Genevieve Marcoux, Audrée Laroche, Stephan Hasse, Marie Bellio, Maroua Mbarik, Marie Tamagne, Isabelle Allaeys, Anne Zufferey, Tania Lévesque, Johan Rebetz, Annie Karakeussian-Rimbaud, Julie Turgeon, Sylvain G Bourgoin, Hind Hamzeh-Cognasse, Fabrice Cognasse, Rick Kapur, John W Semple, Marie-Josée Hebert, France Pirenne, Herman Overkleeft, Bogdan Florea, Mélanie Dieude, Benoit Vingert, Eric Boilard
In addition to their hemostatic role, platelets play a significant role in immunity. Once activated, platelets release extracellular vesicles (EVs) formed by budding of their cytoplasmic membranes. Because of their heterogeneity, platelet EVs (PEVs) are thought to perform diverse functions. It is unknown, however, whether the proteasome is transferred from platelets to PEVs or whether its function is retained. We hypothesized that functional protein processing and antigen presentation machinery is transferred to PEVs by activated platelets...
July 22, 2021: Blood
Marit Jalink, Sigbjørn Berentsen, Jorge Castillo, Steven P P Treon, Marjan Cruijsen, Bruno Fattizzo, Ramona Cassin, Despina Fotiou, Efstathios Kastritis, Masja de de Haas, Liesbeth E M Oosten, Henrik Frederiksen, Andrea Patriarca, Shirley D'Sa, Josephine M I Vos
No abstract text is available yet for this article.
July 22, 2021: Blood
Michele Cavo, Jesus F F San-Miguel, Saad Z Usmani, Katja C Weisel, Meletios A A Dimopoulos, Hervé Avet-Loiseau, Bruno Paiva, Nizar J Bahlis, Torben Plesner, Vania Tietsche de Moraes Hungria, Philippe Moreau, Maria Victoria Mateos, Aurore Perrot, Shinsuke Iida, Thierry Facon, Shaji K Kumar, Niels W C J van de Donk, Pieter Sonneveld, Andrew Spencer, Maria Krevvata, Christoph Heuck, Jianping Wang, Jon Ukropec, Rachel Kobos, Steven Sun, Mia Qi, Nikhil C Munshi
We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible newly diagnosed multiple myeloma (TIE NDMM) using data from four phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD-negativity rates and reduced the risk of disease progression or death by approximately half versus standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response (CR) or better with MRD-negative status, and progression-free survival (PFS)...
July 21, 2021: Blood
Hardikkumar Jetani, Almudena Navarro-Bailón, Marius Maucher, Silke Frenz, Christina Mathilde Verbruggen, Ana Yeguas, María-Belén Vidriales, Marcos González, Judit Rial Saborido, Sabrina Kraus, Katrin Mestermann, Simone Thomas, Halvard Bonig, Maik Luu, Razieh Monjezi, Dimitrios Mougiakakos, Markus Sauer, Hermann Einsele, Michael Hudecek
Acute myeloid leukemia (AML) is attractive for the development of CAR T-cell immunotherapy because AML blasts are susceptible to T-cell-mediated elimination. Here, we introduce sialic-acid-binding immunoglobulin-like lectin (Siglec)-6 as a novel target for CAR T-cells in AML. We designed a Siglec-6-specific CAR with a targeting-domain derived from a human monoclonal antibody JML‑1. We found that Siglec-6 is prevalently expressed on AML cell lines and primary AML blasts, including the subpopulation of AML stem cells...
July 21, 2021: Blood
Steven P P Treon, Kirsten E Meid, Zachary R Hunter, Catherine Flynn, Shayna Sarosiek, Carly Leventoff, Timothy P White, Yang Cao, Aldo Roccaro, Antonio Sacco, Maria Demos, Maria Luisa Guerrera, Amanda Kofides, Xia Liu, Lian Xu, Christopher J Patterson, Manit Munshi, Nicholas Tsakmaklis, Guang Yang, Irene M Ghobrial, Andrew R Branagan, Jorge Castillo
MYD88 and CXCR4 mutations are common in Waldenström Macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a Phase I trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/day with Cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1-6, with a 3+3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, nine treatment-naive were enrolled...
July 21, 2021: Blood
Elena Tonc, Yoshiko Takeuchi, Chun Chou, Yu Xia, Melanie Holmgren, Chika Fujii, Saravanan Raju, Gue Su Chang, Masahiro Iwamoto, Takeshi Egawa
The proliferative burst of B lymphocytes is essential for antigen receptor repertoire diversification during the development and selective expansion of antigen-specific clones during immune responses. High proliferative activity inevitably promotes oncogenesis, the risk of which is further elevated in B lymphocytes by endogenous gene rearrangement and somatic mutations. However, B cell-derived cancers are rare, perhaps owing to putative intrinsic tumor-suppressive mechanisms. We show that c-MYC not only facilitates B cell proliferation as a pro-tumorigenic driver but unexpectedly also co-engages counteracting tumor suppression through its downstream factor TFAP4...
July 20, 2021: Blood
Miriam Butler, Dorette S van Ingen Schenau, Jiangyan Yu, Silvia Jenni, Maria Pamela Dobay, Rico Hagelaar, Britt M T Vervoort, Trisha M Tee, Fieke W Hoff, Jules P Meijerink, Steven M Kornblau, Beat Bornhauser, Jean-Pierre Bourquin, Roland P Kuiper, Laurens T van der Meer, Frank N van Leeuwen
Asparaginase (ASNase) therapy has been a mainstay of Acute Lymphoblastic Leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we employed a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's Tyrosine Kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc mediated suppression of GCN2 activity...
July 19, 2021: Blood
Christian Augsberger, Gerulf Hänel, Wei Xu, Vesna Pulko, Lydia Jasmin Hanisch, Angelique Augustin, John Challier, Katharina Hunt, Binje Vick, Pier Edoardo Rovatti, Christina Krupka, Maurine Rothe, Anne Schönle, Johannes Sam, Emmanuelle Lezan, Axel Ducret, Daniela Ortiz-Franyuti, Antje-Christine Walz, Jörg Benz, Alexander Bujotzek, Felix S Lichtenegger, Christian Gassner, Alejandro Carpy, Victor Lyamichev, Jigar Patel, Nikola P Konstandin, Antje Tunger, Marc Schmitz, Michael von Bergwelt-Baildon, Karsten Spiekermann, Luca Vago, Irmela Jeremias, Estelle Marrer-Berger, Pablo Umaña, Christian Klein, Marion Subklewe
Antibody-based immunotherapy is a promising strategy for targeting chemo-resistant leukemic cells. However, classical antibody-based approaches are restricted to targeting lineage-specific cell-surface antigens. By targeting intracellular antigens, a large number of other leukemia-associated targets would become accessible. In this study, we evaluated a novel T-cell bispecific (TCB) antibody, generated using CrossMab and knob-into-holes technology, containing a bivalent T-cell receptor-like binding domain that recognizes the RMFPNAPYL peptide derived from the intracellular tumor antigen Wilms' tumor 1 (WT1) in the context of human leukocyte antigen (HLA) A*02...
July 19, 2021: Blood
Andreas Greinacher, Kathleen Selleng, Julia Mayerle, Raghavendra Palankar, Jan Wesche, Sven Reiche, Andrea Aebischer, Theodore E Warkentin, Maximilian Muenchhoff, Johannes Christian Hellmuth, Oliver Keppler, Daniel Duerschmied, Achim Lother, Siegbert Rieg, Meinrad Gawaz, Karin Anne Lydia Mueller, Christian Scheer, Matthias Napp, Klaus Hahnenkamp, Guglielmo Lucchese, Antje Vogelgesang, Agnes Floeel, Piero Lovreglio, Angela Stufano, Rolf Marschalek, Thomas Thiele
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and COVID-19 vaccine Janssen (Ad26.COV2.S), and associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcgRIIa receptors. Antibodies activating platelets through FcgRIIa receptors have also been identified in COVID-19 patients. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4...
July 19, 2021: Blood
Jesus F San-Miguel, Hervé Avet-Loiseau, Bruno Paiva, Shaji K Kumar, Meletios A A Dimopoulos, Thierry Facon, Maria-Victoria Mateos, Cyrille Touzeau, Andrzej J Jakubowiak, Saad Z Usmani, Gordon Cook, Michele Cavo, Hang Quach, Jon Ukropec, Priya Ramaswami, Huiling Pei, Mia Qi, Steven Sun, Jianping Wang, Maria Krevvata, Nikki DeAngelis, Christoph Heuck, Rian Van Rampelbergh, Anupa Kudva, Rachel Kobos, Ming Qi, Nizar J Bahlis
In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone; D-Rd) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone; D-VMP). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better, and after ≥CR at 12, 18, 24, and 30 months from the first dose...
July 16, 2021: Blood
Amanda Casto, Sachiko Seo, David Levine, Barry E Storer, Xinyuan Dong, John A Hansen, Michael Boeckh, Paul J Martin
Human cytomegalovirus (CMV) reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Despite routine screening for CMV reactivation and early antiviral treatment, the rates of CMV-related complications after HCT remain high. Genetic variants in both the donor and recipient have been associated with the risk of CMV reactivation and disease after HCT, but these associations have not been validated and their clinical importance remains unclear. In this study, we assessed 117 candidate variants previously associated with CMV-related phenotypes for association with CMV reactivation and disease in a cohort of 2169 CMV-seropositive HCT recipients...
July 16, 2021: Blood
Izumi Yanatori, Des R Richardson, Herschel Shrikant Dhekne, Shinya Toyokuni, Fumio Kishi
Extracellular vesicles (EVs) transfer functional molecules between cells. CD63 is a widely recognized EV marker that contributes to EV secretion from cells. However, the regulation of its expression remains largely unknown. Ferritin is a cellular iron storage protein that can be also secreted by the exosome pathway (Truman-Rosentsvit M. et al. BLOOD 131 (2018) 342-352), with serum ferritin levels classically reflecting body iron stores. Iron metabolism-associated proteins, such as ferritin, are intricately regulated by cellular iron levels via the iron responsive element (IRE)-iron regulatory protein (IRP) system...
July 15, 2021: Blood
Corey S Cutler, Stephanie J Lee, Sally Arai, Marcello Rotta, Behyar Zoghi, Aleksandr Lazaryan, Aravind Ramakrishnan, Zachariah DeFilipp, Amandeep Salhotra, Wanxing Chai-Ho, Rohtesh S Mehta, Trent Wang, Mukta Arora, Iskra Pusic, Ayman Saad, Nirav N Shah, Sunil Abhyankar, Carlos Bachier, John Patrick Galvin, Annie Im, Amelia Langston, Jane L Liesveld, Mark Juckett, Aaron Logan, Levanto Schachter, Asaf Alavi, Dianna S Howard, Harlan Waksal, John Ryan, David Eiznhamer, Sanjay Kumar Aggarwal, Jonathan Ieyoub, Olivier Schueller, Laurie Suzanne Green, Zhongming Yang, Heidi Krenz, Madan Jagasia, Bruce R Blazar, Steven Z Pavletic
Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant...
July 15, 2021: Blood
Judith Trotman, Andrew R Pettitt
18F-fluorodeoxyglucose (FDG) Positron Emission Tomography-Computerised Tomography (PET) is now established as the gold-standard imaging modality for both staging and response assessment of follicular lymphoma (FL). In this Perspective, we propose where PET can, and cannot, guide clinicians in their therapeutic approach. PET at diagnosis/pre-treatment is important for staging, with greater sensitivity compared to standard CT and consequent improved outcomes in truly limited stage FL. Small datasets suggesting a high baseline SUVmax identifies de-novo histologic transformation (HT) are not corroborated by data from GALLIUM, the largest prospective study using modern therapies for FL...
July 14, 2021: Blood
Yanchuan Li, Xiaoping Xie, Zuliang Jie, Lele Zhu, Jin-Young Yang, Chun-Jung Ko, Tianxiao Gao, Antrix Jain, Sung Yun Jung, Natalia Baran, Marina Y Konopleva, Xuhong Cheng, Shao-Cong Sun
B cell-activating factor (BAFF) mediates B cell survival and, when deregulated, also contributes to autoimmune diseases and B cell malignancies. The mechanism connecting BAFF receptor (BAFFR) signal to downstream pathways and pathophysiological functions is not well understood. Here we identified DYRK1a as a kinase that responds to BAFF stimulation and mediates BAFF-induced B cell survival. B cell-specific DYRK1a deficiency causes peripheral B cell reduction and ameliorates autoimmunity in a mouse model of lupus...
July 13, 2021: Blood
Anna Galli, Gabriele Todisco, Eulalia Catamo, Cinzia Sala, Chiara Elena, Sara Pozzi, Elisa Bono, Virginia V Ferretti, Ettore Rizzo, Elisabetta Molteni, Silvia Zibellini, Martina Sarchi, Emanuela Boveri, Jacqueline Ferrari, Nicolas Fiorelli, Clara Camaschella, Paolo Gasparini, Daniela Toniolo, Mario Cazzola, Luca Malcovati
Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that are associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n=355) or with unexplained anemia (n=177), and 592 patients with overt MN...
July 13, 2021: Blood
Yue Sheng, Jiangbo Wei, Fang Yu, Huanzhou Xu, Chunjie Yu, Qiong Wu, Yin Liu, Lei Li, Xiao-Long Cui, Xueying Gu, Bin Shen, Wei Li, Yong Huang, Sumita Bhaduri-Mcintosh, Chuan He, Zhijian Qian
YTHDC1 has distinct functions as a nuclear N6-methyladenosine (m6A) reader in regulating RNA metabolism. Here we show that YTHDC1 is overexpressed in Acute Myeloid Leukemia (AML) and that it is required for proliferation and survival of human AML cells. Genetic deletion of Ythdc1 markedly blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo in mice. We find that Ythdc1 is also required for normal hematopoiesis and hematopoietic stem/progenitor cell (HSPC) maintenance in vivo...
July 13, 2021: Blood
Vandana Chaturvedi, Nora Lakes, Minh H Tran, Natalie Castillo, Michael B Jordan
Hemophagocytic lymphohistiocytosis (HLH) is an inflammatory disorder in which numerous cytokines are elevated, though interferon gamma (IFN-g) is central to disease pathogenesis and a key therapeutic target. Experimental and early clinical reports have shown that ruxolitinib, a small molecule inhibitor of Janus kinases (JAKs) which are essential for cytokine signaling, may be therapeutic in HLH. In contrast, we found that intermittently administered ruxolitinib at various dose levels failed to prevent HLH development or treat established murine HLH...
July 7, 2021: Blood
Allistair A Abraham, John F Tisdale
Gene therapy as a potential cure for sickle cell disease (SCD) has long been pursued given that this hemoglobin disorder results from a single point mutation. Advances in genomic sequencing, increased understanding of hemoglobin regulation and discoveries of molecular tools for genome modification of hematopoietic stem cells have made gene therapy for SCD possible. Gene addition strategies using gene transfer vectors have been optimized over the last few decades to enable expression of normal or anti-sickling globins as strategies to ameliorate SCD...
July 7, 2021: Blood
Zhonghao Wang, Rui Guo, Stephen J Trudeau, Emma Wolinsky, Tsliil Ast, Jin-Hua Liang, Chang Jiang, Yijie Ma, Mingxiang Teng, Vamsi Mootha, Ben Gewurz
Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma, the leading childhood cancer in sub-Saharan Africa. Burkitt cells retain aspects of germinal center B-cell physiology with MYC-driven B-cell hyperproliferation, yet little is presently known about their iron metabolism. CRISPR/Cas9 analysis highlighted the little studied ferrireductase CYB561A3 as critical for Burkitt proliferation, but not for that of closely related EBV-transformed lymphoblastoid cells or nearly all other Cancer Dependency Map cell lines...
July 7, 2021: Blood
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