Blood最新文献

{"title":"Adult T-cell leukemia/lymphoma coexistent with immune dysregulation-associated EBV+ lymphoproliferative disorder.","authors":"Xuan Wang,Hongmei Yi","doi":"10.1182/blood.2025028361","DOIUrl":"https://doi.org/10.1182/blood.2025028361","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"55 1","pages":"2396"},"PeriodicalIF":20.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992032","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":"A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations.","authors":"Natalia Borbaran Bravo, Ekaterina Deordieva, Larissa Doll, Mohammad ElGamacy, Benjamin Dannenmann, Joana Azevedo, Alberto Iannuzzo, Selket Delafontaine, Moritz Lehners, Marius Kolodziej, Birte Hernandez Alvarez, Anna-Sophia Hellmuth, Malte Ritter, Betül Findik, Viktoria Zakharova, Sandro Bräuning, Sergey Kandabarau, Claudia Lengerke, Robert Feil, Isabelle Meyts, Jérôme Delon, Markus Templin, Marc Sturm, Olaf Rieß, Cornelia Zeidler, Karl Welte, Anna Shcherbina, Maksim Klimiankou, Julia Skokowa","doi":"10.1182/blood.2023022576","DOIUrl":"10.1182/blood.2023022576","url":null,"abstract":"<p><strong>Abstract: </strong>We have identified a new inherited bone marrow failure syndrome with severe congenital neutropenia (CN) caused by autosomal recessive mutations in the coatomer protein complex I (COPI) subunit zeta 1 (COPZ1) gene. A stop-codon COPZ1 mutation and a missense (MS) mutation were found in 3 patients from 2 unrelated families. Although 2 affected siblings with a stop-codon COPZ1 mutation suffered from CN that involves other hematologic lineages and nonhematologic tissues, the patient with a MS COPZ1 mutation had isolated neutropenia. Both COPZ1 mutations were localized to a highly evolutionarily conserved region. The resulting truncated (TR) COPZ1 protein was predicted to display diminished interaction with its COPI complex partner, COPG1. These findings were consistent with the observed block in retrograde protein transport from the Golgi apparatus to the endoplasmic reticulum (ER) in human fibroblasts carrying TR COPZ1. Human CD34+ cells with TR or MS COPZ1 had significantly impaired granulocytic differentiation, and in zebrafish embryos, TR Copz1 also resulted in defective myelopoiesis. Intracellularly, TR COPZ1 downregulated JAK/STAT/CEBPE/G-CSFR signaling and hypoxia-responsive pathways, while inducing STING, interferon-stimulated genes, stimulating oxidative phosphorylation activity, and increasing reactive oxygen species levels in hematopoietic cells. MS COPZ1 deregulated interferon and JAK/STAT signaling but less than the TR protein. Finally, treatment with the small molecule HIF1α stabilizer IOX2 or transduction of cells with COPZ2 restored defective granulopoiesis in COPZ1-mutated human CD34+ cells, offering potential therapeutic options.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2317-2335"},"PeriodicalIF":21.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789610","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":"N-homocysteinylation of β-arrestins biases GPCR signaling and promotes platelet activation.","authors":"Lin-Qi Zhang, Chang-Xiao Che, Ya-Qin Du, Lu-Lu Han, Jia-Le Wang, Chen-Yu Zhang, Shen-Ming Huang, Zhong-Yuan Zheng, Qing-Tao He, Zhao Yang, Long Zhang, Nan Chen, Fan Yang, Ying-Li Jia, Shi-Min Zhao, De-Min Zhou, Chu Wang, Xian Wang, Jin-Peng Sun, Lu Tie","doi":"10.1182/blood.2024025593","DOIUrl":"10.1182/blood.2024025593","url":null,"abstract":"<p><strong>Abstract: </strong>Hyperhomocysteinemia (HHcy) is strongly associated with cardiovascular diseases (CVDs), and it has been identified as a risk factor for thrombotic diseases. Most patients with HHcy die from various complications closely related to thrombotic diseases. However, the underlying mechanisms have not been fully elucidated. G protein-coupled receptors (GPCRs), the central regulators of the cardiovascular system, primarily control platelet activation. By examining the effects of HHcy on a panel of GPCRs involved in platelet aggregation, we found that HHcy systematically modulated biased GPCR signaling through the inhibition of desensitization by β-arrestins and the amplification of G protein signals. We further revealed that the N-homocysteinylation of β-arrestin1/2 at lysine (K) residues (K294/K296) disrupted the interaction between β-arrestins and GPCRs. The aforementioned phenomenon may be universal because HHcy was found to modulate the signaling bias of 9 other randomly selected GPCRs. Moreover, we found that the proinflammatory effects of homocysteine and homocysteine thiolactone were weakened in Arrb2-/- mice and that the reintroduction of wild-type but not K296R β-arrestin2 mutants (in mice) into primary peritoneal macrophages reversed these effects. Notably, in Arrb2K296R mice, HHcy-induced thrombus formation and platelet aggregation were reversed. Our results suggest that a G-biased agonist could be a better choice for disease therapy under HHcy conditions. Collectively, our findings demonstrate that the N-homocysteinylation of β-arrestin1/β-arrestin2 actively modulates the biased property of GPCR signaling, which contributes to the pathophysiology of HHcy-related CVDs and provides insight into the selection of agonists for the treatment of diseases under HHcy conditions.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2374-2389"},"PeriodicalIF":21.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389997","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":"Sustained MRD negativity drives maintenance stop.","authors":"","doi":"10.1182/blood.2025029434","DOIUrl":"https://doi.org/10.1182/blood.2025029434","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"8 1","pages":"2397"},"PeriodicalIF":20.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991974","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":"Platelet NLRP6 protects from microvascular thrombosis in sepsis.","authors":"Huimin Jiang,Shuang Chen,Xiang Gui,Yingying Li,Yueyue Sun,Hui Zhu,Yue Dai,Jie Zhang,Xiaoqian Li,Wen Ju,Zhenyu Li,Lingyu Zeng,Kailin Xu,Jianlin Qiao","doi":"10.1182/blood.2025028739","DOIUrl":"https://doi.org/10.1182/blood.2025028739","url":null,"abstract":"Sepsis is characterized by a systemic inflammation and microvascular thrombosis induced by infection. NLRP6 possesses both pro- and anti-inflammatory effects with cell-type- or tissue-specific functions. However, the role of cell-type-specific NLRP6 in sepsis remains poorly understood. In the present study, we detected NLRP6 expression in platelets. By using platelet-specific NLRP6 knockout mice and the cecal ligation and puncture model of sepsis, we demonstrated that deletion of platelet NLRP6 increased the mortality, enhanced microvascular thrombosis in the lung and liver, and promoted platelet activation, platelet-neutrophil interactions as well as the neutrophil extracellular traps (NETs) formation following sepsis. Platelet function analysis in vitro showed that deletion of NLRP6 enhanced platelet aggregation, activation, and granules release. In addition, NLRP6 deletion promoted platelet NF-κB signaling via sustaining TAB1 expression independent of the inflammasome. Moreover, inhibition of NF-κB signaling abolished the aggravated effects of the absence of platelet NLRP6 on the intravascular microthrombosis and NETs formation in sepsis and increased the overall survival. Mechanistically, NLRP6 facilitated the interaction between TRIM21 and TAB1 in activated platelets, resulting in K48-linked polyubiquitination of TAB1 and subsequent degradation. Finally, sepsis plasma triggered TAB1 degradation mediated by NLRP6/TRIM21 in normal healthy platelets through TLR4/MyD88. Our study identifies a novel protective role of platelet NLRP6 in the microvascular thrombosis during sepsis, implying it as a novel target for the treatment of sepsis.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"8 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065799","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 manage pregnant patients who are alloimmunized to RBC antigens.","authors":"Helen Frances Savoia, Anna Parakh, Stefan Charles Kane","doi":"10.1182/blood.2023022894","DOIUrl":"10.1182/blood.2023022894","url":null,"abstract":"<p><strong>Abstract: </strong>Hemolytic disease of the fetus and newborn (HDFN) remains an important cause of perinatal morbidity and mortality. HDFN is caused by maternal alloimmunization to red blood cell (RBC) antigens. This article describes and highlights issues in the care of pregnant women with RBC alloimmunization. This includes monitoring for, and management of fetal anemia caused by maternal red cell alloantibodies, but also considerations for transfusion support for the woman in the event of major bleeding. Many aspects of care for women with RBC alloantibodies are not covered within specific guidelines, particularly with respect to best practice for antenatal management of women with prior significant obstetric morbidity or mortality due to HDFN, and we outline our approach in these cases. The use of noninvasive monitoring for fetal anemia through measurement of the middle cerebral artery peak systolic velocity has led to a paradigm shift in antenatal care for women with high-risk antibodies, and medical therapies hold promise for women with the most severe disease.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2275-2282"},"PeriodicalIF":21.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920286","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 manage major hemorrhage.","authors":"Jeannie L Callum, Ronald B George, Keyvan Karkouti","doi":"10.1182/blood.2023022901","DOIUrl":"10.1182/blood.2023022901","url":null,"abstract":"<p><strong>Abstract: </strong>Acute hemorrhage can be a life-threatening emergency that is complex in its management and affects many patient populations. The past 15 years has seen the introduction of comprehensive massive hemorrhage protocols, wider use of viscoelastic testing, new coagulation factor products, and the publication of robust randomized controlled trials in diverse bleeding patient populations. Although gaps continue to exist in the evidence base for several aspects of patient care, there is now sufficient evidence to allow for an individualized hemostatic response based on the type of bleeding and specific hemostatic defects. We present 3 clinical cases that highlight some of the challenges in acute hemorrhage management, focusing on the importance of interprofessional communication, rapid provision of hemostatic resuscitation, repeated measures of coagulation, immediate administration of tranexamic acid, and prioritization of surgical or radiologic control of hemorrhage. This article provides a framework for the clear and collaborative conversation between the bedside clinical team and the consulting hematologist to achieve prompt and targeted hemostatic resuscitation. In addition to providing consultations on the hemostatic management of individual patients, the hematology service must be involved in setting hospital policies for the prevention and management of patients with major hemorrhage.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2245-2256"},"PeriodicalIF":21.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287752","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":"Transcriptional remodeling shapes therapeutic vulnerability to necroptosis in acute lymphoblastic leukemia.","authors":"Anna Saorin,Anna Dehler,Bartimée Galvan,Fabio Daniel Steffen,Marine Ray,Dong Lu,Xin Yu,James Kim,Aneta Drakul,Samanta Kisele,Jin Wang,Jean-Pierre Bourquin,Beat Bornhauser","doi":"10.1182/blood.2025028938","DOIUrl":"https://doi.org/10.1182/blood.2025028938","url":null,"abstract":"Insufficient eradication of cancer cells and survival of drug tolerant clones are major relapse driving forces. Underlying molecular mechanisms comprise activated pro-survival and anti-apoptotic signaling leading to insufficient apoptosis and drug resistance. The identification of programmed cell death pathways alternative to apoptosis opens up for possibilities to antagonize apoptosis escape routes. We have earlier shown that acute lymphoblastic leukemia (ALL) harbours a distinct propensity to undergo cell death by RIPK1-dependent necroptosis, activated by small molecule second mitochondria-derived activators of caspase (SMAC) mimetics. Despite demonstrated safety and tolerability of SMAC mimetics in clinical trials, their efficacy as single agent appears still limited, highlighting the need for combinatorial treatments. Here, we investigate so far unexplored regulatory mechanisms of necroptosis and identify targets for interference to augment the necroptotic anti-leukemia response. Ex vivo drug response profiling in a model of the bone marrow microenvironment reveals powerful synergy of necroptosis induction with histone deacetylase inhibition. Subsequent transcriptome analysis and functional in vivo CRISPR screening identify gene regulatory circuitries through the master transcription regulators SP1, p300 and HDAC2 to drive necroptosis. While deletion of SP1 or p300 confers resistance to necroptosis, loss of HDAC2 sensitizes to RIPK1-dependent cell death by SMAC mimetics. Consequently, our data inform strong in vivo anti-leukemic activity of combinatorial necroptosis induction and HDAC inhibition in patient-derived human leukemia models. Thus, transcriptional dependency of necroptosis activation is a key regulatory mechanism that identifies novel targets for interference, pointing out a strategy to exploit alternative non-apoptotic cell death pathways to eradicate resistant disease.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"123 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945388","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":"Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR-T cells.","authors":"Corynn Kasap, Adila Izgutdina, Bonell Patiño-Escobar, Amrik Singh Kang, Nikhil Chilakapati, Naomi Akagi, Ananya Mishu Manoj, Haley Johnson, Tasfia Rashid, Juwita Werner, Abhilash Barpanda, Huimin Geng, Yu-Hsiu Tony Lin, Sham Rampersaud, Daniel Gil-Alós, Amin Sobh, Daphné Dupéré-Richer, Adolfo Aleman, Gianina Wicaksono, K M Kawehi Kelii, Radhika Dalal, Emilio Ramos, Anjanaa Vijayanarayanan, Kiran Lakhani, Fernando Salangsang, Paul Phojanakong, Juan Antonio Camara Serrano, Ons Zakraoui, Isa Tariq, Ajai Chari, Alfred Chung, Anupama Deepa Kumar, Thomas Martin, Jeffrey Lee Wolf, Sandy Wong, Veronica Steri, Mala Shanmugam, Lawrence H Boise, Tanja Kortemme, Samir Parekh, Elliot Stieglitz, Jonathan D Licht, William Karlon, Benjamin G Barwick, Arun Wiita","doi":"10.1182/blood.2024025536","DOIUrl":"https://doi.org/10.1182/blood.2024025536","url":null,"abstract":"<p><p>Despite the success of BCMA-targeting CAR-Ts in multiple myeloma, patients with high-risk cytogenetic features still relapse most quickly and are in urgent need of additional therapeutic options. Here, we identify CD70, widely recognized as a favorable immunotherapy target in other cancers, as a specifically upregulated cell surface antigen in high-risk myeloma tumors. We use a structure-guided design to define a CD27-based anti-CD70 CAR-T design that outperforms all tested scFv-based CARs, leading to >80-fold improved CAR-T expansion in vivo. Epigenetic analysis via machine learning predicts key transcription factors and transcriptional networks driving CD70 upregulation in high-risk myeloma. Dual-targeting CAR-Ts against either CD70 or BCMA demonstrate a potential strategy to avoid antigen escape-mediated resistance. Together, these findings support the promise of targeting CD70 with optimized CAR-Ts in myeloma as well as future clinical translation of this approach.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963707","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":"Shear-Dependent Platelet Aggregation by ChAdOx1 nCoV-19 Vaccine: A Novel Biophysical Mechanism for Arterial Thrombosis.","authors":"Yiyao Catherine Chen,Naveen Eugene Louis Richard Louis,Angela Huang,Allan Sun,Alexander Dupuy,Laura Moldovan,Tiana Pelaia,Jianfang Ren,Taylor S Cohen,Sarah Gilbert,Huyen A Tran,Karlheinz Peter,James D McFadyen,Lining Arnold Ju","doi":"10.1182/blood.2024027675","DOIUrl":"https://doi.org/10.1182/blood.2024027675","url":null,"abstract":"Rare thrombotic events associated with ChAdOx1 nCoV-19 (ChAdOx1) vaccination have raised concerns; however, the underlying mechanisms remain elusive. Here we report a novel biophysical mechanism by which ChAdOx1 directly interacts with platelets under arterial shear conditions, potentially contributing to post-vaccination arterial thrombosis. Using microfluidic post assays, we demonstrate that ChAdOx1 induces shear-dependent platelet aggregation, distinct from conventional von Willebrand factor-mediated adhesion. This interaction is mediated by platelet integrin αIIbβ3 and requires biomechanical activation, explaining the absence of significant binding under static conditions. Molecular dynamics simulations and docking studies reveal preferential binding of ChAdOx1's penton RGD motif to the activated conformation of αIIbβ3. Inhibiting integrin αIIbβ3 completely abolishes ChAdOx1-induced platelet aggregation, whereas blocking GPIb has minimal effect, confirming a mechanism that bypasses the conventional GPIb-dependent platelet adhesion pathway. Mutagenesis of the RGD motif to AAA eliminates platelet binding, verifying the specificity of this interaction. These findings provide a potential explanation for the association between ChAdOx1 vaccination and arterial thrombotic events, distinct from vaccine-induced immune thrombotic thrombocytopenia (VITT). Our results highlight the importance of considering biomechanical factors in vaccine-related thrombotic complications and suggest that shear-dependent integrin activation may be another determinant in the pathogenesis of these rare adverse events.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"38 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945391","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}