Blood最新文献

{"title":"Therapy-related juvenile myelomonocytic leukemia.","authors":"Ahmed Mohamed, Aida I Richardson","doi":"10.1182/blood.2025028952","DOIUrl":"https://doi.org/10.1182/blood.2025028952","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"146 1","pages":"127"},"PeriodicalIF":21.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552218","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":"Interferon-γ sparks inflammatory fire in Castleman disease.","authors":"Frits van Rhee,David Fajgenbaum","doi":"10.1182/blood.2025029270","DOIUrl":"https://doi.org/10.1182/blood.2025029270","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"36 1","pages":"5-7"},"PeriodicalIF":20.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547729","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":"Restoring p53 wild-type conformation in TP53-Y220C-mutant acute myeloid leukemia.","authors":"Bing Z Carter, Po Yee Mak, Edward Ayoub, Xiaogang Wu, Baozhen Ke, Yuki Nishida, Andrew Futreal, Lauren B Ostermann, Andrea D Bedoy, Steffen Boettcher, Courtney D DiNardo, Anna Puzio-Kuter, Masha V Poyurovsky, Arnold J Levine, Michael Andreeff","doi":"10.1182/blood.2025028935","DOIUrl":"10.1182/blood.2025028935","url":null,"abstract":"<p><p>TP53-Y220C is a recurrent hotspot mutation in cancers and leukemias. It is observed predominantly in acute myeloid leukemia (AML)/myelodysplastic syndromes among hematological malignancies and is associated with poor outcome. The mutation creates a structural pocket in the p53 protein. PC14586 (rezatapopt) is a small molecule designed to bind to this pocket and thus restore a p53-wild type (p53-WT) conformation. We demonstrate that PC14586 converts p53-Y220C into a p53-WT conformation and activates p53 transcriptional targets, but surprisingly induces limited/no apoptosis in TP53-Y220C AML. Mechanistically, MDM2 induced by PC14586-activated conformational p53-WT and the nuclear exporter XPO1 reduce the transcriptional activities of p53, which are fully restored by inhibition of MDM2 and/or XPO1. Importantly, p53-WT protein can bind to BCL-2, competing with BAX in the BH3 binding pocket of BCL-2 and also binds to BCL-xL and MCL-1. However, such binding by PC14586-activated conformational p53-WT is not detected. Pharmacological inhibition of the BCL-2/BAX interaction with venetoclax fully compensates for this deficiency, induces massive cell death in AML cells and stem/progenitor cells in vitro and prolongs survival of TP53-Y220C AML xenografts in vivo. Collectively, we identified transcription-dependent and -independent mechanisms that limit the apoptogenic activities of reactivated conformational p53-WT and suggest approaches to optimize apoptosis induction in TP53-mutant leukemia. A clinical trial of PC14586 in TP53-Y220C AML/myelodysplastic syndromes has recently been initiated (NCT06616636).</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559142","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":"Marstacimab Prophylaxis in Hemophilia A/B Without Inhibitors: Results from the Phase 3 BASIS Trial.","authors":"Davide Matino, Andrew Palladino, Carrie Turich Taylor, Eunhee Hwang, Sangeeta Raje, Satyaprakash Nayak, Regina McDonald, Suchitra Acharya, Johnny Mahlangu, Victor Jiménez-Yuste, Nirmalkumar G Choraria, Renchi Yang, Chi-Kong Li, Murtadha Al-Khabori, Yasser Ahmed Mohamed Soliman Wali, Javier De Jesus Morales-Adrian, Young-Shil Park, Osman Bülent Zülfikar, John Teeter","doi":"10.1182/blood.2024027468","DOIUrl":"https://doi.org/10.1182/blood.2024027468","url":null,"abstract":"<p><p>Marstacimab is a monoclonal antibody that targets the tissue factor pathway inhibitor to rebalance hemostasis. Previous phase 1 and 2 trials established marstacimab safety and efficacy in adults with severe hemophilia A or B. BASIS is an open-label, phase 3 trial of marstacimab in males aged 12-74 years with severe hemophilia A (factor VIII <1%) or moderately severe to severe hemophilia B (factor IX ≤2%). Participants without inhibitors received on-demand (OD) or routine prophylaxis (RP) factor replacement during a 6-month observational phase (OP) before receiving once-weekly subcutaneous 150 mg marstacimab prophylaxis during a 12-month active treatment phase (ATP). Primary endpoints were annualized bleeding rate (ABR) for treated bleeds vs prior OD or RP during the OP and safety. Of 128 participants enrolled in the OP, 116 received marstacimab in the ATP. In the OD group (n=33), mean ABR (95% CI) decreased from 39.86 (33.05-48.07) in the OP to 3.20 (2.10-4.88) in the ATP, demonstrating superiority of marstacimab (estimated ABR ratio, 0.080 [0.057-0.113]; P < .0001). In the RP group (n=83), mean ABR decreased from 7.90 (5.14-10.66) in the OP to 5.09 (3.40-6.78) in the ATP, demonstrating noninferiority and superiority of marstacimab (estimated ABR difference, -2.81 [-5.42 to -0.20]; P = .0349). There were no deaths or thromboembolic events. Weekly subcutaneous marstacimab reduced ABR compared with OD or RP therapy in the OP in individuals with severe hemophilia A or moderately severe to severe hemophilia B without inhibitors. Marstacimab was safe and well tolerated with no unanticipated side effects. This trial was registered at www.clinicaltrials.gov as # NCT03938792.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559141","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":"SRSF2-mutated MDS: bortezomib STAT?","authors":"Aly Karsan","doi":"10.1182/blood.2025029269","DOIUrl":"https://doi.org/10.1182/blood.2025029269","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"146 1","pages":"9-11"},"PeriodicalIF":21.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552217","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 life span.","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":"10.1182/blood.2024025776","url":null,"abstract":"<p><strong>Abstract: </strong>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, using clusterin (Clu)-green fluorescent protein (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 behavior in the bone marrow, favoring 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":"62-75"},"PeriodicalIF":21.0,"publicationDate":"2025-07-03","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}

{"title":"Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma.","authors":"Matteo Claudio Da Vià, Francesca Lazzaroni, Antonio Matera, Alessio Marella, Akihiro Maeda, Claudio De Magistris, Loredana Pettine, Antonio Giovanni Solimando, Vanessa Desantis, Giuseppe M Peretti, Laura Mangiavini, Riccardo Giorgino, Sonia Fabris, Stefania Pioggia, Alfredo Marchetti, Marzia Barbieri, Silvia Lonati, Alessandra Cattaneo, Marta Tornese, Margherita Scopetti, Emanuele Calvi, Nayyer Latifinavid, Giancarlo Castellano, Federica Torricelli, Antonino Neri, Cathelijne Fokkema, Tom Cupedo, Marta Lionetti, Francesco Passamonti, Niccolò Bolli","doi":"10.1182/blood.2024025643","DOIUrl":"10.1182/blood.2024025643","url":null,"abstract":"<p><strong>Abstract: </strong>Multiple myeloma (MM) is driven by clonal plasma cell (cPC)-intrinsic factors and changes in the tumor microenvironment (TME). To investigate whether residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNA sequencing (scRNA-seq) and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 21 healthy donors (HDs). Of 234 789 PCs, 64 432 were genotypically identified as pPCs with frequencies decreasing over different disease stages, from 23.66% in monoclonal gammopathy of undetermined significance to 3.23% in MMs (P = .00012). Both cPCs and pPCs had a comparable expression of typical lineage markers (ie, CD38 and CD138), whereas others were more variable (CD27 and ITGB7). Only cPCs overexpressed oncogenes (eg, CCND1/2 and NSD2), but CCND3 was often expressed in pPCs. B-cell maturation antigen was expressed on both pPCs and cPCs, whereas GPRC5D was mostly upregulated in cPCs with implications for on-target, off-tumor activity of targeted immunotherapies. In comparison with HDs, pPCs from patients showed upregulated autophagy and disrupted interaction with TME. Importantly, interferon-related pathways were significantly enriched in pPCs from patients vs HDs (adjusted P < .05) showing an inflamed phenotype affecting genotypically normal PCs. The function of pPCs was consequently affected and correlated with immunoparesis, driven by disrupted cellular interactions with TME. Leveraging our scRNA-seq data, we derived a \"healthy PC signature\" that could be applied to bulk transcriptomics from the CoMMpass data set and predicted significantly better progression-free survival and overall survival (log-rank P < .05 for both). Our findings show that genotypic sc identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"3124-3138"},"PeriodicalIF":21.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514588","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":"Use of machine learning techniques to predict poor survival after hematopoietic cell transplantation for myelofibrosis.","authors":"Juan Carlos Hernández-Boluda, Adrián Mosquera-Orgueira, Luuk Gras, Linda Koster, Joe Tuffnell, Nicolaus Kröger, Massimiliano Gambella, Thomas Schroeder, Marie Robin, Katja Sockel, Jakob Passweg, Igor Wolfgang Blau, Ibrahim Yakoub-Agha, Ruben Van Dijck, Mattias Stelljes, Henrik Sengeloev, Jan Vydra, Uwe Platzbecker, Moniek de Witte, Frédéric Baron, Kristina Carlson, Javier Rojas, Carlos Pérez Míguez, Davide Crucitti, Kavita Raj, Joanna Drozd-Sokolowska, Giorgia Battipaglia, Nicola Polverelli, Tomasz Czerw, Donal P McLornan","doi":"10.1182/blood.2024027287","DOIUrl":"10.1182/blood.2024027287","url":null,"abstract":"<p><strong>Abstract: </strong>With the incorporation of effective therapies for myelofibrosis (MF), accurately predicting outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) is crucial for determining the optimal timing for this procedure. Using data from 5183 patients with MF who underwent first allo-HCT between 2005 and 2020 at European Society for Blood and Marrow Transplantation centers, we examined different machine learning (ML) models to predict overall survival after transplant. The cohort was divided into a training set (75%) and a test set (25%) for model validation. A random survival forests (RSF) model was developed based on 10 variables: patient age, comorbidity index, performance status, blood blasts, hemoglobin, leukocytes, platelets, donor type, conditioning intensity, and graft-versus-host disease prophylaxis. Its performance was compared with a 4-level Cox regression-based score and other ML-based models derived from the same data set, and with the Center for International Blood and Marrow Transplant Research score. The RSF outperformed all comparators, achieving better concordance indices across both primary and postessential thrombocythemia/polycythemia vera MF subgroups. The robustness and generalizability of the RSF model was confirmed by Akaike information criterion and time-dependent receiver operating characteristic area under the curve metrics in both sets. Although all models were prognostic for nonrelapse mortality, the RSF provided better curve separation, effectively identifying a high-risk group comprising 25% of patients. In conclusion, ML enhances risk stratification in patients with MF undergoing allo-HCT, paving the way for personalized medicine. A web application (https://gemfin.click/ebmt) based on the RSF model offers a practical tool to identify patients at high risk for poor transplantation outcomes, supporting informed treatment decisions and advancing individualized care.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"3139-3152"},"PeriodicalIF":21.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717944","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":"B-lymphoblastic leukemia with KMT2A rearrangement with mature B-cell phenotype and surface λ light-chain restriction.","authors":"Pratik Q Deb,Xinmin Zhang","doi":"10.1182/blood.2025029108","DOIUrl":"https://doi.org/10.1182/blood.2025029108","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"242 1","pages":"3194"},"PeriodicalIF":20.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488100","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":"Association of Epstein-Barr virus genomic alterations with human pathologies.","authors":"Htet Thiri Khine,Yoshitaka Sato,Motoharu Hamada,Miki Umeda,Akira Iizuka,Shika Son,Haruto Arai,Yuki Kojima,Takahiro Watanabe,Azumi Naruse,Kimitoshi Goto,Koichi Ohshima,Yuta Akutsu,Masato Nakaguro,Akira Satou,Hiromi Kataoka,Yoshinori Ito,Akihisa Sawada,Seiichi Kato,Jun-Ichi Kawada,Takayuki Murata,Yusuke Okuno,Hiroshi Kimura","doi":"10.1182/blood.2024028055","DOIUrl":"https://doi.org/10.1182/blood.2024028055","url":null,"abstract":"Epstein-Barr virus (EBV) infects over 90% of humans and is associated with both hematological and epithelial malignancies. Here, we analyzed 990 EBV genomes (319 newly sequenced and 671 from public databases) from patients with various diseases to comprehensively characterize genomic variations, including single nucleotide variations (SNVs) and structural variations (SVs). While most SNVs were a result of conservative evolution and reflected the geographical origins of the viral genomes, we identified several convergent SNV hotspots within the central homology domain of EBNA3B, the transactivation domain of EBNA2, and the second transmembrane domain of LMP1. These convergent SNVs appear to fine-tune viral protein functionality and immunogenicity. SVs, particularly large deletions, were frequently observed in chronic active EBV disease (28%), EBV-positive diffuse large B-cell lymphoma (48%), extranodal NK/T-cell lymphoma (41%), and Burkitt lymphoma (25%), but were less common in infectious mononucleosis (11%), post-transplant lymphoproliferative disorder (7%), and epithelial malignancies (5%). In hematological malignancies, deletions often targeted viral microRNA clusters, potentially promoting viral reactivation and lymphomagenesis. Non-deletion SVs, such as inversions, were also prevalent, with several inversions disrupting the C promoter to suppress latent gene expression, thereby maintaining viral dormancy. Furthermore, recurrent EBNA3B deletions suggested that this viral transcription factor functions as a tumor suppressor. EBNA3B knockout experiments in vitro revealed downregulation of human tumor suppressors, including PTEN and RB1, which could explain the enhanced lymphomagenesis observed in EBNA3B-deficient lymphoblastoid cell line xenografts. Our findings highlight both disease-specific and general contributions of EBV genomic alterations to human cancers, particularly in hematological malignancies.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"635 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488108","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}