Blood最新文献

{"title":"Wagner DL, Elsallab M, Maus MV. Promises and potential pitfalls of in vivo CAR gene therapy. Blood. 2026;148(5):535-544.","authors":"","doi":"10.1182/blood.2026036165","DOIUrl":"https://doi.org/10.1182/blood.2026036165","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"148 14","pages":"1854"},"PeriodicalIF":23.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104160","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":"Enhanced factor VIII activation accelerates thrombin generation and hemostatic potency in mice","authors":"Lacramioara Ivanciu,Mettine H.A. Bos,Sudharsan Parthasarathy,Raffaella Toso,Rodney M. Camire","doi":"10.1182/blood.2026034984","DOIUrl":"https://doi.org/10.1182/blood.2026034984","url":null,"abstract":"Factor VIII (FVIII) circulates as an inactive procofactor and is converted to its active form (FVIIIa) by proteolytic cleavage at Arg372, Arg740, and Arg1689. Although these cleavage events are well characterized, their individual contributions to FVIII activation and hemostatic function remain incompletely defined. To address this, we engineered a FVIII variant (FVIII-2RKR) in which the B-domain and acidic region 3 region were replaced with a PACE/furin processing site, generating a molecule that requires only cleavage at Arg372 for conversion to FVIIIa. FVIII-2RKR exhibited markedly increased apparent activity in plasma-based assays, shortened thrombin generation lag time, and enhanced factor Xa (FXa) generation compared with B-domain-deleted FVIII, whereas both proteins were functionally equivalent following thrombin activation. FVIII-2RKR was cleaved more rapidly at Arg372 by thrombin and FXa, demonstrating that processing at Arg740 and Arg1689 regulates the rate of Arg372 cleavage rather than directly contributing to cofactor activity. In hemophilia A mice, FVIII-2RKR consistently enhanced early hemostatic function across ferric chloride, laser injury, and tail bleeding models, achieving improved efficacy at lower doses. Despite reduced half-life due to impaired von Willebrand factor (vWF) binding, FVIII-2RKR remained effective in vWF-deficient mice, indicating that vWF is not required for local FVIII function at sites of vascular injury. Together, these findings define distinct roles for FVIII activation cleavage sites and demonstrate that processing at Arg740 and Arg1689 regulates activation through Arg372, linking the rate of FVIII activation to hemostatic efficacy in vivo.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"8 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092353","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":"Systems reboot: a niche-based approach to AML","authors":"David T. Scadden","doi":"10.1182/blood.2026035279","DOIUrl":"https://doi.org/10.1182/blood.2026035279","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"16 1","pages":"1758-1759"},"PeriodicalIF":20.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088550","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":"Fetal Anemia and Hemodynamic Adaptation in Hemoglobin H Disease: A Longitudinal Prospective Study","authors":"Theera Tongsong,Suchaya Luewan,Pimlak Charoenkwan,Chanane - Wanapirak,Supatra Sirichotiyakul,Pakorn Chaksuwat,Rajavadi Tanvisut,Wisit Chankhunaphas,Phenphan Santanapipatkul,Panwad Harn-a-morn,Nitchanut Chaipongpun,Krittaya Phirom,Srimeunwai Ake-sittipaisarn,Panisa Hantrakun,Rapeepat Auekitrungrueng","doi":"10.1182/blood.2026034839","DOIUrl":"https://doi.org/10.1182/blood.2026034839","url":null,"abstract":"Hemoglobin H (Hb H) disease, including deletional (Hb H-del) and non-deletional forms such as Hb H-Constant Spring disease (Hb H-CS), is highly prevalent in Asia. Its natural history and fetal hemodynamic changes remain inadequately characterized. The objective of this study is to characterize the natural history of fetal anemia and associated hemodynamic alterations in Hb H-del and Hb H-CS. At-risk pregnancies identified through α-thalassemia carrier screening prospectively underwent serial assessment of fetal anemia using middle cerebral artery-peak systolic velocity (MCA-PSV) and hemodynamic parameters using fetal echocardiography. Cordocentesis and intrauterine transfusion (IUT) were performed when indicated. Neonatal hematologic and genotypic evaluations were conducted postnatally. Among 389 at-risk pregnancies, 60 fetuses had Hb H-del and 22 had Hb H-CS. MCA-PSV MoM was significantly elevated in affected fetuses, particularly in Hb H-CS. In affected fetuses, MCA-PSV increased after mid-gestation, reached the highest level in the late second to early third trimester, and partially normalized near term. Cardiac enlargement, Tei index, and cardiac output were significantly increased, more prominently in Hb H-CS. Rates of significant anemia, reflected by MCA-PSV>1.5 MoM, and hydrops were higher in Hb H-CS than Hb H-del; 22.7% vs 13.6% and 8.3% vs 1.7%, respectively. In conclusion, Hb H disease is characterized by an exacerbation of fetal anemia and cardiac overload after mid-gestation with more severity in Hb H-CS fetuses. These findings provide a rationale for incorporating antenatal assessment into the management of pregnancies affected by Hb H disease and support further evaluation of proactive intrauterine management strategies in selected cases.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"21 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088551","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":"­­Paneth cell niche function is critical for intestinal stem cells in radiation injury but dispensable in GVHD","authors":"Viktor Arnhold,Winston Yun-Han Chang,Marco Calafiore,Riley Outen,Shuichiro Takashima,Marina Burgos da Silva,Ya-Yuan Fu,Paola Vinci,Takahiro Ito,Anastasiya Egorova,Jason Kuttiyara,Chen Liu,Doris M. Ponce,Alan M. Hanash","doi":"10.1182/blood.2025032430","DOIUrl":"https://doi.org/10.1182/blood.2025032430","url":null,"abstract":"Paneth cells (PCs) produce WNT3 and EGF in the small intestine and are thought to contribute to the intestinal stem cell (ISC) niche, which is a target of graft vs. host disease (GVHD). However, PC deletion models have failed to demonstrate substantial consequences for ISCs or other epithelial pathology. The physiologic role of PC niche function has thus remained opaque, and the significance of this function after bone marrow transplantation (BMT) is poorly understood. Using Lysozyme1-DTR mice to ablate PCs, we found stable WNT3 expression in vivo, and crypts from PC-ablated mice retained organoid-forming capacity, further reflecting persistent WNT3 production. However, PC ablation reduced EGF expression and increased intestinal radiation injury. Irradiated PC-deficient mice exhibited attenuated epithelial regeneration and exacerbated ISC and crypt loss, which were restored by exogenous EGF administration, thus indicating EGF-dependent PC contributions in radiation injury. In contrast, after allogeneic BMT, PC ablation and the associated EGF reduction had no substantial impact on intestinal pathology or systemic GVHD. WNT3 levels were comparable between PC-intact and PC-deficient BMT recipients, and other secretory cells emerged as potential alternative WNT3 sources. Furthermore, human duodenal biopsies from transplant patients demonstrated persistence of goblet and enteroendocrine cells in clinical GVHD, despite PC reductions, resulting in overall stable secretory lineage frequencies. These findings highlight an essential role for PC niche function as a nonredundant source of EGF in radiation injury. However, this function is dispensable in experimental GVHD. PC reductions in GVHD may thus reflect injury severity more than they contribute to it.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"8 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088605","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":"Liso-cel delivers: is the debate over for 3L FL?","authors":"Karina N. Ruiz-Esteves,Caron A. Jacobson","doi":"10.1182/blood.2026035205","DOIUrl":"https://doi.org/10.1182/blood.2026035205","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"5 1","pages":"1756-1758"},"PeriodicalIF":20.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088552","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":"Inhibition of mitochondrial permeability transition selectively suppresses thrombogenic platelet procoagulant activity","authors":"Yiheng Zhang,Jordan Sandler,Osamede Clinton Owegie,Xu Zhang,Vrishank Shivaprakash,Jack Kurth,Yong Sun,Mayu Morita,Raquel Mote,Neva Scott,Gavin Hutchison,Eliana Choi,Helena Ventosa-Capell,Jiaqing Pang,Cristina Puy,Yabing Chen,Terry Morgan,Owen JT McCarty,Moua Yang,Michael Cohen,Joseph E Aslan","doi":"10.1182/blood.2025032930","DOIUrl":"https://doi.org/10.1182/blood.2025032930","url":null,"abstract":"Platelets support coagulation by externalizing phosphatidylserine (PS), creating a catalytic surface for thrombin generation and fibrin formation. Although platelet PS exposure is required for hemostasis, excessive procoagulant platelet activity drives thrombosis. Sustained calcium influx after strong agonist stimulation promotes mitochondrial permeability transition pore (mPTP) opening, mitochondrial depolarization and calcium amplification that commit platelets to PS-high procoagulant states. Existing approaches to suppress this pathway are limited by the hemostatic requirement for platelet PS exposure and pleiotropic effects of cyclophilin-targeting agents. Here, we use a series of newly developed cyclophilin D-independent small molecule mPTP inhibitors to define how mPTP opening regulates procoagulant platelet activity. Under GPVI/PAR-driven procoagulant conditions, MC63, TR001 and TR002 preserved mitochondrial membrane potential, prevented intracellular calcium overload and reduced PS/P-selectin-positive platelets, microparticle release and membrane blebbing, while preserving agonist-induced calcium mobilization, secretion, integrin activation, aggregation, F-actin assembly and clot retraction. Mechanistically, mPTP inhibition limited calcium-dependent phosphatase, protease and mitochondrial activities associated with procoagulant platelet conversion. MC63, TR001 and TR002 reduced platelet-dependent thrombin generation and fibrin formation without affecting platelet-independent thrombin activity. In whole blood perfused over collagen, mPTP inhibitors reduced PS-positive platelets within thrombi without impairing platelet accumulation. In vivo, mPTP inhibitors decreased platelet and fibrin accumulation after laser-induced arteriolar injury but did not prolong tail bleeding alone or in combination with acetylsalicylic acid. Together, these findings identify mPTP opening as a druggable checkpoint for platelet procoagulant commitment and support mPTP inhibition as an antithrombotic strategy that may preserve hemostasis.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"9 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092351","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":"Efficacy and safety of tirabrutinib monotherapy for relapsed/refractory primary CNS lymphoma: PROSPECT phase 2 trial","authors":"Christian Grommes,Lakshmi Nayak,Avyakta Kallam,David Peereboom,Prakash Ambady,Joe S Mendez,Dawit Aregawi,Ashley Sumrall,Antonio Omuro,Fabio M. Iwamoto,Jörg Dietrich,Yoshie Umemura,Reinhold Munker,Ugonma Nnenna Chukwueke,Lauren R. Schaff,Andrew Ip,Neel K. Gupta,Jan Drappatz,Vyshak A Venur,Katherine B. Peters,Ka-Wai G Ho,Ryan Merrell,Sergio Prados,Akira Takazawa,Arata Aoi,Tracy T Batchelor","doi":"10.1182/blood.2026034926","DOIUrl":"https://doi.org/10.1182/blood.2026034926","url":null,"abstract":"Primary central nervous system lymphoma (PCNSL) is an aggressive subtype of non-Hodgkin lymphoma with a poor prognosis, high rate of refractory or relapsed (R/R) disease, and no established standard of care for R/R PCNSL. This phase 2 study evaluated the efficacy and safety of tirabrutinib, a potent, highly selective, second-generation Bruton tyrosine kinase inhibitor, in patients with R/R PCNSL in the US. In the open-label PROSPECT study, adults with R/R PCNSL whose disease progressed on or after ≥1 high-dose methotrexate-based therapy received once-daily oral tirabrutinib 480 mg. The primary endpoint was overall response rate (ORR), and secondary endpoints included complete response (CR) rate, duration of response (DOR), and time to response (TTR), as assessed by independent review committee. Safety was assessed by frequency and severity of treatment-emergent adverse events (TEAEs). Among 48 enrolled patients, median follow-up was 11.5 months, ORR was 67% (95% confidence interval [CI], 52-80), and CR rate was 44% (95% CI, 29-59). Median DOR was 9.3 months (95% CI, 4.6-14.6), and median TTR was 1.0 month (range, 0.9-3.7). Treatment-related TEAEs occurred in 36 patients (75%), most commonly anemia (19%), maculopapular rash (17%), fatigue (15%), neutropenia (15%), lymphocytopenia (15%), pruritus (15%), and other rash (15%). Grade ≥3 treatment-related TEAEs occurred in 13 patients (27%), most commonly neutropenia (8%) and maculopapular rash (6%). One death (bronchopulmonary aspergillosis) was treatment related. In patients with R/R PCNSL, once-daily oral tirabrutinib monotherapy resulted in rapid and durable responses and demonstrated a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04947319.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"167 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088554","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":"Leukemia-associated myeloid cells support distinct T-ALL subtypes via unique signals converging on metabolic alterations","authors":"Seohee Nam,Doris Narki Tetteh,Elizabeth M Kappil,Eleanor D. Mauk,John F Moore,Dhivya Arasappan,Dennis C Wylie,Aram Lyu,Ryan S. Humphrey,Xiaolu A Cambronne,Terzah M. Horton,Lauren I R Ehrlich","doi":"10.1182/blood.2026033335","DOIUrl":"https://doi.org/10.1182/blood.2026033335","url":null,"abstract":"Although intensified chemotherapy regimens have improved survival of T-cell acute lymphoblastic leukemia (T-ALL) patients, treatment-related toxicities and poor outcomes following relapse highlight the need for alternative therapeutics. Our previous studies showed that leukemia-associated myeloid cells support T-ALL progression, suggesting myeloid cells or associated signals could serve as therapeutic targets. It remains unknown whether leukemia-associated myeloid cells support multiple molecular subtypes of T-ALL, and if so, whether subtype-specific mechanisms are involved. We demonstrate that tumor-associated myeloid cells support survival of both Early T-cell Progenitor (ETP)-like and non-ETP-like T-ALL subtypes from the LMO2 mouse model in vitro and in vivo. Transcriptional profiling and in vitro assays of mouse and human T-ALL reveal that myeloid cells support distinct T-ALL subtypes via different signaling pathways: IL6ST/STAT3 signaling supports ETP-like T-ALL, while growth factor receptor signaling supports non-ETP-like T-ALL. Notably, both subtypes require AKT activation for myeloid-mediated support, and acute myeloid depletion in vivo induces a common metabolic shift towards oxidative phosphorylation (OxPhos). These findings suggest that myeloid cells promote T-ALL survival via subtype-specific signals that converge on a common pathway regulating metabolism. The shared metabolic adaptation to myeloid cell loss suggests a compensatory mechanism enabling T-ALL persistence under stress. Consistent with this possibility, combining myeloid depletion with OxPhos inhibition reduces survival of mouse and patient T-ALL cells and prolongs leukemic mouse survival more than either single treatment. Our data highlight unique and shared mechanisms by which myeloid cells support T-ALL subtypes and implicate tumor-myeloid interactions and downstream metabolic reprogramming as promising therapeutic targets.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"14 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088555","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":"Functional Classification of Monoallelic TP53 Mutations Refines Prognostic Stratification in Myelodysplastic Neoplasms","authors":"Alexander Streuer,Yotaro Ochi,Stephan Hutter,Vladimir Riabov,Yasuhito Nannya,Laurenz Steiner,Mohammed Abba,Georgia Metzgeroth,Eva Altrock,Felicitas Rapp,Verena Nowak,Edin Hepgülüm,Steffen Boettcher,Torsten Haferlach,Daniel Nowak,Wolf-Karsten Hofmann,Seishi Ogawa,Nanni Schmitt","doi":"10.1182/blood.2026034224","DOIUrl":"https://doi.org/10.1182/blood.2026034224","url":null,"abstract":"TP53 mutations represent one of the strongest adverse prognostic factors in myelodysplastic neoplasms (MDS). While multi-hit TP53 (TP53multiHit) alterations uniformly lead to very poor outcomes, the prognostic relevance of monoallelic TP53 (TP53mono) mutations remains controversial. TP53 variants can cause dominant-negative, loss-of-function, or gain-of-function effects. We hypothesized that functional heterogeneity among TP53 variants contributes to the variable clinical behavior observed in TP53mono-mutated MDS. Therefore, we analyzed pretreatment samples from 4,505 patients with MDS from two independent cohorts (IWG: n=3,173; J-MDS: n=1,332), including 271 patients with TP53mono and 499 with TP53multiHit. Functional annotation of TP53 variants was performed using a previously published phenotype score (PS) derived from saturation mutagenesis screens, capturing dominant-negative and loss-of-function effects. Median leukemia-free survival (LFS) differed significantly by TP53 allelic state (TP53 wild-type (TP53wt) 37.2 months; TP53mono 19.2 months; TP53multiHit 7.8 months; p<0.001). Within the TP53mono subgroup, functional annotation identified marked heterogeneity. Patients with high PS (≥7) showed a significantly inferior median LFS compared with those with low PS (12.6 vs. 43.3 months; p<0.001), particularly for IPSS-R and IPSS-M low-risk cases. Combining PS and variant allele frequency (VAF) further improved risk stratification. TP53mono patients with PS ≥7 and VAF ≥22% had a median LFS comparable to TP53multiHit cases (9.2 vs. 7.8 months, p=0.3), whereas those with PS <7 and VAF <22% exhibited a median LFS similar to TP53wt cases (44.7 vs. 37.2 months, p=0.8). Overall, functional annotation of TP53 variants refines prognostication in TP53mono-mutated MDS and may enhance individualized risk assessment.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"13 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088606","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}