia cells against several novel small molecule signal transduction inhibitors. A determination of the expression levels of this gene may have prognostic value when treatment with such classes of drugs is contemplated.

    更新日期:2019-11-01
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