Blood最新文献

{"title":"Aging platelets shift their hemostatic properties to inflammatory functions.","authors":"Afra Anjum, Magdalena Mader, Shaan Mahameed, Abhinaya Muraly, Frederik Denorme, Fabian P Kliem, Dario Rossaro, Sezer Agköl, Lea Di Fina, Maité Mulkers, Lisa Laun, Lukas Li, Nadja Kupper, Keyang Yue, Marie-Louise Hoffknecht, Anastassia Akhalkatsi, Quentin Loew, Joachim Pircher, Raphael Escaig, Erwin Strasser, Christian Wichmann, Kami Pekayvaz, Bernhard Nieswandt, Christian Schulz, Maria S Robles, Rainer Kaiser, Steffen Massberg, Robert Campbell, Leo Nicolai","doi":"10.1182/blood.2024024901","DOIUrl":"10.1182/blood.2024024901","url":null,"abstract":"<p><strong>Abstract: </strong>Platelets are crucial players in hemostasis and thrombosis but also contribute to immune regulation and host defense, using different receptors, signaling pathways, and effector functions, respectively. Whether distinct subsets of platelets specialize in these diverse tasks is insufficiently understood. Here, we used a pulse-labeling method in Mus musculus models for tracking in vivo platelet aging and its functional implications. Using in vitro and in vivo assays, we reveal that young, reticulated platelets show heightened responses in the setting of clot formation, with corresponding, increased responses to agonists, adhesion, and retractile function. Unexpectedly, aged platelets lose their hemostatic proficiency but are more prone to react to inflammatory challenge: compared with reticulated platelets, this cohort was more likely to form platelet-leukocyte aggregates and showed increased adhesion to neutrophils in vitro, as well as enhanced bactericidal function. In vivo, this was reflected in increased pulmonary recruitment of aged platelets in an acute lung injury model. Proteomic analyses confirmed the upregulation of immune pathways in this cohort, including enhanced procoagulant function. In mouse models of prolonged platelet half-life, this resulted in increased pulmonary leukocyte infiltration and inflammation upon acute lung injury. Similarly, human platelet concentrates decreased their hemostatic function and elevated their putative immunomodulatory potential in vitro over time, and in a mouse model of platelet transfusion, aged platelet concentrates resulted in augmented inflammation. In summary, we show that platelets exhibit age-dependent phenotypic shifts, allowing them to fulfill their diverse tasks in the vasculature. Because functional alterations of aging platelets extend to platelet concentrates, this may hold important implications for transfusion medicine.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1568-1582"},"PeriodicalIF":21.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000107","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":"Progressive chromatin rewiring by ETO2::GLIS2 revealed in a genome-edited human iPSC model of pediatric leukemia initiation.","authors":"Fabien Boudia, Marie Baille, Loélia Babin, Zakia Aid, Elie Robert, Julie Rivière, Klaudia Galant, Verónica Alonso-Pérez, Laura Anselmi, Brahim Arkoun, Nassera Abermil, Christophe Marzac, Salvatore Nicola Bertuccio, Alexia de Prémesnil, Cécile K Lopez, Alexandre Eeckhoutte, Audrey Naimo, Betty Leite, Cyril Catelain, Christophe Metereau, Patrick Gonin, Nathalie Gaspar, Jürg Schwaller, Olivier A Bernard, Hana Raslova, Muriel Gaudry, Antonin Marchais, Hélène Lapillonne, Arnaud Petit, Françoise Pflumio, Marie-Laure Arcangeli, Erika Brunet, Thomas Mercher","doi":"10.1182/blood.2024024505","DOIUrl":"10.1182/blood.2024024505","url":null,"abstract":"<p><strong>Abstract: </strong>Pediatric acute myeloid leukemia frequently harbors fusion oncogenes associated with poor prognosis, including KMT2A, NUP98, and GLIS2 rearrangements. Although murine models have demonstrated their leukemogenic activities, the steps from a normal human cell to leukemic blasts remain unclear. Here, we precisely reproduced the inversion of chromosome 16 resulting in the ETO2::GLIS2 fusion in human induced pluripotent stem cells (iPSCs). iPSC-derived ETO2::GLIS2-expressing hematopoietic cells showed differentiation alterations in vitro and efficiently induced in vivo development of leukemia that closely phenocopied human acute megakaryoblastic leukemia (AMKL), reflected by flow cytometry and single-cell transcriptomes. Comparison of iPS-derived cells with patient-derived cells revealed altered chromatin accessibility at early and later bona fide leukemia stages, with aberrantly higher accessibility and expression of the osteogenic homeobox factor DLX3 that preceded increased accessibility to ETS factors. DLX3 overexpression in normal CD34+ cells increased accessibility to ETS motifs and reduced accessibility to GATA motifs. A DLX3 transcriptional module was globally enriched in both ETO2::GLIS2 AMKL and some aggressive pediatric osteosarcoma. Importantly, DLX3 knockout abrogated leukemia initiation in this ETO2::GLIS2 iPSC model. Collectively, the characterization of a novel human iPSC-derived AMKL model revealed that hijacking of the osteogenic homeobox transcription factor DLX3 is an essential early step in chromatin changes and leukemogenesis driven by the ETO2::GLIS2 fusion oncogene.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1510-1525"},"PeriodicalIF":21.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827448","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":"X-linked sideroblastic anemia in females.","authors":"Sarah Ducamp, Dean R Campagna, Anoop K Sendamarai, Paul J Schmidt, Harrison K Tsai, Matthew M Heeney, Sylvia S Bottomley, Mark D Fleming","doi":"10.1182/blood.2024024475","DOIUrl":"10.1182/blood.2024024475","url":null,"abstract":"<p><strong>Abstract: </strong>X-linked sideroblastic anemia (XLSA) in female carriers of 5-aminolevulinic acid synthase 2 mutations is not uncommon. We describe unique features and genotype/phenotype correlations in females with XLSA and evaluate the contributions of X-chromosome skewing and clonal hematopoiesis, emphasizing the importance of distinguishing it from myelodysplastic syndromes with ring sideroblasts.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1583-1587"},"PeriodicalIF":21.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254587","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":"Incorporation of immunotherapy into frontline treatment for adults with B-cell precursor acute lymphoblastic leukemia.","authors":"Talha Badar, Selina M Luger, Mark R Litzow","doi":"10.1182/blood.2023022921","DOIUrl":"10.1182/blood.2023022921","url":null,"abstract":"<p><strong>Abstract: </strong>Although complete remission rates in adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have improved over the last 2 decades, it is still inferior to that of the pediatric population, and once in remission, the risk of relapse is still high. Furthermore, although pediatric-inspired chemotherapy regimens have improved long-term outcomes for adolescents and young adults, these intensive chemotherapy regimens are not well tolerated in older patients and are associated with higher morbidity and mortality. Immunotherapeutic agents offer a potential opportunity to improve response and decrease relapse without increasing toxicity. The incorporation of rituximab (anti-CD20 monoclonal antibody) into chemotherapy regimens has been shown to improve outcomes. The treatment of BCP-ALL in adults has been transformed with the approval of inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate), blinatumomab (CD3/CD19 bispecific antibody construct), and chimeric antigen receptor T cells for relapsed or refractory disease and of blinatumomab for measurable residual disease (MRD)-positive remission. More recently, studies of inotuzumab and blinatumomab have shown promising results when used up front either with or without multiagent chemotherapy. Blinatumomab has also been shown in a randomized trial to provide a survival benefit in patients with MRD-negative first remission when added to chemotherapy, which recently led to its additional US Food and Drug Administration approval for use in consolidation. In this review, we highlight the evolution of chemoimmunotherapy-based treatment approaches in the management of treatment-naïve BCP-ALL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1475-1484"},"PeriodicalIF":21.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139282","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":"Genetic subtypes of B-cell acute lymphoblastic leukemia in adults.","authors":"Marie Passet, Rathana Kim, Emmanuelle Clappier","doi":"10.1182/blood.2023022919","DOIUrl":"10.1182/blood.2023022919","url":null,"abstract":"<p><strong>Abstract: </strong>B-cell acute lymphoblastic leukemia (B-ALL) is a rare malignancy in adults, with outcomes remaining poor, especially compared with children. Over the past 2 decades, extensive whole-genome studies have identified numerous genetic alterations driving leukemia, leading to the recognition of >20 distinct subtypes that are closely associated with treatment response and prognosis. In pediatric B-ALL, large correlation studies have made genetic classification a central component of risk-adapted treatment strategies. Notably, genetic subtypes are unevenly distributed according to age, and the spectrum of genetic alterations and their prognostic relevance in adult B-ALL have been less extensively studied, with treatment primarily based on the presence or absence of BCR::ABL1 fusion. This review provides an overview of genetic subtypes in adult B-ALL, including recent biological and clinical insights in well-established subtypes as well as data on newly recognized subtypes. Their relevance for risk classification, disease monitoring, and therapeutic management, including in the context of B-cell-directed therapies, is discussed. This review advocates for continuing efforts to further improve our understanding of the biology of adult B-ALL to establish the foundation of future precision medicine in B-ALL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1451-1463"},"PeriodicalIF":21.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944635","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":"Odronextamab monotherapy in R/R DLBCL after progression with CAR T-cell therapy: primary analysis of the ELM-1 study.","authors":"Max S Topp, Matthew Matasar, John N Allan, Stephen M Ansell, Jeffrey A Barnes, Jon E Arnason, Jean-Marie Michot, Neta Goldschmidt, Susan M O'Brien, Uri Abadi, Irit Avivi, Yuan Cheng, Dina M Flink, Min Zhu, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Srikanth Ambati, Jennifer L Crombie","doi":"10.1182/blood.2024027044","DOIUrl":"10.1182/blood.2024027044","url":null,"abstract":"<p><strong>Abstract: </strong>Patients with relapsed/refractory diffuse large B-cell lymphoma progressing after chimeric antigen receptor T-cell (CAR-T) therapy have dismal outcomes. The prespecified post-CAR-T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR-Ts. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary end point was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range, 2-9), 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR-T products and time to relapse on CAR-T therapy. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no grade ≥3 events). No cases of immune effector cell-associated neurotoxicity syndrome were reported. Grade ≥3 infections occurred in 12 patients (20.0%), 2 of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for patients after CAR-T therapy. This trial was registered at www.clinicaltrials.gov as #NCT02290951.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1498-1509"},"PeriodicalIF":21.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944649","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":"Blood-Based Proteomic Profiling Identifies OSMR as a Novel Biomarker of AML Outcomes.","authors":"Patrick K Reville, Bofei Wang, Jennifer Marvin-Peek, Bin Yuan, Yu-An Kuo, Araceli Isabella Garza, Jessica L Root, Wei Qiao, Andrea Arruda, Ivo Veletic, Yiwei Liu, Nicholas J Short, Courtney D DiNardo, Tapan M Kadia, Naval G Daver, Philip L Lorenzi, Koji Sasaki, Steven M Kornblau, Mark D Minden, Farhad Ravandi, Hagop M Kantarjian, Hussein A Abbas","doi":"10.1182/blood.2024027244","DOIUrl":"10.1182/blood.2024027244","url":null,"abstract":"<p><p>Inflammation is increasingly recognized as a critical factor in acute myeloid leukemia (AML) pathogenesis. We performed blood-based proteomic profiling of 251 inflammatory proteins in 543 newly diagnosed AML patients. Using a machine learning model, we derived an eight-protein prognostic score termed Leukemia Inflammatory Risk Score (LIRS). Individual proteins were evaluated in multivariable cox models and model performance was assessed by cumulative concordance index. Findings were validated in internal and external cohorts across two institutions. Blood-based LIRS significantly outperformed the European LeukemiaNet (ELN) 2022 risk model and was independently prognostic of overall survival after accounting for known clinical and molecular prognostic factors. OSMR was uniquely identified as the strongest independent predictor of survival, early mortality, and induction chemotherapy response, and further validated in an independent assay. These blood-based biomarkers could have significant clinical implications for risk stratification and prognostication in patients with newly diagnosed AML.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779147","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":"Introduction to a review series on acute lymphoblastic leukemia.","authors":"Hervé Dombret","doi":"10.1182/blood.2024028229","DOIUrl":"https://doi.org/10.1182/blood.2024028229","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 14","pages":"1439"},"PeriodicalIF":21.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771267","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":"Diagnostic BRAFV600E blood predicts treatment failure and neurodegeneration and redefines paradigms of pediatric LCH.","authors":"Howard Lin, Akanksha Batajoo, Erin Peckham-Gregory, Daniel Zinn, Olive S Eckstein, Nader K El-Mallawany, Nitya Gulati, Zachary Prudowsky, Brooks P Scull, Jessica Velazquez, Harshal A Abhyankar, Stephen J Simko, Daria Vakula, Ryan Fleischmann, Vivekanudeep Karri, John Hicks, Kevin E Fisher, Choladda V Curry, Angshumoy Roy, Deborah E Schiff, Kenneth Heym, Michael E Scheurer, Donald Williams Parsons, Miriam Merad, Tsz-Kwong Man, Kenneth L McClain, Jennifer Picarsic, Carl E Allen","doi":"10.1182/blood.2024026671","DOIUrl":"https://doi.org/10.1182/blood.2024026671","url":null,"abstract":"<p><p>Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder driven by MAPK activation in hematopoietic cells. Historically, LCH has been staged according to involvement of \"risk organs\" (ROpos; bone marrow, liver, spleen), based on risk of death. With improvements in supportive care and efficacy of MAPK pathway inhibitors, LCH patients now rarely die. However, most LCH patients with multi-system disease are not cured with current front-line chemotherapy, and treatment failure is associated with long-term morbidity, including LCH-associated neurodegeneration (LCH-ND). In this study, we evaluated the impact of extent of LCH at presentation, tumor genotype, and BRAFV600E in pre-therapy peripheral blood mononuclear cells (PBMC) and bone marrow on systemic and CNS outcomes in a cohort of 385 pediatric LCH patients and 115 adults, followed for a median of 4 years (0.02-18). Five year event-free survival was 50.7% for pediatric patients and 32.7% for adult LCH patients. In the pediatric cohort, presence of BRAFV600E PBMC was strongly associated with front-line treatment failure (hazard ratio 7.7). Remarkably, BRAFV600E PBMC at diagnosis also identified patients at the highest risk of developing LCH-ND (hazard ratio 23.1). These findings support an updated model of pediatric LCH pathogenesis in which persistence of disease reservoir and cell of origin determine extent of disease and clinical risks. We therefore propose a major revision of pediatric LCH diagnostic staging shifting from focus on historical risk of death to risks of systemic treatment failure and LCH-ND based on lesion location, lesion genotype, and peripheral LCH reservoir (e.g. BRAFV600E PBMC).</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751115","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":"IFN-γ promotes the progression of iMCD by activating inflammatory monocytes.","authors":"Xuejiao Yin, Yi Liu, Shengnan Ding, Jiaying Ge, Min Yang, Zhenbo Wang, Zuopo Lv, Xuxia Luo, Liya Ma, Wenjuan Yu, Juying Wei, Chunmei Yang, Qiumei Yao, Li Zhu, Shuqi Zhao, Yu Chen, Meng Haitao, Jie Jin, Hongyan Tong, Liangshun You","doi":"10.1182/blood.2024027689","DOIUrl":"https://doi.org/10.1182/blood.2024027689","url":null,"abstract":"<p><p>A deeper understanding of the immune landscape in patients with idiopathic multicentric Castleman disease (iMCD) is essential to establish early prognostic stratification and uncover novel therapeutic targets. We employed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from a cohort of 15 patients with iMCD and four healthy controls. To explore the sources of interleukin-6 (IL-6), we included lymph node and bone marrow samples for comparison with PBMCs. Our results indicate that IL-6 primarily originates from the lymph nodes, particularly from activated B cells. Similarly, in peripheral blood, activated B cells are also the main source of IL-6. IL-6 receptor (IL-6R) is primarily expressed in monocytes in PBMCs, with CCL monocytes showing the strongest activation of the IL-6 signaling pathway. This suggests that CCL monocytes in iMCD may play an important role in driving peripheral inflammatory storms. CellChat analysis reveals that during disease flares, CCL monocytes interact with specific NK/NKT cells through enhanced type II interferon (IFN-II) signaling, while this interaction significantly diminishes during remission, indicating a significant role for IFN-II in the pathogenesis of iMCD. Notably, serum IFN-γ levels positively correlate with both disease severity and treatment resistance, a finding was validated by a large independent iMCD cohort. Our findings confirm that the IL-6 pathway remains central to iMCD pathogenesis and highlight a significant role of IFN-II pathway activation in amplifying inflammatory storms. Our findings provide valuable biomarkers for assessing disease severity and identify new therapeutic targets for iMCD.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751129","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}