Huiying Han, Gao Fan, Sha Song, Yunxin Jiang, Chen'ao Qian, Weimin Zhang, Qi Su, Xiaofeng Xue, Wenzhuo Zhuang, Bingzong Li
The initiation and progression of diffuse large B-cell lymphoma (DLBCL) is governed by genetic and epigenetic aberrations. As the most abundant eukaryotic message RNA modification, N6-methyladenosine (m6A) is known to influence various fundamental bioprocesses by regulating target gene; however, the function of m6A modifications in DLBCL is unclear. PIWI-interacting RNAs (piRNAs) have been indicated to be epigenetic effectors in cancer. Here, we show that high expression of piRNA-30473 supports the aggressive phenotype of DLBCL, and piRNA-30473 depletion decreases proliferation and induces cell cycle arrest in DLBCL cells...
September 23, 2020: Blood
Jordan Gauthier, Evandro D Bezerra, Alexandre V Hirayama, Salvatore Fiorenza, Alyssa Sheih, Cassie K Chou, Erik L Kimble, Barbara S Pender, Reed M Hawkins, Aesha Vakil, Tinh-Doan Phi, Rachel N Steinmetz, Abby W Jamieson, Merav Bar, Ryan Cassaday, Aude Chapuis, Andrew J Cowan, Damian J Green, Hans-Peter Kiem, Filippo Milano, Mazyar Shadman, Brian Till, Stanley R Riddell, David G Maloney, Cameron J Turtle
CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (ALL, n=14; CLL, n=9; NHL, n=21) who received CART2 on a phase 1/2 trial at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 CRS, 9%; grade ≥3 neurotoxicity, 11%)...
September 23, 2020: Blood
David D W Twa, Derrick G Lee, King L Tan, Graham W Slack, Susana Ben-Neriah, Diego Villa, Joseph M Connors, Laurie H Sehn, Anja Mottok, Randy D Gascoyne, David W Scott, Christian Steidl, Kerry J Savage
No abstract text is available yet for this article.
September 23, 2020: Blood
Xianchi Dong, Timothy A Springer
No abstract text is available yet for this article.
September 22, 2020: Blood
Yasunobu Nagata, Ran Zhao, Hassan Awada, Cassandra M Kerr, Inom Mirzaev, Sunisa Kongkiatkamon, Aziz Nazha, Hideki Makishima, Tomas Radivoyevitch, Jacob G Scott, Mikkael A Sekeres, Brian P Hobbs, Jaroslaw P Maciejewski
Morphological interpretation is the standard in diagnosing myelodysplastic syndrome (MDS), but it has limitations, such as varying reliability in pathologic evaluation and lack of integration with genetic data. Somatic events shape morphologic features, but the complexity of morphologic and genetic changes make clear associations challenging. This article interrogates novel clinical subtypes of MDS using a machine learning technique devised to identify patterns of co-occurrence among morphologic features and genomic events...
September 22, 2020: Blood
Clementine Sarkozy, Stacy S Hung, Elizabeth A Chavez, Gerben Duns, Katsuyoshi Takata, Lauren C Chong, Tomohiro Aoki, Aixiang Jiang, Tomoko Miyata-Takata, Adèle Telenius, Graham W Slack, Thierry Jo Molina, Susana Ben-Neriah, Pedro Farinha, Peggy Dartigues, Diane Damotte, Anja Mottok, Gilles Andre Salles, Rene-Olivier Casasnovas, Kerry J Savage, Camille Laurent, David W Scott, Alexandra Traverse-Glehen, Christian Steidl
The mutational landscape of grey zone lymphoma (GZL) has not yet been established and differences to related entities are largely unknown. Here, we studied coding sequence mutations of 50 EBV-negative GZL and 20 polymorphic EBV-positive DLBCL NOS (poly-EBV-L) in comparison to classical Hodgkin lymphoma (cHL), primary mediastinal large B cell lymphoma (PMBCL), and diffuse large B cell lymphoma (DLBCL). Exomes of 21 GZL and 7 poly-EBV-L cases along with paired normals were analyzed as a discovery cohort followed by targeted sequencing of 217 genes in an extension cohort of 29 GZL and 13 poly-EBV-L cases...
September 22, 2020: Blood
Peter Miller, Adam S Sperling, Christopher James Gibson, Kaushik Viswanathan, Cecilia Anne Castellano, Marie E McConkey, John J Ceremsak, Martin S Taylor, Sebastian Birndt, Florian Perner, Jon E Arnason, Mridul Agrawal, Alison Schram, Sarah Nikiforow, German Pihan, Robert P Hasserjian, Jon C Aster, Paul La Rosée, Elizabeth A Morgan, Nancy Berliner, Benjamin L Ebert
Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Though numerous precipitating etiologies have been identified, the reason that HLH only occurs in a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH...
September 22, 2020: Blood
Sebastian Oberbeck, Alexandra Schrader, Kathrin Warner, Dennis Jungherz, Giuliano Crispatzu, Jana von Jan, Markus Chmielewski, Aleksandr Ianevski, Hans H Diebner, Petra Mayer, Aichatou Kondo Ados, Linus Wahnschaffe, Till Braun, Tony A Müller, Prerana Wagle, Alyssa Bouska, Tom Neumann, Sabine Pützer, Lesley Varghese, Natali Pflug, Martin Thelen, Jennifer Makalowski, Nicole Riet, Hedwig Julia Maria Göx, Gunter Rappl, Janine Altmüller, Michaela Kotrova, Thorsten Persigehl, Georg Hopfinger, Martin L Hansmann, Hans Schlößer, Stephan Stilgenbauer, Jan Dürig, Dimitrios Mougiakakos, Michael von Bergwelt-Baildon, Ingo Roeder, Sylvia Hartmann, Michael Hallek, Richard H Moriggl, Monika Brüggemann, Tero Aittokallio, Javeed Iqbal, Sebastian Newrzela, Hinrich Abken, Marco Herling
T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell-leukemia-1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular post-thymic T-cells. We assessed here activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent non-canonical patterns...
September 21, 2020: Blood
Fieke W Hoff, Anneke D van Dijk, Yi Hua Qiu, Peter P Ruvolo, Robert B Gerbing, Amanda R Leonti, Gaye N Jenkins, Alan S Gamis, Richard Aplenc, E Anders Kolb, Todd Alonzo, Soheil Meshinchi, Eveline De Bont, Sophia Wm Bruggeman, Steven M Kornblau, Terzah M Horton
Bortezomib (BTZ) was recently evaluated in a randomized Phase 3 clinical trial which compared standard chemotherapy (cytarabine, daunorubicin, etoposide; ADE) to standard therapy with BTZ (ADEB) for de novo pediatric acute myeloid leukemia. While the study concluded that BTZ did not improve outcome overall, we examined patient subgroups benefitting from BTZ-containing chemotherapy using proteomic analyses. The proteasome inhibitor BTZ disrupts protein homeostasis and activates cytoprotective heat shock responses...
September 21, 2020: Blood
Thomas Hueso, Cécile Pouderoux, Hélène Péré, Anne-Lise Beaumont, Laure-Anne Raillon, Florence Ader, Lucienne Chatenoud, Déborah Eshagh, Tali-Anne Szwebel, Martin Martinot, Fabrice Camou, Etienne Crickx, Marc Michel, Matthieu Mahevas, David Boutboul, Elie Azoulay, Adrien Joseph, Olivier Hermine, Claire Rouzaud, Stanislas Faguer, Philippe Petua, Fanny Pommeret, Sébastien Clerc, Benjamin Planquette, Fatiha Merabet, Jonathan London, Valérie Zeller, David Ghez, David Veyer, Amani Ouedrani, Pierre Gallian, Jérôme Pacanowski, Arsène Mékinian, Marc Garnier, France Pirenne, Pierre Tiberghien, Karine Lacombe
Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2-antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative IgG-IgM SARS-CoV-2 serology and a positive RNAemia measured by digital PCR who were treated with four units of COVID-19 convalescent plasma...
September 21, 2020: Blood
Franck Morschhauser, Pierre Feugier, Ian W Flinn, Robin Gasiorowski, Richard Greil, Arpad Illes, Nathalie A Johnson, Jean-François Larouche, Pieternella J Lugtenburg, Caterina Patti, Gilles Andre Salles, Marek Trneny, Sven de Vos, Farheen Mir, Divya Samineni, Su Young Kim, Yanwen Jiang, Elizabeth Punnoose, Arijit Sinha, Emma Clark, Nathalie Spielewoy, Kathryn Humphrey, Alexandra Bazeos, Andrew D Zelenetz
The phase II CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective, B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC-positive). Eligible patients ≥18 years with previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2-5...
September 21, 2020: Blood
Marie Le Cann, Françoise Bouhour, Karine Viala, Laurence Simon, Céline Tard, Cédric Rossi, Guillaume Morel, Emmeline Lagrange, Laurent Magy, Alain Créange, Maud Michaud, Jerome Franques, Andoni Echaniz-Laguna, Jean-Christophe Antoine, Marine Baron, Bertrand Arnulf, Angela Puma, Emilien Delmont, Thierry Maisonobe, Veronique Leblond, Damien Roos-Weil
CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular and/or bulbar motor weakness, in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurological symptoms...
September 21, 2020: Blood
Joseph Hai Oved, Andrew James Paris, Kandace Gollomp, Ning Dai, Kathryn Rubey, Ping Wang, Lynn Spruce, Steven H Seeholzer, Mortimer Poncz, G Scott Worthen
Neutrophils are critical mediators of host defense in pathogen-induced and sterile inflammation. Excessive neutrophil activation has been associated with increased host pathology through collateral organ damage. The beneficial aspects of neutrophil activation, particularly in sterile inflammation, are less well defined. We observed accumulation of nuclear debris in the lungs of neutropenic mice exposed to acid-induced injury compared to wild-type. Size analysis of DNA-debris showed that neutropenic mice were unable to degrade extracellular DNA fragments...
September 21, 2020: Blood
Fatemeh Shahneh, Grill Alexandra, Matthias Klein, Felix Frauhammer, Tobias Bopp, Katrin Schäfer, Verena Raker, Christian Becker
The cells and mechanisms involved in blood clot resorption are only partially known. We show that regulatory T (Treg) cells accumulate in venous blood clots and regulate thrombolysis by controlling the recruitment, differentiation and matrix metalloproteinase (MMP) activity of monocytes. We describe a clot Treg population that forms the matricellular acid- and cysteine-rich protein (SPARC), show that SPARC enhances monocyte MMP activity and that SPARC+ Treg are crucial for blood clot resorption. By comparing different treatment times, we define a therapeutic window of Treg expansion that accelerates clot resorption...
September 15, 2020: Blood
Reiner K Mailer, Mikel Allende, Marco Heestermans, Michaela Schweizer, Carsten Deppermann, Maike Frye, Giordano Pula, Jacob Odeberg, Mathias P Gelderblom, Stefan Rose-John, Albert Sickmann, Stefan Blankenberg, Tobias B Huber, Christian Kubisch, Coen Maas, Stepan Gambaryan, Dimitri Firsov, Evi X Stavrou, Lynn Butler, Thomas Renné
Polyphosphate is a procoagulant inorganic polymer of linear linked orthophosphate residues. Multiple investigations have established the importance of platelet polyphosphate in blood coagulation, however the mechanistic details of polyphosphate homeostasis in mammalian species remain largely undefined. Here, we show that xenotropic and polytropic retrovirus receptor 1 (XPR1) regulates polyphosphate in platelets and is implicated in thrombosis in vivo. We used bioinformatic analyses of omics data to identify XPR1 as a major phosphate transporter in platelets...
September 15, 2020: Blood
Paolo Strati, Preetesh Jain, Ralph J Johnson, Sheryl G Forbes, Lei Feng, Felipe Samaniego, Maria A Rodriguez, Luis E Fayad, Frederick Hagemeister, Jason Westin, Michael L Wang, Sattva S Neelapu, Loretta Nastoupil, Nathan Fowler
No abstract text is available yet for this article.
September 15, 2020: Blood
Leandro Venturutti, Ari Melnick
Activated B-cell (ABC)-Diffuse large B-cell lymphomas (DLBCLs) are clinically aggressive and phenotypically complex malignancies, whose transformation mechanisms remain unclear. Partially differentiated antigen-secreting cells (plasmablasts) have long been regarded as cells-of-origin for these tumors, despite lack of definitive experimental evidence. Recent DLBCL re-classification based on mutational landscapes identified "MCD/C5" tumors as specific ABC-DLBCLs with unfavorable clinical outcome, activating mutations in the signaling adaptors MYD88 and CD79B, and immune evasion through mutation of antigen presenting genes...
September 15, 2020: Blood
Geoffrey L Uy, Ibrahim Aldoss, Matthew C Foster, Peter H Sayre, Matthew J Wieduwilt, Anjali S Advani, John E Godwin, Martha L Arellano, Kendra Sweet, Ashkan Emadi, Farhad Ravandi, Harry P Erba, Michael Byrne, Laura C Michaelis, Max S Topp, Norbert Vey, Fabio Ciceri, Matteo Giovanni Carrabba, Stefania Paolini, Gerwin Huls, Mojca Jongen-Lavrencic, Martin Wermke, Patrice Chevallier, Emmanuel Gyan, Christian Récher, Patrick Stiff, Kristen Pettit, Bob Löwenberg, Sarah Church, Erica Katherine Anderson, Jayakumar Vadakekolathu, Marianne T Santaguida, Michael P Rettig, John Muth, Teia Curtis, Erin Fehr, Kuo Guo, Jian Zhao, Ouiam Bakkacha, Kenneth Jacobs, Kathy Tran, Patrick Kaminker, Maya Kostova, Ezio Bonvini, Roland B Walter, Jan Kenneth Davidson-Moncada, Sergio Rutella, John F DiPersio
Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after <6 months (early relapse, ER). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART® antibody-based molecule to CD3ε and CD123. This study reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in adults with relapsed/refractory AML...
September 14, 2020: Blood
Tao Zhen, Yaqiang Cao, Gang Ren, Ling Zhao, R Katherine Hyde, Guadalupe Lopez, Dechun Feng, Lemlem Alemu, Keji Zhao, P Paul Liu
Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia (AML M4Eo), which generates a CBFB-MYH11 fusion gene. It is generally considered that CBFβ-SMMHC, the fusion protein encoded by CBFB-MYH11, is a dominant negative repressor of RUNX1. However, recent findings challenge the RUNX1-repression model for CBFβ-SMMHC mediated leukemogenesis. To definitively address the role of Runx1 in CBFB-MYH11 induced leukemia, we crossed conditional Runx1 knockout mice (Runx1f/f)with conditional Cbfb-MYH11 knockin mice (Cbfb+/56M)...
September 14, 2020: Blood
Karin Golan, Abhishek K Singh, Orit Kollet, Mayla Bertagna, Mark Althoff, Eman Khatib-Massalha, Ekaterina Petrovich-Kopitman, Ashley Wellendorf, Hassan Massalha, Smadar Levin-Zaidman, Tali Dadosh, Breanna Bohan, Mruniya V Gawali, Biplab Dasgupta, Tsvee Lapidot, Jose A Cancelas
Hematopoietic stem and progenitor cells (HSPC) fate is tightly regulated by their bone marrow (BM) microenvironment (ME). BM transplantation (BMT) frequently requires irradiation pre-conditioning to ablate endogenous hematopoietic cells. Whether the stromal ME is damaged and how it recovers following irradiation is unknown. We report that BM mesenchymal stromal cells (MSC) undergo massive damage to their mitochondrial function following irradiation. Donor healthy HSPC transfer functional mitochondria to the stromal ME, thus improving mitochondria activity in recipient MSC...
September 14, 2020: Blood
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