Blood最新文献

{"title":"Jumping barriers in clinical trials: release the brake.","authors":"Lionel Adès","doi":"10.1182/blood.2024027711","DOIUrl":"https://doi.org/10.1182/blood.2024027711","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 13","pages":"1335-1336"},"PeriodicalIF":21.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Taming JAK cytokine release in haplo-transplant.","authors":"Nikolas von Bubnoff","doi":"10.1182/blood.2024027588","DOIUrl":"https://doi.org/10.1182/blood.2024027588","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 13","pages":"1336-1338"},"PeriodicalIF":21.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE2 signaling in NK cells.","authors":"Charlotte Rothfuß, Tobias Baumann, Sainitin Donakonda, Bettina Brauchle, Anetta Marcinek, Christian Urban, Julia Mergner, Anna-Marie Pedde, Anna Hirschberger, Christina Krupka, Anne-Sophie Neumann, Gerulf Hänel, Camilla Merten, Rupert Öllinger, Judith S Hecker, Tanja Bauer, Christian Schmid, Katharina S Götze, Jennifer Altomonte, Veit Bücklein, Roland Jacobs, Roland Rad, Corina Dawid, Luca Simeoni, Burkhart Schraven, Andreas Pichlmair, Marion Subklewe, Percy A Knolle, Jan P Böttcher, Bastian Höchst","doi":"10.1182/blood.2024025706","DOIUrl":"10.1182/blood.2024025706","url":null,"abstract":"<p><strong>Abstract: </strong>Loss of anticancer natural killer (NK) cell function in patients with acute myeloid leukemia (AML) is associated with fatal disease progression and remains poorly understood. Here, we demonstrate that AML blasts isolated from patients rapidly inhibit NK cell function and escape NK cell-mediated killing. Transcriptome analysis of NK cells exposed to AML blasts revealed increased CREM expression and transcriptional activity, indicating enhanced cyclic adenosine monophosphate (cAMP) signaling, confirmed by uniform production of the cAMP-inducing prostanoid prostaglandin E2 (PGE2) by all AML-blast isolates from patients. Phosphoproteome analysis disclosed that PGE2 induced a blockade of lymphocyte-specific protein tyrosine kinase (LCK)-extracellular signal-regulated kinase signaling that is crucial for NK cell activation, indicating a 2-layered escape of AML blasts with low expression of NK cell-activating ligands and inhibition of NK cell signaling. To evaluate the therapeutic potential to target PGE2 inhibition, we combined Fcγ-receptor-mediated activation with the prevention of inhibitory PGE2 signaling. This rescued NK cell function and restored the killing of AML blasts. Thus, we identify the PGE2-LCK signaling axis as the key barrier for NK cell activation in 2-layered immune escape of AML blasts that can be targeted for immune therapy to reconstitute anticancer NK cell immunity in patients with AML.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1395-1406"},"PeriodicalIF":21.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of new medications on the treatment of immune TTP.","authors":"Marie Scully, Lara Howells, William A Lester","doi":"10.1182/blood.2024026390","DOIUrl":"10.1182/blood.2024026390","url":null,"abstract":"<p><strong>Abstract: </strong>The last decade has seen the introduction of 2 new licensed therapies for thrombotic thrombocytopenic purpura (TTP), caplacizumab and recombinant ADAMTS13 (rADAMTS13), for immune and congenital TTP (cTTP), respectively. They improve acute TTP outcomes, and reduce the need for plasma therapy, time to clinical response, and treatment burden. Future pathways need to replace plasma exchange in acute TTP and optimize/personalize rADAMTS13 in cTTP. Future emphasis should focus on additional monoclonals/treatments to tackle ADAMTS13 antibodies.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1353-1357"},"PeriodicalIF":21.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Pathways in Deep Vein Thrombosis: A New Frontier for Therapeutic Intervention.","authors":"Ivan Budnik, Mariia Kumskova, Anil Chauhan","doi":"10.1182/blood.2024027636","DOIUrl":"https://doi.org/10.1182/blood.2024027636","url":null,"abstract":"<p><p>Venous thromboembolism, which includes deep vein thrombosis (DVT) and pulmonary embolism, is a common cardiovascular disorder associated with significant morbidity and mortality. Current treatment options primarily involve anticoagulants, which reduce the risk of fatal events and DVT recurrence but increase the risk of bleeding, particularly in patients requiring prolonged thromboprophylaxis. Growing evidence characterizes DVT as a complex inflammation-driven process rather than a merely coagulation-dependent thrombosis, with endothelial cells, neutrophils, and platelets playing major roles in its initiation. Recent studies demonstrate that these cell types undergo profound metabolic reprogramming in response to stasis, hypoxia, and inflammatory stimuli, including shifts in glycolysis, the pentose phosphate pathway, and redox balance. This review summarizes current insights into these metabolic adaptations, examines evidence from preclinical DVT models showing that targeting metabolic pathways can reduce venous thrombus formation without impairing hemostasis, and highlights potential metabolic targets for intervention. By modulating metabolic pathways that underlie the prothrombotic and proinflammatory phenotypes, it may be possible to prevent DVT initiation or limit its progression while reducing the reliance on anticoagulants and the risk of associated bleeding complications. This metabolism-centered perspective opens new avenues for the development of safer, more effective treatments for DVT.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based design of therapeutics to control hemostasis.","authors":"Luke Tucker, Krista Hilmas, Ashley Brown","doi":"10.1182/blood.2024025323","DOIUrl":"https://doi.org/10.1182/blood.2024025323","url":null,"abstract":"<p><p>Hemorrhage causes millions of deaths and hundreds of billions of dollars in medical costs every year, and a large percentage of trauma bleeding associated deaths occur in the pre-hospital setting. Bleeding is typically treated with transfused blood products, but this is difficult in the prehospital setting due to limitations in transportation and storage, especially in rural and remote military settings. Advancements in cold-stored platelets and lyophilized blood products have the potential to address some of these limitations. However, devising novel products that continue to improve shelf life, portability, scalability, cost, and safety for patients experiencing bleeding in pre-hospital settings could greatly improve treatment options and patient outcomes. This review primarily focuses on rationale design of material-based approaches to develop novel hemostatic agents that strive to meet limitations of current blood products, especially for use in the pre-hospital setting. Key topics of consideration include how material design can lead to identification of effective therapies that stop bleeding as well as strategies to iterate on existing designs to enhance healing after cessation of bleeding. Improving performance and functionality of existing and emerging materials could be achieved through the incorporation of transglutaminases, growth factors, cellular components, or inorganic molecules. Finally, consideration of patient specific factors that influence bleeding, such as patient sex and age, through evaluation of therapies in specific populations and/or design of materials targeted for specific patient populations is a key area for development of next generation hemostatic materials.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NGS-based IG/TR rearrangement profiling in acute lymphoblastic leukemia: age dependence of immunogenetic maturation.","authors":"Michaela Kotrova, Constantin Proske, Nikos Darzentas, Anna Laqua, Britta Kehden, Jan Christian Kässens, Sonja Bendig, Saskia Kohlscheen, Monika Szczepanowski, Wiebke Wessels, Željko Antić, Christiane Pott, Matthias Ritgen, Jacques J M van Dongen, Nicola Gökbuget, Guranda Chitadze, Anke Bergmann, Lorenz Bastian, Claudia D Baldus, Gunnar Cario, Martin Schrappe, Stefan Schwartz, Julia Alten, Rolf Koehler, Monika Brüggemann","doi":"10.1182/blood.2024027175","DOIUrl":"https://doi.org/10.1182/blood.2024027175","url":null,"abstract":"<p><p>We comprehensively profiled the landscape of immunoglobulin (IG) and T-cell receptor (TR) rearrangements at diagnosis in 1212 acute lymphoblastic leukemia (ALL) patients (573 children, 639 adults) diagnosed in Germany between 2017 and 2022.Our findings indicate that immunogenetic maturity in ALL patients is age-dependent, with younger patients exhibiting more mature profiles. In fact, 68.7% of pediatric B-ALL and 85.7% T-ALL patients carried IGK, or complete TRB and/or TRD rearrangements, respectively; compared to 39.0% and 67.3% in adults (B-ALL: p<2.2e-16, T-ALL: p=6.7e-03). Additionally, children carried more IG/TR markers compared to adults (mean 6/patient versus 4/patient, respectively; p=2.5e-38). Only 0.5% of pediatric patients lacked markers, contrasted with 6.7% of adults.IGH clonal evolution was most pronounced among pro-B ALL cases (60.9%), with the V-to-DJ mechanism driving pro-B evolution (78.6%), while V-replacement dominated other immunophenotypes. Additionally, we observed that the presence of expanded accompanying T-cell clones of unknown significance in B-ALL patients increased with age.This next-generation sequencing (NGS)-based study offers an unprecedented characterization of IG/TR rearrangement patterns across ALL subtypes and age groups. It highlights the higher immunogenetic maturity in children, which may be explained by the infection-driven abnormal activity of the IG/TR recombination machinery in pediatric ALL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Destabilization of PF4-antigenic complexes in heparin-induced thrombocytopenia.","authors":"Lubica Rauova, Khalil Bdeir, Ann H Rux, Manu Thomas Kalathottukaren, Jenna Oberg, Chanel C La, David Thiam En Lim, Vincent M Hayes, Gavin T Koma, Amrita Sarkar, Mortimer Poncz, Jayachandran N Kizhakkedathu, Douglas B Cines","doi":"10.1182/blood.2024025653","DOIUrl":"https://doi.org/10.1182/blood.2024025653","url":null,"abstract":"<p><p>Heparin-induced thrombocytopenia (HIT) is initiated by antibodies that recognize large antigenic complexes composed of multiple molecules of cationic platelet factor 4 (PF4) and polyanions such as unfractionated heparin (UFH) that bind to each other primarily through electrostatic interactions. We asked whether the formation and stability of these HIT antigenic or ultralarge immune complexes (ULICs) would be inhibited by biocompatible synthetic polycationic molecules shown previously to dissociate unfractionated heparin from antithrombin III and to inhibit polyphosphates. Members of this family of molecules, designated Universal Heparin Reversal Agents (UHRAs), inhibited formation and dissociated preformed ultralarge PF4-UFH complexes (ULCs), dissociated ULICs composed of the HIT-like monoclonal antibody KKO and ULCs, blocked binding of human HIT IgG antibodies to PF4/heparin, binding of KKO to platelets, KKO-induced adhesion of platelets to activated human endothelium under flow, and microvascular thrombosis induced by KKO in a mouse model of HIT. These data suggest that UHRAs might provide a rationale intervention that acts at an early step in the pathogenesis of HIT to enhance the benefits and lessen the risks of non-heparin anticoagulants. Destabilization of immune complexes using polycationic inhibitors might also find a role in management of other polyanion-PF4-antibody-mediated conditions, including vaccine-induced thrombocytopenia/thrombosis, post-viral, and autoimmune HIT.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How I treat chronic myeloid leukemia in children and adolescents.","authors":"Jing Chen, Meinolf Suttorp, Nobuko Hijiya","doi":"10.1182/blood.2024026514","DOIUrl":"https://doi.org/10.1182/blood.2024026514","url":null,"abstract":"<p><p>Chronic myeloid leukemia (CML) is rare in children and adolescents. Although outcomes have dramatically improved owing to tyrosine kinase inhibitors (TKIs) in the last two decades, there are still many challenges related to the management of pediatric CML, including the impact of TKIs on growth deceleration and unknown long-term adverse effects as well as defining the role of treatment-free remission. Unlike adult CML, which is driven by evidence-based guidelines, management of pediatric CML is often extrapolated from adult guidelines. However, pediatric CML differs from adult CML in many ways, presenting with different biological, molecular, and most importantly, host factors that make it necessary for a different treatment approach. Following the initial approval of first-generation imatinib for pediatric CML in 2003, three TKIs, all second-generation TKIs (2G-TKIs), have been approved, including dasatinib, nilotinib and bosutinib, which has greatly expanded therapeutic options but also added complexity to treatment determination. The expanded treatment options also call into question the treatment choice for pediatric CML, long-term efficacy and safety profiles of these TKIs. We present three cases commonly encountered in pediatric CML, their challenges and relevant issues as well as recommended managements.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracking clusterin expression in hematopoietic stem cells reveals their heterogeneous composition across the lifespan.","authors":"Shuhei Koide, Motohiko Oshima, Takahiro Kamiya, Zhiqian Zheng, Zhaoyi Liu, Ola Rizq, Akira Nishiyama, Koichi Murakami, Yuta Yamada, Yaeko Nakajima-Takagi, Bahityar Rahmutulla, Atsushi Kaneda, Kazuaki Yokoyama, Nozomi Yusa, Seiya Imoto, Fumihito Miura, Takashi Ito, Tomohiko Tamura, Claus Nerlov, Masayuki Yamashita, Atsushi Iwama","doi":"10.1182/blood.2024025776","DOIUrl":"https://doi.org/10.1182/blood.2024025776","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) exhibit significant age-related phenotypic and functional alterations. Although single-cell technologies have elucidated age-related compositional changes, prospective identification of aging-associated HSC subsets has remained challenging. In this study, utilizing Clusterin (Clu)-GFP reporter mice, we demonstrated that Clu expression faithfully marks age-associated myeloid/platelet-biased HSCs throughout life. Clu-GFP expression clearly segregates a novel age-associated HSC subset that overlaps with but is distinct from those previously identified using antibodies against aging maker proteins or reporter systems of aged HSC signature genes. Clu-positive (Clu+) HSCs emerge as a minor population in the fetus and progressively expand with age. Clu+ HSCs display not only an increased propensity for myeloid/platelet-biased differentiation but also a unique behaviour in the BM, favouring self-renewal over differentiation into downstream progenitors. In contrast, Clu-negative (Clu-) HSCs exhibit lineage-balanced differentiation, which predominates in the HSC pool during development but becomes underrepresented as aging progresses. Both subsets maintain long-term self-renewal capabilities even in aged mice but contribute differently to hematopoiesis. The predominant expansion of Clu+ HSCs largely drives the age-related changes observed in the HSC pool. Conversely, Clu- HSCs preserve youthful functionality and molecular characteristics into old age. Consequently, progressive changes in the balance between Clu+ and Clu- HSC subsets account for HSC aging. Our findings establish Clu as a novel marker for identifying aging-associated changes in HSCs and provide a new approach that enables lifelong tracking of the HSC aging process.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}