Blood advances最新文献

{"title":"Of mice and FVIIIa mimetics: new hemophilia A models for in vivo evaluation.","authors":"Benjamin J Samelson-Jones, Sebastian E Leyes Porello","doi":"10.1182/bloodadvances.2026021345","DOIUrl":"10.1182/bloodadvances.2026021345","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6771-6773"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Yu H, Schroeder JA, Mattson JG, Gao C, and Shi Q. Impact of antiplatelet therapy on the hemostatic efficacy of platelet-targeted FVIII gene therapy in hemophilia A mice. Blood Adv. 2026;10(6):1883-1896.","authors":"","doi":"10.1182/bloodadvances.2026022295","DOIUrl":"10.1182/bloodadvances.2026022295","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":"10 19","pages":"6729"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase 1/1b study of the all-oral regimen CC-486 and venetoclax in acute myeloid leukemia.","authors":"Maria L Amaya, Diana Abbott, Christine McMahon, Marc Schwartz, Jonathan Gutman, Andrew Kent, Mathew Angelos, Connor Sohalski, Ayele Belachew, Jessica Dell-Martin, Katelyn Anttila, Brett Stevens, Angelo D'Alessandro, William Showers, Austin E Gillen, Craig T Jordan, Daniel A Pollyea","doi":"10.1182/bloodadvances.2026020179","DOIUrl":"10.1182/bloodadvances.2026020179","url":null,"abstract":"<p><strong>Abstract: </strong>Venetoclax with azacitidine is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are unfit for intensive induction chemotherapy. CC-486 is the oral formulation of azacitidine that is currently approved for postinduction chemotherapy maintenance in AML. In this single-center, open-label, phase 1/1b study, we investigated CC-486 and venetoclax in patients with relapsed and refractory AML and in those with newly diagnosed disease. In the dose-escalation phase, patients received CC-486 at 1 of 2 cohorts (200 mg by mouth on days 1-14 and 300 mg by mouth on days 1-14). Venetoclax was given at 400 mg/d by mouth for 28 days after an initial intrapatient dose escalation per the standard of care. Using a 3+3 study design for these 2 cohorts, we determined the recommended dose of CC-486 to be 300 mg daily on days 1 to 14. The most common adverse events included nausea, diarrhea, fatigue, and cytopenias. The incidence of grade ≥3 neutropenia or thrombocytopenia was 97% and 66%, respectively. There were no dose-limiting toxicities in either cohort. The expansion phase of the study consisted of 10 additional patients with relapsed and refractory AML and 16 patients with newly diagnosed AML. Responses were seen in all phases of the study, and 6 patients were successfully bridged to hematopoietic stem cell transplant. Correlative analyses including sequencing and metabolomics performed on patient samples suggested that this regimen had a similar effect on leukemia stem cells compared with conventional (IV) azacitidine and venetoclax. This trial was registered at www.clinicaltrials.gov as NCT05287568.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6666-6674"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Hi-C sequencing to detect oncogene rearrangements for diagnosis and treatment of large B-cell lymphoma.","authors":"Zijun Y Xu-Monette, Chang Wang, Dehong Wu, Alexandar Tzankov, Michael B Møller, Carlo Visco, Eric D Hsi, Xiaoxian Zhao, Beibei Lv, Bangchen Wang, Xin Cao, Shuna Yao, April Chiu, Karen Dybkaer, Govind Bhagat, Youli Zu, Santiago Montes-Moreno, Zenggang Pan, Leon Bernal-Mizrachi, J Han van Krieken, William Choi, Wayne Tam, Weina Chen, Maurilio Ponzoni, Andrés J M Ferreri, Benjamin M Parsons, Farzaneh Khajouei, Kristin Sikkink, Yong Li, Alex R Hastie, Anthony D Schmitt, Ken H Young","doi":"10.1182/bloodadvances.2026019675","DOIUrl":"10.1182/bloodadvances.2026019675","url":null,"abstract":"<p><strong>Abstract: </strong>Diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, arises from various pathogenic mechanisms, including gene translocations and fusions. Detection of gene rearrangements using fluorescence in situ hybridization (FISH) is a standard practice for DLBCL diagnosis and guides treatment decisions. High-throughput chromosome conformation capture (Hi-C) DNA sequencing is a next-generation sequencing-based technology to identify genome-wide rearrangements using a single assay. In this study, Hi-C sequencing was performed using formalin-fixed paraffin-embedded tissues from 159 patients with DLBCL, identifying 746 cancer genes at or proximal to the rearrangement breakpoints, with a total of 1903 occurrences. Focusing on clinically important rearrangements, Hi-C detected 102 rearrangements of MYC, BCL2, and/or BCL6 in 92 patients and revealed the fusion partners, including 25 rearrangements missed by FISH. Causes of FISH-negative results included FISH-cryptic breakpoints, complex or faint FISH signals, low percentage of FISH positivity, and issues related to tissue fixation. Moreover, in 20 patients (12.6%), Hi-C sequencing detected 22 rearrangements characteristic of other lymphoma types, including CCND1 rearrangements that could lead to reclassification as mantle cell lymphoma. Survival analysis of genome-wide rearrangements using machine learning models identified MYC, PD-L1, CCND1, BCL2, NTRK1/PRCC, RRAS, and FANCE rearrangements with significant prognostic effects in the DLBCL cohort. In conclusion, Hi-C sequencing detects gene rearrangements crucial for diagnosis in an unbiased and molecular manner and showed high sensitivity and specificity in our study. These advantages of Hi-C sequencing offer help to improve the workflow of clinical pathology laboratories, diagnostic precision, and treatment of large B-cell lymphoma.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6828-6844"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tenecteplase and other TNK formulations lose PAI-1 resistance in their 2-chain form: comparison with alteplase.","authors":"Zikou Liu, Isabel Tippett, Fiona McCutcheon, Charithani B Keragala, Amy McDonald, Gagan Sharma, Longting Lin, Yunyun Xiong, Yongjun Wang, Tammy Lam, Geoffrey C Cloud, Bruce C V Campbell, Mark W Parsons, Robert L Medcalf","doi":"10.1182/bloodadvances.2026020921","DOIUrl":"10.1182/bloodadvances.2026020921","url":null,"abstract":"<p><strong>Abstract: </strong>Alteplase is synthesized as a single-chain protease that requires plasmin-mediated conversion to its fully active 2-chain form for maximal thrombolysis. Tenecteplase (TNK), an alteplase variant, is widely regarded as being more fibrin selective and more resistant to plasminogen activator inhibitor 1 (PAI-1) than alteplase. However, the PAI-1 sensitivity of TNK after 2-chain conversion and that of newly available TNK formulations has not been evaluated. Alteplase and 4 TNK formulations, Metalyse (Boehringer Ingelheim, Ingelheim am Rheim, Germany), Tenectase (Gennova, Pune, India), GenetPA (BioApower, Jiangsu, Yancheng, China), and Mingfule (CSPC Pharmaceutical Company Ltd, Guangdong, Guangzhou, China) were compared in their native state and after 2-chain conversion. Proteolytic activity and PAI-1 resistance and binding were evaluated using an amidolytic assay, fibrinolysis assays, and western blotting. Alteplase, but not Metalyse, was converted into its 2-chain form in plasma in a fibrinogen-dependent manner, resulting in off-target fibrinogenolysis. When directly reconstituted from the manufacturer's vial (native form), TNK was approximately fourfold more resistant to PAI-1 than alteplase; however, 2-chain conversion significantly reduced PAI-1 resistance by ∼40%, concomitant with increased PAI-1 binding. Native Metalyse contained approximately threefold more preexisting 2-chain species than the other TNK formulations, explaining its higher amidolytic activity. However, after 2-chain conversion, all TNK formulations showed similar fibrinolytic activity, although with substantially reduced PAI-1 resistance. Metalyse and all new TNK formulations display similar fibrinolytic activity in their fully active 2-chain states, but this is associated with substantial loss of PAI-1 resistance, challenging the view that the fully active 2-chain form of TNK maintains PAI-1 resistance during thrombolysis.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6626-6636"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct epitope engagement confers differential activity of linvoseltamab vs teclistamab across BCMA mutations.","authors":"Yi Zhou, Olga Sineshchekova, Ken Lee, Aneesha Doshi, Kyle Brown, Matthew Franklin, Erica Ullman, Aynur Hermann, Glenn S Kroog, Anita Boyapati, Eric Smith, John C Lin, William Olson, Kara Olson","doi":"10.1182/bloodadvances.2026020381","DOIUrl":"10.1182/bloodadvances.2026020381","url":null,"abstract":"<p><strong>Abstract: </strong>B-cell maturation antigen (BCMA) is a well-established therapeutic target in multiple myeloma (MM). BCMA mutations have been identified among patients who relapsed after treatment with approved BCMA×CD3 bispecific antibodies (bsAbs; eg, teclistamab). BCMA mutations can impair bsAb binding and cytotoxic activity in vitro, suggesting an acquired resistance mechanism leading to clinical relapse. Linvoseltamab (human BCMA×CD3 bsAb) was recently approved for adults with heavily pretreated relapsed/refractory MM. Here, we compared the activity of linvoseltamab in the presence of cell lines expressing 4 BCMA mutations reported among patients treated with teclistamab: R27P, S30del, P34del (associated with resistance), and the germ line variant P33S (identified in a patient who relapsed but was not associated with resistance). Linvoseltamab retained binding to cells expressing BCMA R27P and S30del mutations and demonstrated robust Jurkat-nuclear factor of activated T cells (NFAT) reporter and primary T-cell activation, as well as targeted cytotoxicity against mutated BCMA that was comparable to wild-type BCMA. Conversely, teclistamab exhibited reduced binding and functional activity against these mutations. Both linvoseltamab and teclistamab showed impaired binding against P34del, consistent with diminished Jurkat-NFAT reporter, primary T-cell activation, and cytotoxicity. Both bsAbs retained activity against P33S. Cryogenic electron microscopy uncovered distinct binding orientations for linvoseltamab and teclistamab, consistent with the respective sensitivities to the studied BCMA mutations (ie, the selected residues contributed less to linvoseltamab binding than teclistamab binding, consistent with the broader activity of linvoseltamab across BCMA mutations). Although linvoseltamab may be less susceptible than teclistamab to resistance mechanisms involving R27P and S30del, the clinical relevance of our findings is to be established.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6730-6741"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD20 bispecific T-cell engager depletes B-cell progenitors preventing EBV-associated lymphomagenesis in humanized mice.","authors":"Michelle Böni, Patrick Schuhmachers, Saskia von Boxberg, Amanda Poon, Emeline Thevenon, Daniele Mennonna, Melissa Ramones, Lucas Romann, Svenja L Walter, Éanna Fennell, Francesca Rucci, Elisabetta Traggiai, Christian Münz","doi":"10.1182/bloodadvances.2025019375","DOIUrl":"10.1182/bloodadvances.2025019375","url":null,"abstract":"<p><strong>Abstract: </strong>Epstein-Barr virus (EBV) infection is associated with ∼1.5% of human tumors, including B-cell lymphoproliferative diseases (LPDs). A common approach to treating EBV-associated LPDs is targeting infected tumor cells with a CD20 monoclonal antibody, such as rituximab, although this often fails to prevent relapses and refractory disease. In this study, we show using a preclinical humanized mouse model the superior efficacy of a CD3×CD20 bispecific T-cell engager in preventing systemic virus spread and EBV-associated tumor formation, compared with rituximab treatment. This increased efficacy is associated with a deep depletion of human precursor B cells in the bone marrow. Progenitor B cells are permissive to infection with EBV in vitro and correlate with EBV persistence during B-cell depletion therapy, also in vivo. Thus, deep depletion of B cells, including bone marrow progenitors, might target EBV-associated LPDs more efficiently. Infected progenitors should be considered an EBV reservoir from which associated pathologies could relapse.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6585-6597"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Venous thromboembolism is not associated with plasmin(ogen): reevaluating plasmin and mechanisms that degrade fibrin.","authors":"Yaqiu Sang, Amy D Shapiro, Alisa S Wolberg","doi":"10.1182/bloodadvances.2025018558","DOIUrl":"10.1182/bloodadvances.2025018558","url":null,"abstract":"<p><strong>Abstract: </strong>The plasminogen activation and plasmin activity (PA) system is a central mechanism for degrading fibrin and has long been viewed as essential for preventing venous thrombosis/thromboembolism. However, clinical and experimental data challenge this paradigm. Here, we examine evidence that reduced PA does not predispose individuals to venous thrombosis/thromboembolism. We discuss potential mechanisms that may rationalize this apparent paradox, including compensatory vascular and inflammatory pathways that may degrade intravascular fibrin. These data suggest venous thromboembolism is a multifactorial disease in which an impaired PA system is neither necessary nor sufficient to drive thrombosis. We also discuss alternative biological roles of the PA system. Reframing the role of the PA system has important implications for developing therapies that modulate fibrinolysis. A more nuanced understanding of PA biology may enable strategies that balance bleeding risk with efficient clot resolution.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6661-6665"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148535041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comutation of asxl1 and IDH2R172K enhances leukemogenesis and correlates with epigenetic activation of MAPK and AP-1 in zebrafish.","authors":"Eleanor Fangfang He, Yao Ruan, Lingge Tu, Dandan Wang, Xinyu Miao, Jun Mun Liew, Lichuan Zheng, Chun-Fung Sin, Xudong Liu, Yanwen Shao, Kenneth Kin Leung Kwan, Leslie Kar-Fai Chan, Jeffrey Wan Hei Hui, Annie Wan Yu Ho, Sze Pui Tsui, Runsheng Li, Carmen Chak-Lui Wong, Alvin Chun Hang Ma, Yiyue Zhang, Wenqing Zhang, Anskar Yu Hung Leung, Xuan Sun","doi":"10.1182/bloodadvances.2026019586","DOIUrl":"10.1182/bloodadvances.2026019586","url":null,"abstract":"<p><strong>Abstract: </strong>Comutations of addition of sex combs-like 1 (asxl1) and isocitrate dehydrogenases 2 (IDH2) are associated with aggressive acute myeloid leukemia (AML), yet the underlying mechanisms have remained poorly understood. We generated a zebrafish model combining an asxl1 mutation and an IDH2R172K mutation that recapitulates the clinicopathological and molecular features of high-risk AML with differentiation blockade and reduced animal survival. The double mutants exhibited promoter hypermethylation, downregulation of tet2 expression, and global changes in methylation profiles. Genes pertaining to MAPK and activator protein-1 (AP-1) pathways were upregulated, which was associated with reduced NAD phosphate oxidase expression and an increase in reactive oxygen species (ROS). Single-cell RNA sequencing confirmed differentiation arrest in hematopoietic stem and progenitor cells, with activation of MAPK and AP-1 signaling. The double mutants showed resistance to the IDH2 inhibitor but were sensitive to ROS or DNA methylation targeting. In silico analysis of gene expression in human AML carrying comutation of ASXL1/IDH2 also showed activation of the MAPK and AP-1 pathways. Our findings underscore an epigenetic-metabolic signaling circuit driving leukemogenesis and reveal novel therapeutic strategies for this AML subtype.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6610-6625"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148577227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bispecific antibodies are becoming the preferred standard of care in relapsed/refractory multiple myeloma.","authors":"Murali Janakiram","doi":"10.1182/bloodadvances.2026020073","DOIUrl":"10.1182/bloodadvances.2026020073","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"6641-6644"},"PeriodicalIF":7.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}