Blood最新文献

{"title":"3D insights: JAK2 46/1 haplotype shapes MPN development.","authors":"Inge van der Werf,Catriona H M Jamieson","doi":"10.1182/blood.2025028547","DOIUrl":"https://doi.org/10.1182/blood.2025028547","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"37 1","pages":"2112-2114"},"PeriodicalIF":20.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921051","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":"STING activation improves T-cell-engaging immunotherapy for acute myeloid leukemia.","authors":"Andreas Linder, Daniel Nixdorf, Niklas Kuhl, Ignazio Piseddu, TengTeng Xu, Anne V Holtermann, Gunnar Kuut, Rebekka Endres, Nora Philipp, Veit Bücklein, Johann de Graaff, Thomas Carell, Sebastian Kobold, Roman Kischel, Veit Hornung, Marion Subklewe","doi":"10.1182/blood.2024026934","DOIUrl":"10.1182/blood.2024026934","url":null,"abstract":"<p><strong>Abstract: </strong>T-cell-recruiting bispecific antibodies (BsAbs) are in clinical development for relapsed/refractory acute myeloid leukemia (AML). Despite promising results, early clinical trials have failed to demonstrate durable responses. We investigated whether activation of the innate immune system through stimulator of interferon (IFN) genes (STING) can enhance target cell killing by a BsAb targeting CD33 (CD33 bispecific T-cell engager molecule; AMG 330). Indeed, we show that cytotoxicity against AML mediated by AMG 330 can be greatly enhanced when combined with the STING agonist 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) or diamidobenzimidazole (diABZI). We used in vitro cytotoxicity assays, immunoblotting, transcriptomic analyses, and extensive CRISPR-Cas9 knockout experiments to investigate the enhancing effect of a STING agonist on the cytotoxicity of AMG 330 against AML. Importantly, we validated our findings with primary AML cells and in a xenograft AML model. Mechanistically, in addition to direct cytotoxic effects of STING activation on AML cells, activated T cells render AML cells more susceptible to STING activation through their effector cytokines, IFN-γ and tumor necrosis factor, resulting in enhanced type I IFN production and induction of IFN-stimulated genes. This feeds back to the T cells, leading to a further increase in effector cytokines and an overall cytotoxic T-cell phenotype, contributing to the beneficial effect of cGAMP/diABZI in enhancing AMG 330-mediated lysis. We established a key role for IFN-γ in AMG 330-mediated cytotoxicity against AML cells and in rendering AML cells responsive to STING agonism. Here, we propose to improve the efficacy of CD33-targeting BsAbs by combining them with a STING agonist.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2149-2160"},"PeriodicalIF":21.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514609","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":"STING activation enhances immunotherapy of AML.","authors":"Dieter Kabelitz,Guranda Chitadze","doi":"10.1182/blood.2025028653","DOIUrl":"https://doi.org/10.1182/blood.2025028653","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"44 1","pages":"2106-2108"},"PeriodicalIF":20.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921053","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":"CpG island methylator phenotype classification improves risk assessment in pediatric T-cell acute lymphoblastic leukemia.","authors":"Fernanda Schäfer Hackenhaar, Nina Refhagen, Melanie Hagleitner, Frank van Leeuwen, Hanne Vibeke Marquart, Hans Ole Madsen, Mattias Landfors, Pia Osterman, Kjeld Schmiegelow, Trond Flaegstad, Ólafur Jónsson, Jukka Kanerva, Jonas Abrahamsson, Mats Heyman, Ulrika Norén Nyström, Magnus Hultdin, Sofie Degerman","doi":"10.1182/blood.2024026027","DOIUrl":"10.1182/blood.2024026027","url":null,"abstract":"<p><strong>Abstract: </strong>Current intensive treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has substantial side effects, highlighting a need for novel biomarkers to improve risk stratification. Canonical biomarkers, such as genetics and immunophenotype, are largely not used in pediatric T-ALL stratification. This study aimed to validate the prognostic relevance of DNA methylation CpG island methylator phenotype (CIMP) risk stratification in 2 pediatric T-ALL patient cohorts: the Nordic Society of Paediatric Haematology (NOPHO) ALL2008 T-ALL study cohort (n = 192) and the Dutch Childhood Oncology Group (DCOG) ALL-10/ALL-11 validation cohorts (n = 156). Both cohorts revealed that combining CIMP classification at diagnosis with measurable residual disease (MRD) at treatment day 29 (D29) or 33 (D33) significantly improved outcome prediction. The poor prognosis subgroup, characterized by CIMP low/D29 or D33 MRD ≥ 0.1%, had a cumulative incidence of relapse (pCIR5yr) of 29% and 23% and overall survival (pOS5yr) of 59.7% and 65.4%, in NOPHO and DCOG, respectively. Conversely, a good prognosis subgroup was also identified representing CIMP high/D29 or D33 MRD < 0.1% with pCIR5yr of 0% and 3.4% and pOS5yr of 98.2% and 94.8%, in NOPHO and DCOG, respectively. For NOPHO, MRD was also evaluated on D15, and the relapse prediction accuracy of CIMP/D29 MRD (0.79) and CIMP/D15 MRD (0.75) classification was comparable, indicating potential for earlier stratification. The evaluation of the biology behind the CIMP subgroups revealed associations with transcriptome profiles, genomic aberrations, and mitotic history, suggesting distinct routes for leukemia development. In conclusion, integrating MRD assessment with the novel CIMP biomarker has the potential to improve risk stratification in pediatric T-ALL and guide future therapeutic decisions.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2161-2178"},"PeriodicalIF":21.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999345","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":"Babesiosis and sickle red blood cells: loss of deformability, altered osmotic fragility, and hypervesiculation.","authors":"Divya Beri, Marilis Rodriguez, Manpreet Singh, Daniel McLaughlin, Yunfeng Liu, Hui Zhong, Avital Mendelson, Xiuli An, Deepa Manwani, Karina Yazdanbakhsh, Cheryl A Lobo","doi":"10.1182/blood.2024027602","DOIUrl":"10.1182/blood.2024027602","url":null,"abstract":"<p><strong>Abstract: </strong>Babesiosis in sickle cell disease (SCD) is marked by severe anemia but the underlying red blood cell (RBC) rheologic parameters remain largely undefined. Here, we describe altered RBC deformability from both primary (host RBC sickle hemoglobin mediated) and secondary changes (Babesia parasite infection mediated) to the RBC membrane using wild-type AA, sickle trait AS, and sickle SS RBCs. Our ektacytometry analysis demonstrates that the changes in the host RBC biomechanical properties, before and after Babesia infection, reside on a spectrum of severity, with wild-type infected AA cells, despite showing a significant reduction of deformability under both shear and osmolarity gradients, exhibiting only a mild phenotype, compared with infected AS RBCs that show median changes in deformability and infected SS RBCs that exhibit the most dramatic impact of infection on cellular rheology, including an increase in point of sickling values. Furthermore, using ImageStream cytometric technology to quantify changes in cellular shape and area along with a tunable resistive pulse sensor to measure release of extracellular vesicles from these host RBCs, before and after infection, we offer a potential mechanistic basis for this extreme SS RBC rheologic profile, which include enhanced sickling rates and altered osmotic fragility, loss of RBC surface area, and hypervesiculation in infected SS host RBCs. These results underline the importance of understanding the impact of intraerythrocytic parasitic infections of SCD RBCs, especially on their cellular membranes and studying the mechanisms that lead to hyperhemolysis and extreme anemia in patients with SCD.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2202-2213"},"PeriodicalIF":21.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051772","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":"The JAK2 46/1 haplotype influences PD-L1 expression.","authors":"Gonzalo Carreño-Tarragona, María Tiana, Raquel Rouco, Alejandra Leivas, Jesús Victorino, Roberto García-Vicente, Andrew J Chase, Andrea Maidana, William J Tapper, Rosa Ayala, Nicholas C P Cross, Joaquín Martínez-López, Miguel Manzanares","doi":"10.1182/blood.2023023787","DOIUrl":"10.1182/blood.2023023787","url":null,"abstract":"<p><strong>Abstract: </strong>Although described more than a decade ago, the mechanism by which the JAK2 46/1 haplotype increases the risk of developing JAK2-mutated myeloproliferative neoplasms (MPNs) remains unexplained. Inflammation and immunity are linked to MPN development and thus could be relevant to the mechanism by which 46/1 mediates its effect. Here, we show that programmed death-1 receptor ligand (PD-L1) expression is elevated in 46/1 haplotype, both in healthy carriers and in CD34+ cells from patients with MPN. Using circular chromosome conformation capture, we observed that PD-L1 and the neighboring PD-L2 loci physically interact with JAK2 in a manner that differs between 46/1 and nonrisk haplotypes. CRISPR/Cas9 genome editing identified a region within JAK2 intron 2 that influences both JAK2 and PD-L1 expression. We suggest that increased PD-L1 expression may be relevant to the mechanism by which 46/1 leads to an increased inherited risk of developing MPN.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2196-2201"},"PeriodicalIF":21.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370299","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":"Defining pathogenic IL-17 and CSF-1 gene expression signatures in chronic graft-versus-host disease.","authors":"Julie R Boiko, Kathleen S Ensbey, Olivia G Waltner, Isaac C Jenkins, Shruti S Bhise, Kelli P A MacDonald, Bruce R Blazar, A Marcie Hall, Ted A Gooley, Simone A Minnie, Stephanie J Lee, Scott N Furlan, Geoffrey R Hill","doi":"10.1182/blood.2024025337","DOIUrl":"10.1182/blood.2024025337","url":null,"abstract":"<p><strong>Abstract: </strong>Chronic graft-versus-host disease (cGVHD) remains the leading cause of nonrelapse morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Effective therapeutic agents targeting dysregulated cytokines including interleukin-17 (IL-17) and colony-stimulating factor 1 (CSF-1) have been defined in preclinical models of cGVHD, and efficacy in subsequent clinical trials has led to their recent US Food and Drug Administration approval. Despite this, these agents are effective in only a subset of patients, expensive, difficult to access outside the United States, and used in a trial-and-error fashion. The ability to readily discern druggable, dysregulated immunity in these patients is desperately needed to facilitate the selection of appropriate treatment and to potentially identify high-risk individuals for preemptive therapy. We used single-cell sequencing-based approaches in our informative preclinical cGVHD models to \"reverse engineer\" temporal IL-17 and CSF-1 signatures in mouse blood that could be used to interrogate patients. We defined distinct, nonintuitive IL-17 and CSF-1 signatures in mouse blood monocytes that could be identified in relevant monocyte populations within 70% of patients at diagnosis of cGVHD and in half of patients at day +100 after HCT who subsequently developed cGVHD. These signatures can now be evaluated prospectively in clinical studies to help delineate potential responder and nonresponders to relevant therapeutics targeting these pathways.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2214-2228"},"PeriodicalIF":21.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466937","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":"Hu L, Shi Y, Hsu J, Gera J, Van Ness B, Lichtenstein A. Downstream effectors of oncogenic ras in multiple myeloma cells. Blood. 2003;101(8):3126-3135.","authors":"","doi":"10.1182/blood.2025029190","DOIUrl":"10.1182/blood.2025029190","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2232"},"PeriodicalIF":21.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613270","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":"Babesia not only is invasive but creates RBC inflexibility.","authors":"Ryan P Jajosky,Sean R Stowell","doi":"10.1182/blood.2025028446","DOIUrl":"https://doi.org/10.1182/blood.2025028446","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"26 1","pages":"2114-2115"},"PeriodicalIF":20.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921054","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":"Luskin MR, Murakami MA, Keating J, et al. Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia. Blood. 2025;145(6):577-589.","authors":"","doi":"10.1182/blood.2025029277","DOIUrl":"https://doi.org/10.1182/blood.2025029277","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"56 1","pages":"2231"},"PeriodicalIF":20.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921058","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}