Blood最新文献

{"title":"Single-cell and clonal analysis of AL amyloidosis plasma cells and their bone marrow microenvironment.","authors":"Nicolas A Gort-Freitas, Maria Moscvin, Matteo C Da Vià, Francesca Lazzaroni, Alice Nevone, Sam Sadigh, Samuel Boullt, Benjamin Evans, Tianzeng Chen, Tanya Karagiannis, Albert Tai, Sean Rowell, Srinidhi Raghav, Antonia F Chen, Jacob P Laubach, Caitlin Edwards, Jon C Aster, Zizhang Sheng, Joao A Paulo, Chi N Chan, Mario Nuvolone, Niccolò Bolli, Raymond L Comenzo, Allon M Klein, Giada Bianchi","doi":"10.1182/blood.2024024719","DOIUrl":"10.1182/blood.2024024719","url":null,"abstract":"<p><strong>Abstract: </strong>AL amyloidosis is a disorder characterized by expansion of clonal plasma cells in the bone marrow and distant end organ damage mediated by misfolded immunoglobulin free light chains. There are currently limited data regarding the functional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment. We performed 5' single-cell RNA sequencing on newly diagnosed, treatment-naïve patients with AL amyloidosis and healthy subjects. We identified generalized suppression of normal bone marrow hematopoiesis with distinct expansion of monocytes and subsets of CD4+ T cells in patients with AL amyloidosis. We detected significant transcriptional changes broadly occurring among immune cells with increased tumor necrosis factor-α signaling and interferon response accompanied by increased inflammatory response in bone marrow plasma, as measured via quantitative proteomics with specific elevation of costimulatory molecule soluble CD276 (sB7-H3). A transcriptionally distinct population of nonmalignant plasma cells was disproportionately expanded in patients with AL amyloidosis and characterized by increased expression of CRIP1. Finally, clonal AL amyloidosis plasma cells were identified based on their unique variable-diversity-joining. rearrangement and showed increased expression of genes involved in proteostasis when compared with autologous, polyclonal plasma cells. Interpatient transcriptional heterogeneity was evident, with transcriptional states reflective of common genomic translocations easily identifiable. This study defines the transcriptional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment with identification of altered genes previously involved in the pathogenesis of other protein deposition disorders. Our data provide the rationale for functional validations of these genes in future studies.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1476-1492"},"PeriodicalIF":23.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265232","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":"Introduction to a review series on the structural underpinnings of hemostatic plugs and thrombotic occlusions.","authors":"Thomas L Ortel","doi":"10.1182/blood.2025030314","DOIUrl":"https://doi.org/10.1182/blood.2025030314","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"25 1","pages":"1377-1378"},"PeriodicalIF":20.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078128","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":"All in one place: the future of blood group typing.","authors":"Aline Floch,Thierry Peyrard","doi":"10.1182/blood.2025030071","DOIUrl":"https://doi.org/10.1182/blood.2025030071","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"28 1","pages":"1387-1388"},"PeriodicalIF":20.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078130","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":"Exploring the thrombus niche: lessons learned and potential therapeutic opportunities.","authors":"John W Weisel, Rustem I Litvinov","doi":"10.1182/blood.2024025319","DOIUrl":"10.1182/blood.2024025319","url":null,"abstract":"<p><strong>Abstract: </strong>Thrombus structure and composition are the main determinants of the severity, course, and outcomes of thrombosis. Detailed thrombus morphology has become available due to mechanical thrombectomy, which allows for the extraction of fresh thrombi from patients, followed by scanning electron microscopy. The major structural elements of a thrombus are platelets, erythrocytes, and fibrin, each playing a critical role in the determination of biological and physical properties of thrombi, such as permeability, stiffness, and lytic and mechanical stability. The minor components include neutrophils, monocytes, von Willebrand factor, cellular microvesicles, plasma proteins, cholesterol crystals, and other structures. Platelets are responsible for the contraction (retraction) of thrombi, which results in compaction with very little free space, low permeability, and high stiffness. Because of clot contraction, erythrocytes, which are prevalent in all types of thrombi, undergo compressive deformation to polyhedral (polyhedrocytes) and polyhedral-like cells, altogether comprising pressure-deformed cells (piezocytes). Fibrin is the structural and mechanical scaffold of thrombi that changes in time and space both quantitatively and qualitatively during their formation. Fibrin is an equilibrium polymer that can adapt to forced deformations by reorientation at the microscopic level and unfolding at the molecular level. The relative volume fractions of thrombus components, along with their functional and structural forms, vary substantially, providing a basis for the diverse pathogenic mechanisms and clinical manifestations of thrombosis. Modulating any of these components leads to prospective therapeutic approaches. This review summarizes recent research describing the quantitative and qualitative morphologic characteristics of arterial and venous thrombi, which provide a basis for new therapeutic opportunities in thrombosis.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1389-1399"},"PeriodicalIF":23.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522546","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":"Dangerous clones with complex ties to AL amyloidosis.","authors":"Giovanni Palladini,Stefan Schönland","doi":"10.1182/blood.2025029888","DOIUrl":"https://doi.org/10.1182/blood.2025029888","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"53 1","pages":"1384-1385"},"PeriodicalIF":20.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078125","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":"Diverse ancestry genotyping of blood cell antigens.","authors":"","doi":"10.1182/blood.2025031166","DOIUrl":"https://doi.org/10.1182/blood.2025031166","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"42 1","pages":"1525"},"PeriodicalIF":20.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078133","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 genome-wide screen identifies Runx2 as a novel regulator of hematopoietic stem cell expansion and T-cell commitment.","authors":"Grace A Meaker,Matthew Nicholls,Catherine Chahrour,Ian Hsu,Alastair Smith,Yavor Bozhilov,Maurice Ga Hay Leung,Hugo Vassort,Leonid Olender,Oliver Beaven,Xinran Huang,Elizabeth J Brown,Marlies Vanden Bempt,Hwei Minn Khoo,Joydeep Bhadury,Thomas A Milne,Adam C Wilkinson","doi":"10.1182/blood.2025029115","DOIUrl":"https://doi.org/10.1182/blood.2025029115","url":null,"abstract":"Self-renewing multipotent hematopoietic stem cells (HSCs) are a rare but important cell population which can reconstitute the entire blood and immune system following transplantation. Due to their rarity, it has been difficult to comprehensively study the mechanisms regulating HSC activity. However, recent improvements in hematopoietic stem and progenitor cell (HSPC) culture methods using polyvinyl alcohol-based media now facilitate large-scale ex vivo HSC expansion. Here we performed a genome-wide CRISPR knockout (KO) screen in primary mouse HSPCs to discover novel regulators of ex vivo expansion. The screen identified Runx2 as a strong negative regulator of HSC expansion, which we validated using ex vivo and in vivo assays. Loss of Runx2 increased the frequency of immunophenotypic HSCs in HSPC cultures by ~3-fold. Following expansion, these Runx2-KO HSCs engrafted at ~5-fold higher levels in transplantation assays. Non-cultured Runx2-KO HSCs also displayed enhanced reconstitution potential, but loss of Runx2 did not alter blood parameters. Notably however, T-cell reconstitution was diminished from Runx2-KO HSCs, and we further validated an additional role for Runx2 in T-cell commitment using ex vivo and in vivo assays. In summary, we have identified a multifaceted role for Runx2 in HSCs, as a negative regulator of HSC self-renewal and as a facilitator of T-cell commitment. These results will contribute understanding transcriptional regulation of hematopoiesis and improve HSC therapies.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"73 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077721","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":"Drug development in MZL: caring for the forgotten child.","authors":"Catherine Thieblemont,Sylvain Carras,Côme Bommier","doi":"10.1182/blood.2024028270","DOIUrl":"https://doi.org/10.1182/blood.2024028270","url":null,"abstract":"Marginal zone lymphoma (MZL) encompasses biologically heterogenous group of indolent B-cell lymphomas that remains substantially underrepresented in clinical research. Despite recent and significant therapeutic advancess in B-cell malignancies, trial design in MZL continues to face persistent challenges including diagnostic heterogeneity, inconsistent control arms, suboptimal endpoints, and economic barriers. In this narrative review, we examine these key obstacles and discuss emerging strategies to overcome them, such as the standardization of diagnostic criteria, implementation of subtype-specific treatment approaches, validation of surrogate endpoints, and integration of novel response assessment modalities such as metabolic imaging (positron emission tomography), minimal residual disease assessment in flow cytometry or single cell molecular evaluation, and circulating tumor DNA measurement, but need to be evaluated and harmonized for full appreciation We contend that MZL should be understood as a methodological paradigm, rather than as a clinical exception. This may facilitate the refinement of trial design and ultimately accelerate therapeutic innovation across the broad spectrum of indolent lymphomas.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"37 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078140","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":"Sclerotic GVHD and Scleroderma Share Dysregulated Gene Expression that is Ameliorated by EREG Therapeutic Antibody.","authors":"Nathan M Newton,Kriti Agrawal,Anahi V Odell,Timothy Scott Tracy,Craig Stanway Hackett,Anne B Eldrup,Michael Whitfield,Viktor Martyanov,Michael Girardi,Esen Sefik,Richard A Flavell,Ian D Odell","doi":"10.1182/blood.2025029836","DOIUrl":"https://doi.org/10.1182/blood.2025029836","url":null,"abstract":"Immune driven fibrotic skin diseases including scleroderma/systemic sclerosis (SSc) and chronic graft-versus-host-disease (cGvHD) cause skin stiffening that has major impact on patient quality of life and associated patient mortality. Therapies to improve sclerotic skin resulting from these diseases are largely ineffective. We previously showed that EREG, a DC3 dendritic cell-derived EGFR ligand, is elevated in the skin and lung of patients with SSc and required for maintenance of skin fibrosis. Here, we developed a fully human anti-EREG neutralizing antibody that has both high affinity and specificity. We found this therapeutic antibody to be functional and safe in vivo using human EREG knock-in mice. To understand the antifibrotic mechanism of targeting EREG, we aligned skin single-cell transcriptomic profiles of SSc, morphea (localized scleroderma) and SclGvHD with disease biomarkers. EREG expression in the skin was elevated in all three fibrotic diseases and a driver of TNC production by myofibroblasts in all three fibrotic diseases. TNC is a pro-inflammatory extracellular glycoprotein that functions as an endogenous TLR4 ligand which induces expression of TLR4 target genes CCL2 and IL6. Examination of skin explants from patients with active SclGvHD treated with anti-EREG therapeutic antibody by spatial transcriptomics demonstrated upregulation of matrix degradation by increased MMP and decreased TIMP1 expression. Protein measurements showed reduced secretion of EREG targets TNC, CCL2, and TIMP1 in all patients, and type I collagen and FN1 in 3/4 patients. Thus, sclerotic skin treated with the anti-EREG therapeutic antibody reduced inflammatory and fibrosis biomarkers associated with EGFR and TLR4 signaling.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"38 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078139","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":"Rbm38 Deficiency Impairs Erythroid Heme Biosynthesis and Induces Porphyria via Reduced Ferrochelatase Expression.","authors":"Xinshu Xie,Ailing Zou,Lei Zhang,Xuezhen Ma,Yaohui He,Hanqi Liu,Yating Lu,Yexin Yang,Jie Ouyang,Kang Liu,Pengcheng Zhong,Ji Li,ShuQian Xu,Lifang Zhou,Bing Han,Miao Chen,Kaosheng Lv,Dingxiao Zhang,Lu Liu,Yang Mei","doi":"10.1182/blood.2025028783","DOIUrl":"https://doi.org/10.1182/blood.2025028783","url":null,"abstract":"RNA splicing and processing are critical for erythropoiesis, as dysregulation of RNA splicing ultimately disrupts protein synthesis. The RNA-binding protein Rbm38 is highly expressed during terminal erythropoiesis. While in vitro studies have implicated Rbm38 as a key regulator of erythroid differentiation, the landscape of RNA splicing regulated by Rbm38 and its role in terminal erythropoiesis in vivo have not been fully elucidated. Here, we generated whole-body and conditional knockout mouse models for Rbm38 and found that mature red blood cell production was impaired in the bone marrow of Rbm38-deficient mice. Rbm38-/- red blood cells exhibited reduced hemoglobin content and increased susceptibility to oxidative stress-induced hemolysis. These mutant mice also developed microcytic hypochromic anemia, along with dysregulated iron homeostasis. Additionally, they exhibited decreased mitochondrial heme biosynthesis and accumulation of free protoporphyrin (PPIX) in erythrocytes and feces, resembling human erythropoietic protoporphyria (EPP). Mechanistically, Rbm38 regulates the incorporation of ferrous iron (Fe2+) into PPIX to form heme by modulating alternative splicing, mRNA decay, and translation of the porphyrin metabolic enzyme gene Ferrochelatase (Fech). Importantly, enforced expression of Fech largely restored erythroid differentiation defects and ameliorated anemia in Rbm38-/- transplants. We further demonstrated that genetic variants in the human RBM38 gene locus influence PPIX levels in erythrocytes from healthy cohorts. Our findings demonstrate that Rbm38 governs terminal erythropoiesis by orchestrating RNA splicing, stability, and translation during heme biosynthesis.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"77 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145077722","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}