Blood最新文献_第9页

Structure and interactions of the proteins from the contact system. 接触系统中蛋白质的结构和相互作用。

IF 20.3 1区医学

Blood Pub Date : 2025-07-10 DOI: 10.1182/blood.2024025322

Jonas Emsley,Yujie Ma,Joost C M Meijers

{"title":"Structure and interactions of the proteins from the contact system.","authors":"Jonas Emsley,Yujie Ma,Joost C M Meijers","doi":"10.1182/blood.2024025322","DOIUrl":"https://doi.org/10.1182/blood.2024025322","url":null,"abstract":"The contact system includes factor XII (FXII), factor XI (FXI), prekallikrein (PK) and high-molecular weight kininogen (HK) and has received increased interest as a potential target in immunothrombotic and inflammatory diseases. This system activates two distinct pathways, the intrinsic pathway of coagulation via cleavage of factor IX (FIX) and inflammation via HK cleavage resulting in bradykinin (BK) generation. HK is central to the function of both arms of the system as a substrate for plasma kallikrein (PKa) and critical cofactor which forms interactions with cell receptors and activators. Both FXI and PK circulate in complex with HK and both can be activated by factor XIIa (FXIIa). Reciprocal activation and continuous consumption of PK and FXII is a feature of the contact system. On endothelial cells, PK and FXII become activated but only in the presence of secreted receptor for the globular domain of C1q (gC1qR) and Zn2+ ions. A second mechanism exists on endothelial cells whereby prolylcarboxypeptidase activates the PK-HK complex to generate BK in a FXII independent manner. On platelets, FXI can be cleaved by thrombin, but only in the presence of secreted polyphosphate. This review explores the 3D structure of the contact factors and examines the molecular mechanisms underlying contact activation. We focus on conformational changes that expose cleavage sites and exosites in FXII, PK, and FXI. We also discuss contact factor protein-protein interactions, recognition of polyanions and the role of HK and Zn²⁺ in contact system assembly.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"93 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603964","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}

引用次数: 0

Immune Alterations in Myeloma Evolution and Outcomes: Quo Vadis? 骨髓瘤演变和结果的免疫改变：现状？

IF 20.3 1区医学

Blood Pub Date : 2025-07-07 DOI: 10.1182/blood.2024026227

Madhav V Dhodapkar,Bruno Paiva

{"title":"Immune Alterations in Myeloma Evolution and Outcomes: Quo Vadis?","authors":"Madhav V Dhodapkar,Bruno Paiva","doi":"10.1182/blood.2024026227","DOIUrl":"https://doi.org/10.1182/blood.2024026227","url":null,"abstract":"The pathogenesis of multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS) is linked to an aging immune system. Chronic activation of B/plasma cells may contribute to the origin of MGUS, which is frequent in the elderly. However, only 1% of individuals with MGUS annually experience progression to MM. The immune system can specifically recognize MGUS lesions and preclinical MM models provide evidence for both innate and adaptive immune surveillance. Multiomic studies have identified several systemic alterations at the MGUS stage, suggesting accelerated immune aging prior to evolution into clinical malignancy. MM is further associated with spatial alterations in patterns of tumor growth and in-situ regulation of regional immunity. Both tumor and microenvironment-related factors contribute to immune paresis, which facilitates the dissemination of clonal plasma cells and increases the risk of infections in MM patients. Immune profiles in blood or marrow exhibit considerable heterogeneity and have been linked to outcomes following immune therapies including T cell redirection. Understanding how underlying systemic immune changes impact in-vivo function and durability of natural or synthetic tumor/antigen-specific immunity needs further study. Preserving or restoring immune function may be critical for long-term outcomes both in the context of prevention of clinical MM and of treating active disease. Benchmarking of immune biomarkers followed by its prospective integration into current risk models, together with improved understanding of mechanisms underlying tumor immunity in-vivo, are needed to optimize immune approaches and improve outcomes in MM.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"9 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578665","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}

引用次数: 0

Outcomes of Allogeneic HCT in Hodgkin Lymphoma in the Era of Checkpoint Inhibitors: A Joint CIBMTR and EBMT Analysis. 检查点抑制剂时代同种异体HCT治疗霍奇金淋巴瘤的结果：CIBMTR和EBMT联合分析。

IF 20.3 1区医学

Blood Pub Date : 2025-07-07 DOI: 10.1182/blood.2024027197

Miguel-Angel Perales,Farrukh T Awan,Ariane Boumendil,Jinalben Patel,Luca Castagna,Emanuele Angelucci,Herve Finel,Alexander D Kulagin,Bertram Glass,Paolo Corradini,Alex F Herrera,Didier Blaise,Mohamed A Kharfan-Dabaja,Khalid Halahleh,Sairah Ahmed,Carmen Martinez,Sebastian Giebel,Silvia Montoto,Richard J Jones,Nausheen Ahmed,Ryan C Lynch,Marcos J de Lima,Mazyar Shadman,Craig S Sauter,Kwang Woo Ahn,Mehdi Hamadani,Ali Bazarbachi,Anna Sureda

{"title":"Outcomes of Allogeneic HCT in Hodgkin Lymphoma in the Era of Checkpoint Inhibitors: A Joint CIBMTR and EBMT Analysis.","authors":"Miguel-Angel Perales,Farrukh T Awan,Ariane Boumendil,Jinalben Patel,Luca Castagna,Emanuele Angelucci,Herve Finel,Alexander D Kulagin,Bertram Glass,Paolo Corradini,Alex F Herrera,Didier Blaise,Mohamed A Kharfan-Dabaja,Khalid Halahleh,Sairah Ahmed,Carmen Martinez,Sebastian Giebel,Silvia Montoto,Richard J Jones,Nausheen Ahmed,Ryan C Lynch,Marcos J de Lima,Mazyar Shadman,Craig S Sauter,Kwang Woo Ahn,Mehdi Hamadani,Ali Bazarbachi,Anna Sureda","doi":"10.1182/blood.2024027197","DOIUrl":"https://doi.org/10.1182/blood.2024027197","url":null,"abstract":"Checkpoint inhibitors (CPI) have shown remarkable efficacy in patients with Hodgkin lymphoma (HL) and are now used routinely for this disease. While allogeneic hematopoietic cell transplantation (alloHCT) remains a curative option for HL, there are concerns that prior CPI may exacerbate post alloHCT complications, particularly graft-versus-host disease (GVHD), and lead to worse outcomes. Given the relative paucity of data, we performed a CIBMTR/EBMT study to examine the impact of prior CPI in alloHCT outcomes. We included 2186 adult patients > 18 years who received a first alloHCT using a matched related, unrelated or haploidentical donor from 2008-2023. Twenty-seven percent of patients received prior CPI. GVHD prophylaxis was post-transplant cyclophosphamide in 55.8% patients in the CPI cohort and 35% in the non-CPI cohort. Median follow-up among survivors was longer for the non-CPI (39 months) than CPI cohort (16.5 months). In the multivariate analysis, prior CPI exposure did not affect overall survival or non-relapse mortality but resulted in improved progression-free survival (non-CPI vs. CPI HR 0.81, 0.67-0.98, p=0.03) and lower incidence of relapse (HR 0.58, 0.45-0.76, p<0001). While grade II-IV (HR1.26, 1.04-1.53; p=0.02) and III-IV (HR1.41, 1.04-1.92; p=0.03) acute GVHD were increased differences in chronic GVHD were not significant. Use of post-transplant cyclophosphamide based GVHD prophylaxis resulted in improved OS, lower grade II-IV acute GVHD and chronic GVHD in patients with prior CPI exposure. In summary, allo-HCT should still be considered a curative option for patients with HL in the era of checkpoint inhibitors.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"106 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578664","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}

引用次数: 0

IFN-γ promotes the progression of iMCD by activating inflammatory monocytes. IFN-γ通过激活炎性单核细胞促进iMCD的进展。

IF 21 1区医学

Blood Pub Date : 2025-07-03 DOI: 10.1182/blood.2024027689

Xuejiao Yin, Yi Liu, Shengnan Ding, Jiaying Ge, Min Yang, Zhenbo Wang, Zuopo Lv, Xuxia Luo, Liya Ma, Wenjuan Yu, Juying Wei, Chunmei Yang, Qiumei Yao, Li Zhu, Shuqi Zhao, Yu Chen, Haitao Meng, Jie Jin, Hongyan Tong, Liangshun You

{"title":"IFN-γ promotes the progression of iMCD by activating inflammatory monocytes.","authors":"Xuejiao Yin, Yi Liu, Shengnan Ding, Jiaying Ge, Min Yang, Zhenbo Wang, Zuopo Lv, Xuxia Luo, Liya Ma, Wenjuan Yu, Juying Wei, Chunmei Yang, Qiumei Yao, Li Zhu, Shuqi Zhao, Yu Chen, Haitao Meng, Jie Jin, Hongyan Tong, Liangshun You","doi":"10.1182/blood.2024027689","DOIUrl":"10.1182/blood.2024027689","url":null,"abstract":"Abstract: A deeper understanding of the immune landscape in patients with idiopathic multicentric Castleman disease (iMCD) is essential to establish early prognostic stratification and uncover novel therapeutic targets. We used single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from a cohort of 15 patients with iMCD and 4 healthy controls. To explore the sources of interleukin-6 (IL-6), we included lymph node and bone marrow samples for comparison with PBMCs. Our results indicate that IL-6 primarily originates from the lymph nodes, particularly from activated B cells. Similarly, in peripheral blood, activated B cells are also the main source of IL-6. IL-6 receptor is primarily expressed in monocytes in PBMCs, with CCL monocytes showing the strongest activation of the IL-6 signaling pathway. This suggests that CCL monocytes in iMCD may play an important role in driving peripheral inflammatory storms. CellChat analysis reveals that during disease flares, CCL monocytes interact with specific natural killer (NK)/NKT cells through enhanced type II interferon (IFN-II) signaling, whereas this interaction significantly diminishes during remission, indicating a significant role for IFN-II in the pathogenesis of iMCD. Notably, serum IFN-γ levels positively correlate with both disease severity and treatment resistance, a finding validated by a large independent iMCD cohort. Our findings confirm that the IL-6 pathway remains central to iMCD pathogenesis and highlight a significant role for IFN-II pathway activation in amplifying inflammatory storms. Our findings provide valuable biomarkers for assessing disease severity and identify new therapeutic targets for iMCD.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"76-88"},"PeriodicalIF":21.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751129","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}

引用次数: 0

A novel mouse model of hemoglobin SC disease reveals mechanisms underlying beneficial effects of hydroxyurea. 一种新的小鼠血红蛋白SC疾病模型揭示了羟基脲有益作用的机制。

IF 21 1区医学

Blood Pub Date : 2025-07-03 DOI: 10.1182/blood.2024028136

Tahereh Setayesh, Mengna Chi, Zachery Oestreicher, Masahide Sakabe, Katie Seu, Zhenqi Zhu, Harsimran Kaur, Anifat Tijani, Mei Xin, Amy Shova, Kenneth D Greis, Tim M Townes, József Balla, Katherine VandenHeuvel, Yueh-Chiang Hu, Punam Malik

{"title":"A novel mouse model of hemoglobin SC disease reveals mechanisms underlying beneficial effects of hydroxyurea.","authors":"Tahereh Setayesh, Mengna Chi, Zachery Oestreicher, Masahide Sakabe, Katie Seu, Zhenqi Zhu, Harsimran Kaur, Anifat Tijani, Mei Xin, Amy Shova, Kenneth D Greis, Tim M Townes, József Balla, Katherine VandenHeuvel, Yueh-Chiang Hu, Punam Malik","doi":"10.1182/blood.2024028136","DOIUrl":"10.1182/blood.2024028136","url":null,"abstract":"Abstract: Sickle cell hemoglobin C (HbSC) disease results from compound heterozygosity of hemoglobin S (HbS) and hemoglobin C (HbC), comprising 30% of sickle cell disease (SCD). HbC induces red blood cell (RBC) dehydration/xerocytosis, which promotes sickling. HbSC-SCD causes significant morbidity despite being milder than homozygous HbSS-SCD. Current research/treatment strategies have focused on HbSS-SCD, whereas patients with HbSC are deprived of disease-modifying/transformative therapies because of lack of preclinical models. We generated HbSC mice, which resemble human HbSC-SCD: HbSC erythrocytes showed marked xerocytosis. Anemia, hemolysis, inflammation, and organ damage were milder than HbSS mice but hypoxia/reperfusion injury was similar. Retinopathy developed at higher frequency than HbSS mice (66.7% vs 16.7%; P < .05), as in patients with HbSC-SCD. Although HbSC RBCs sickled at lower oxygen tension than HbSS RBCs, they did not completely recover deformability after hypoxia/reoxygenation. Using the HbSC mice, we studied the mechanism by which hydroxyurea causes significant clinical benefit in patients with HbSC-SCD, despite minimal/modest increases in fetal Hb (HbF). We found hydroxyurea had distinct non-HbF and HbF effects. Hydroxyurea did not increase HbF in adult HbSC/HbSS mice but reduced RBC reactive oxygen species, ferryl Hb, and Heinz-body formation, thereby reducing membrane damage; however, RBC hydration was unaffected. When given to unborn pups before γ-globin expression was switched off, and continued postnatally, we could induce HbF in both HbSC and HbSS mice (higher HbF in HbSS vs HbSC mice). Minimal increases in HbF (∼1%) improved HbSC RBC hydration. Peak HbF levels of 7% in HbSC mice abrogated sickling. Overall, this HbSC model will help bridge the knowledge gap in mechanistic/therapeutic studies in this neglected disease.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"13-28"},"PeriodicalIF":21.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963693","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}

引用次数: 0

Are we ready for an MRD-driven approach in multiple myeloma? 我们准备好mrd驱动的多发性骨髓瘤治疗方法了吗？

IF 20.3 1区医学

Blood Pub Date : 2025-07-03 DOI: 10.1182/blood.2024028273

Francesca Gay,Roberto Mina

引用次数: 0

Large-scale dependency and drug screens to characterize the therapeutic vulnerabilities of multiple myeloma with 1q. 大规模依赖和药物筛选是1q多发性骨髓瘤治疗脆弱性的特征。

IF 21 1区医学

Blood Pub Date : 2025-07-03 DOI: 10.1182/blood.2024025102

Romanos Sklavenitis-Pistofidis, Elizabeth D Lightbody, Mairead Reidy, Junko Tsuji, Jean-Baptiste Alberge, Michelle P Aranha, Daniel Heilpern-Mallory, Harvey G Roweth, Daisy Huynh, Stephen J F Chong, Anna Y Chung, Jeremy Zhang, Liam Hackett, Nicholas J Haradhvala, Ting Wu, Nang K Su, Brianna Berrios, Saveliy Belkin, Ankit K Dutta, Ryan A Knudson, Carolyn Brandt, Patricia T Greipp, Matthew S Davids, Maria Papaioannou, Gad Getz, Irene M Ghobrial, Salomon Manier

{"title":"Large-scale dependency and drug screens to characterize the therapeutic vulnerabilities of multiple myeloma with 1q.","authors":"Romanos Sklavenitis-Pistofidis, Elizabeth D Lightbody, Mairead Reidy, Junko Tsuji, Jean-Baptiste Alberge, Michelle P Aranha, Daniel Heilpern-Mallory, Harvey G Roweth, Daisy Huynh, Stephen J F Chong, Anna Y Chung, Jeremy Zhang, Liam Hackett, Nicholas J Haradhvala, Ting Wu, Nang K Su, Brianna Berrios, Saveliy Belkin, Ankit K Dutta, Ryan A Knudson, Carolyn Brandt, Patricia T Greipp, Matthew S Davids, Maria Papaioannou, Gad Getz, Irene M Ghobrial, Salomon Manier","doi":"10.1182/blood.2024025102","DOIUrl":"10.1182/blood.2024025102","url":null,"abstract":"Abstract: The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"89-103"},"PeriodicalIF":21.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613209","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}

引用次数: 0

How I treat Wiskott-Aldrich syndrome. 我如何治疗Wiskott-Aldrich综合征。

IF 21 1区医学

Blood Pub Date : 2025-07-03 DOI: 10.1182/blood.2024026288

Tanja C Vallée, Michael H Albert, Sung-Yun Pai

{"title":"How I treat Wiskott-Aldrich syndrome.","authors":"Tanja C Vallée, Michael H Albert, Sung-Yun Pai","doi":"10.1182/blood.2024026288","DOIUrl":"10.1182/blood.2024026288","url":null,"abstract":"Abstract: Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder, characterized by thrombocytopenia, eczema, recurrent infections, autoimmunity, and malignancy. Here, we discuss current conservative and definitive approaches to treating WAS, based on recently published evidence. Disease severity in WAS is highly variable. Recent studies confirm that the probability of disease progression depends on the type of genetic variant, supporting early diagnosis and tailored treatment strategies. Milder cases, historically termed X-linked thrombocytopenia (XLT), received supportive care, whereas severe cases were referred for standard allogeneic hematopoietic cell transplantation (HCT) or gene therapy (GT) in clinical trials. Advances in HCT and GT, together with recent knowledge that even patients with XLT are at risk for severe immune complications, suggest that most young patients with WAS should be offered a potentially curative approach at diagnosis. Older patients with a small subset of milder variants may be treated conservatively unless they develop life-threatening autoimmune or malignant complications; regular monitoring and proactive management are critical to preventing irreversible complications. We recommend discontinuing the term XLT as it implies a mild and uncomplicated disease, which is not the norm, and instead tailor treatment for all patients with WAS to their individual genetic profile, disease severity, and clinical course.","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"41-51"},"PeriodicalIF":21.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965204","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}

引用次数: 0

Another 1q bites the dust. 又有1万1千块被吸干了。

IF 21 1区医学

Blood Pub Date : 2025-07-03 DOI: 10.1182/blood.2025028903

Vikas A Gupta, Lawrence H Boise

引用次数: 0

Check the brakes on IRF4! 检查IRF4的刹车！

IF 21 1区医学

Blood Pub Date : 2025-07-03 DOI: 10.1182/blood.2025028615

Charlotte Pawlyn

引用次数: 0