Blood最新文献

{"title":"KPNA2-Mediated MYC Nuclear Import Enhances CAR-T Cell Memory and Potentiates Antitumor Efficacy.","authors":"Shi Han, Delin Kong, Chen Yang, Fang Ye, Juan Yue, Kexin Wang, Haiqiong Zheng, Zhuomao Mo, Xinghua Liang, Kejia Hu, Jianyu Wang, Penglei Jiang, Xia Li, Meng Zhang, Xiangjun Zeng, Yijin Chen, Lin Yang, Yanyan Wang, Mi Shao, Pengxu Qian, Yongxian Hu, He Huang, Dongrui Wang","doi":"10.1182/blood.2026034296","DOIUrl":"https://doi.org/10.1182/blood.2026034296","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy demonstrates remarkable clinical efficacy, yet limited persistence and functional exhaustion impede durable responses. While memory-like phenotypes are associated with sustained CAR-T function and improved clinical outcomes, the underlying molecular mechanisms of CAR-T cell memory maintenance remain incompletely defined and we still lack actionable strategy to sufficiently promote CAR-T cell memory formation. Here, we identified that Karyopherin Subunit Alpha 2 (KPNA2)-mediated MYC nuclear import robustly enhanced CAR-T cell memory and antitumor function. In clinical CAR-T cell products, KPNA2 expression and MYC pathway activation are correlated with superior therapeutic potency. Overexpressing MYC showed negligible effect on CAR-T cell function due to insufficient nuclear import; in contrast, incorporating KPNA2 in CAR-T cells facilitated MYC nuclear import, augmented memory formation, enhanced cytotoxicity and antitumor activity both in vitro and in vivo. Such functional improvement was not associated with risks of transformation in KPNA2-overexpressing CAR-T cells. Mechanistically, our integrated transcriptomic and epigenomic analyses revealed that KPNA2 increased MYC occupancy at memory-associated gene loci, upregulating T cell memory programs. Furthermore, virtual drug screening identified the small molecule TMS which potentiates KPNA2-MYC interaction. TMS treatment of CAR-T cells enhanced MYC nuclear accumulation, promoted memory-oriented transcriptional profiles, and improved antitumor potency in preclinical models. These findings established KPNA2-MYC interaction as a pivotal mechanism governing CAR-T cell memory formation, providing genetic and pharmacological strategies to advance therapeutic T cell design and manufacturing.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135074","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 Identify and Diagnose Carriers of Hemophilia and Women and Girls with Hemophilia.","authors":"Cédric Hermans, Catherine Lambert","doi":"10.1182/blood.2026033367","DOIUrl":"https://doi.org/10.1182/blood.2026033367","url":null,"abstract":"<p><p>Carriers of hemophilia and women and girls with hemophilia remain underdiagnosed despite increasing recognition that they may experience clinically significant bleeding, reduced clotting factor levels, and important reproductive and psychosocial challenges. Advances in coagulation testing, molecular genetics and international recommendations have improved their recognition and classification, yet substantial variability in clinical presentation and limited awareness continue to delay diagnosis and access to appropriate care. Furthermore, important disparities persist across healthcare systems, particularly in resource-limited settings. This article provides a practical, evidence-based approach to the identification, diagnosis and management of carriers of hemophilia and women and girls with hemophilia across a range of clinical situations encountered in everyday practice. We discuss the role of pedigree analysis, bleeding assessment, laboratory investigations, molecular diagnosis, genetic counselling and multidisciplinary management, while highlighting common diagnostic pitfalls, areas of uncertainty and current evidence supporting clinical decision-making. Improving recognition of carriers and women and girls with hemophilia requires a shift from an individual patient-centered approach to a family-centered model of care that promotes systematic identification of at-risk females, timely diagnosis and equitable access to comprehensive hemophilia services. Earlier recognition and appropriate management are essential to reduce bleeding complications, optimize reproductive care and improve lifelong health outcomes.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134991","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":"Prognostic impact of variant allele frequency in intensively treated patients with NPM1-mutated AML: a PETHEMA study.","authors":"José Vicente Gil, Claudia Sargas, Rosa Ayala, Norma Carmen Gutiérrez, José Antonio Pérez-Simón, María Teresa Gómez-Casares, María José Larrayoz, Esther Prados, Isabel Cano-Ferri, Irene Navarro, Cristina Gil, Teresa Bernal, Eduardo Rodríguez-Arbolí, Esther Pérez-Santaolalla, Rafael Colmenares, Mar Tormo, Juan Bergua, María Luz Amigo, Carlos Rodríguez-Medina, Josefina Serrano, Ana Yurena Oliva, Juan Manuel Alonso-Domínguez, Víctor Noriega, Lorenzo Algarra, Mayte Olave, María José García-Pérez, Carmen Couto, Ágata Almela, María García-Fortes, María Dolores Madrigal, María Lourdes Hermosín, Mercedes Colorado, Raimundo García-Boyero, Francisco Ibáñez, María Solé, Carmen Martínez-Chamorro, María Del Carmen Mateos, María Del Carmen García-Garay, Antonio Solana-Altabella, Beatriz Martín-Herreros, Joaquín Martínez-López, María Del Carmen Chillón, Elena Soria, Cristina Bilbao-Syeiro, María José Calasanz, Joaquín Sánchez-García, Eva Barragán, Pau Montesinos","doi":"10.1182/blood.2026033576","DOIUrl":"10.1182/blood.2026033576","url":null,"abstract":"<p><strong>Abstract: </strong>NPM1-mutated acute myeloid leukemia (AML) is genetically well defined, but clinical outcomes remain heterogeneous, suggesting that quantitative clonal features may refine current risk stratification. We analyzed 688 intensively treated NPM1-mutated (NPM1mut) AML integrating variant allele frequency (VAF), mutation order, and clonal architecture inferred by PyClone and ClonEvol. Comutations were present in 97% of patients (median, 3 per case), dominated by DNMT3A (49%), FLT3-ITD (46%), TET2 (22%), and IDH2 (20%). Prognostic modeling of NPM1 VAF identified an optimal cutoff of 31.44%, defining NPM1high and NPM1low groups. NPM1low correlated with splicing-related alterations and independently predicted inferior overall survival (hazard ratio [HR], 1.46; P = .037) and relapse-free survival (HR, 1.40; P = .036). Gene-specific VAF analyses revealed divergent effects across partners: high DNMT3A, FLT3-OTHER (non-ITD/TKD), KRAS, and PTPN11 burdens were adverse, whereas high IDH2 VAF was protective. Combined models showed that patients with NPM1high and favorable comutation VAFs had the best outcomes, whereas dual unfavorable burdens conferred the poorest survival. Mutation ordering inferred from VAFs positioned NPM1 after epigenetic and splicing lesions but before signaling and transcription-factor mutations. Noncanonical orders, such as early FLT3-OTHER/TKD or WT1 before NPM1, significantly stratified outcomes. Clonal reconstruction revealed predominantly linear evolutionary trajectories (84.3%), with increased mutational burden and clonal diversity associating with inferior survival. Notably, intraclonal colocalization of NPM1 with IDH1 or TET2 was associated with improved outcomes, whereas colocalization with WT1 predicted dismal prognosis. These results demonstrate that quantitative and structural dimensions of clonality refine the biological and prognostic landscape of NPM1-mutated AML beyond mutational status alone.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1911-1924"},"PeriodicalIF":23.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204113","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":"Decoding factor XI inhibition.","authors":"Richard C Becker","doi":"10.1182/blood.2026035067","DOIUrl":"https://doi.org/10.1182/blood.2026035067","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"148 15","pages":"1859-1860"},"PeriodicalIF":23.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135118","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":"TGF-β-PDL1 signaling in neutrophils preserves the lung barrier during hyperinflammation.","authors":"Ziyi Li, Andrew R Moore, Hong Zheng, Janmes Karunamurthy, Aanya Bhagrath, Jiangxue Li, Daniel Young, Leonardo F Jurado, Katalina Couto, Amelia Kulle, Haley Park, Ashley Kwak, Vaishnav Belur, Sebastien Talbot, Maziar Divangahi, Antonio DiGiandomenico, Angela Rogers, Taylor S Cohen, Allen J Ehrlicher, Judith N Mandl, Jing Wang, Antoine Dufour, Purvesh Khatri, Ajitha Thanabalasuriar","doi":"10.1182/blood.2025031635","DOIUrl":"10.1182/blood.2025031635","url":null,"abstract":"<p><strong>Abstract: </strong>The hyperinflammatory syndromes in patients who are critically ill, including those with trauma injury, sepsis, and acute lung injury, are characterized by dysregulated neutrophil responses that contribute to tissue damage and poor outcomes. Using murine models of cytokine storm induced by trauma and lung injury, we identified transforming growth factor β (TGF-β) as a central regulator of immune checkpoints in neutrophils. TGF-β signaling modulates neutrophil activation and upregulates the expression of programmed death-ligand 1 (PDL1). Disruption of TGF-β signaling during hyperinflammation restores the migratory capacity of neutrophils but leads to excessive activation, severe pulmonary tissue damage, and increased susceptibility to spontaneous bacterial infection in the lung. Mechanistically, PDL1 expression alters neutrophil behavior within lung capillaries, promoting intravascular clustering and restricting tissue infiltration. Targeted deletion of PDL1 in neutrophils reverses hyperinflammation-induced clustering, restores effective trafficking to infectious foci, and enhances host-protective immune function while limiting pathological neutrophil hyperactivation. These findings define a TGF-β-PDL1 regulatory axis that restrains the pathogenicity of neutrophils during hyperinflammation, revealing a checkpoint mechanism that balances host defense and tissue integrity.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1925-1940"},"PeriodicalIF":23.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970230","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":"From specialized centers to community care: expanding the reach of CAR T-cell therapy.","authors":"Helen E Heslop","doi":"10.1182/blood.2026035567","DOIUrl":"10.1182/blood.2026035567","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"148 15","pages":"1855-1857"},"PeriodicalIF":23.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135105","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":"Anticoagulation with the mechanistically distinct FXI/FXIa antibodies amrecibart (REGN9933A2) and cenvacibart (REGN7508Cat).","authors":"Dan Chalothorn, Aaron P Kithcart, Ethan Marin, Selin Somersan-Karakaya, KehDih Lai, Frederic Cauwberghs, Jonathan Ackroyd, Kusha Mohammadi, Anju Shrestha, George Ehrlich, Ashique Rafique, Ishita Chatterjee, Kei Saotome, Matthew C Franklin, Andrew J Murphy, William Olson, Benjamin A Olenchock, Gary A Herman, David E Gutstein, Andres Sirulnik, George D Yancopoulos, Lori G Morton","doi":"10.1182/blood.2025032276","DOIUrl":"10.1182/blood.2025032276","url":null,"abstract":"<p><strong>Abstract: </strong>Thrombosis is a major contributor to global morbidity and mortality. Current standards of care target the extrinsic and/or common pathways of coagulation, effectively inhibiting thrombosis but also increasing bleeding risk, highlighting the unmet need for additional treatment options. Genetic deficiency in factor XI (FXI), a component of the intrinsic pathway, reduces thrombosis risk without spontaneous bleeding. We generated 2 FXI monoclonal antibodies (mAbs) with distinct profiles to provide new approaches to anticoagulation. Cenvacibart (REGN7508Cat) targets the catalytic domain to completely block FXI activity (induced by activated FXII [FXIIa] or activated FXI [FXIa] in the intrinsic pathway or thrombin in the intrinsic/common pathway amplification loop), thereby maximizing anticoagulation. Amrecibart (REGN9933A2) targets the apple 2 domain of FXI/FXIa to specifically prevent FXI activity induced by FXIIa, delivering perhaps less anticoagulation but with potentially lower bleeding risk. We evaluated the anticoagulant effects of both mAbs in vitro in human and nonhuman primate plasma, in vivo in nonhuman primates, and healthy volunteers. Both mAbs inhibited intrinsic pathway-triggered coagulation, assessed by activated partial thromboplastin time (aPTT); cenvacibart exhibited a greater increase in aPTT vs amrecibart or other FXI-targeted inhibitors. Neither amrecibart nor cenvacibart affected the extrinsic pathway, assessed by prothrombin time (PT). In nonhuman primates, both mAbs prevented thrombosis without increasing bleeding. In first-in-human studies, both mAbs were generally well tolerated and dose-dependently inhibited intrinsic pathway-triggered coagulation, with durable aPTT prolongation without affecting PT. Amrecibart and cenvacibart may offer tailored therapies for patients with different bleeding risk profiles. These trials were registered at www.clinicaltrials.gov as NCT05102136 and NCT05603195.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1867-1879"},"PeriodicalIF":23.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223148","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":"NPM1 mutations in AML: does size matter?","authors":"Peter J M Valk","doi":"10.1182/blood.2026035724","DOIUrl":"https://doi.org/10.1182/blood.2026035724","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"148 15","pages":"1863-1864"},"PeriodicalIF":23.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135095","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 origins of rare glycosylphosphatidylinositol-deficient cells in normal and immune-mediated hematopoiesis","authors":"Yoshitaka Zaimoku,Dung Cao Tran,Kazuyoshi Hosomichi,Hiroki Mizumaki,Yui Kano,Miku Kobayashi,Eriko Morishita,Tatsuya Imi,Kohei Hosokawa,Yasuhito Nannya,Seishi Ogawa,Hirohito Yamazaki,Toshihiro Miyamoto,Shinji Nakao","doi":"10.1182/blood.2026033685","DOIUrl":"https://doi.org/10.1182/blood.2026033685","url":null,"abstract":"Single-cell-resolution PIGA sequencing showed that rare glycosylphosphatidylinositol-deficient cells in healthy individuals are polyclonal, comprising long-lived hematopoietic stem/progenitor-derived clones and nonpersistent populations. Those in acquired aplastic anemia reflect the selective expansion of multipotent PIGA-mutant stem/progenitor cells across myeloid and lymphoid lineages.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"53 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088468","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 Heavy Menstrual Bleeding in Patients with Bleeding Disorder of Unknown Cause","authors":"Johanna Gebhart,Dino Mehic,Ingrid Pabinger","doi":"10.1182/blood.2026033364","DOIUrl":"https://doi.org/10.1182/blood.2026033364","url":null,"abstract":"Bleeding disorder of unknown cause (BDUC) describes patients with a clinically relevant bleeding phenotype despite normal routine hemostatic testing. Heavy menstrual bleeding (HMB) is among the most common symptoms in BDUC, alongside other muco-cutaneous bleeding manifestations. We recommend that women presenting with HMB undergo a systematic evaluation for an underlying bleeding disorder. This assessment should include a structured bleeding and family history, exclusion of acquired causes of bleeding, and comprehensive laboratory investigations. In case of a clinically relevant bleeding phenotype and normal hemostatic results, the diagnosis of BDUC can be established. In BDUC, targeted hemostatic treatments are not available. Management of HMB in BDUC requires an interdisciplinary, multimodal approach that includes hormonal therapy including intrauterine devices, antifibrinolytics and, in selected cases, surgical or other invasive interventions. Iron deficiency is frequent in women with HMB and BDUC and contributes substantially to fatigue and impaired quality of life, thus requiring targeted screening. Despite the considerable clinical burden, evidence to guide management of HMB in women with BDUC remains limited. Here, we report on representative clinical cases to highlight key challenges, summarize the available evidence, and outline a pragmatic approach for the management of HMB in patients with BDUC.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"16 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088469","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}