Blood最新文献

{"title":"Interplay of procoagulatory and neutrophil-derived anticoagulatory proteins in C1q-NET-driven blood coagulation.","authors":"Minnah Thomas,Davor Frleta,KehDih Lai,John O'Brien,Aditi Khatri Patel,Yuanqi Zhao,Keith Adam Kobylarz,Naxin Tu,Gabor Halasz,Chunguang Guo,Lynn Macdonald,Lori Morton,Dan Chalothorn,Kishor B Devalaraja-Narashimha","doi":"10.1182/blood.2024027161","DOIUrl":"https://doi.org/10.1182/blood.2024027161","url":null,"abstract":"Neutrophils interact with the external milieu in both tissue and blood microenvironments and are emerging as important regulators of blood coagulation 1-3. In this study, we explored whether complement induces Neutrophil Extracellular Trap (NET) formation and related blood coagulation using human donor-derived neutrophils. Complement C1q induces NETosis in Lipopolysaccharide (LPS) O127 primed neutrophils, while LPS alone does not induce NETosis. Bulk RNA sequencing revealed a unique LPS-driven altered neutrophil state and complement sensitivity for NETosis was found to be transcriptionally- dependent. Using an arrayed CRISPR Knockout screen in the neutrophil-like differentiated HL60 cells (dHL60), we identified that SCARF1 and Complement Receptor 3 are required for C1q-NETosis. Since NETs contain pro-coagulatory components such as DNA and histones, we investigated whether C1q-related NETs influenced blood coagulation. LPS+ C1q NETs were associated with reduced coagulation activity compared to LPS treatment alone. We further found that LPS upregulated Tissue Factor expression and coagulation-related activity in neutrophils. Furthermore, neutrophils secrete anticoagulant proteins, including Protein C and Tissue Factor Pathway Inhibitors, during C1q-mediated NET formation that functionally regulates NET-related coagulation. C1q- NETs also activate the coagulation factors FXII and FXI, facilitating both intrinsic coagulation and kallikrein-dependent bradykinin production. This study elucidates how NETs regulate both pro-coagulatory and anti-coagulatory components that may influence pathophysiology of disease.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"42 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140248","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":"Deciphering the dynamics of histone acetylation and chromatin remodeling in multiple myeloma: a tale beyond the tails.","authors":"Sinan Xiong, Jianbiao Zhou, Wee-Joo Chng","doi":"10.1182/blood.2025028403","DOIUrl":"10.1182/blood.2025028403","url":null,"abstract":"<p><strong>Abstract: </strong>The development of multiple myeloma is typically associated with various cytogenetic abnormalities; however, these genetic changes alone do not fully account for the observed heterogeneity in patient prognosis and treatment response. Recent studies leveraging next-generation sequencing and genomic approaches have shown that epigenetic alterations are crucial in myeloma development and therapeutic resistance. These changes contribute to high levels of transcriptomic instability and enable cellular adaptation to targeted therapies and immunotherapies through diverse evolutionary trajectories. In this regard, aberrations of histone modifications and chromatin remodeling affect various cellular processes such as DNA repair, DNA damage response, cellular survival, and apoptosis signaling, which provides a strong rationale for developing epigenetic-targeted therapies for myeloma treatment. In this review, we focus on recent advances and research gaps in understanding the deregulation of histone acetylation, a widespread and versatile process of histone modification occurring at lysine residues at the N-terminus of histone tails, and its intimate interplay with chromatin remodeling complexes in orchestrating dynamic chromatin functional states and transcriptional outputs. We also provide an updated review of epigenetic modulatory drugs targeting histone deacetylases (CREB-binding protein/p300) and bromodomain and extraterminal proteins, along with a discussion of their limitations and future perspectives in myeloma treatment.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1550-1560"},"PeriodicalIF":23.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559140","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":"Epstein-Barr virus sequence mutations cause human diseases.","authors":"Paul J Farrell","doi":"10.1182/blood.2025030005","DOIUrl":"https://doi.org/10.1182/blood.2025030005","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"154 1","pages":"1527-1528"},"PeriodicalIF":20.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134380","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":"G6b on the rise (or not?).","authors":"Isabelle C Becker","doi":"10.1182/blood.2025029624","DOIUrl":"https://doi.org/10.1182/blood.2025029624","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"35 1","pages":"1531-1532"},"PeriodicalIF":20.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134379","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":"Genomic landscape of IgM-MGUS and patients with stable or progressive asymptomatic Waldenström macroglobulinemia.","authors":"Tina Bagratuni,Ourania Theologi,Christos Vlachos,Ioannis Kollias,Kylee H Maclachlan,Foteini Aktypi,Nefeli Mavrianou-Koutsoukou,Christine I Liacos,Konstantina Taouxi,Alexandra Papadimou,Katerina Chrisostomidou,Maria Sakkou,Irene Solia,Foteini Theodorakou,Gianmarco Favrin,Maria Gavriatopoulou,Evangelos Terpos,Marzia Varettoni,Zachary R Hunter,Steven P Treon,Francesco Maura,Meletios-Athanasios Athanasios Dimopoulos,Efstathios Kastritis","doi":"10.1182/blood.2025030177","DOIUrl":"https://doi.org/10.1182/blood.2025030177","url":null,"abstract":"IgM-Monoclonal gammopathy of undetermined significance (IgM-MGUS) and asymptomatic Waldenström (aWM) are precursor conditions of symptomatic Waldenström macroglobulinemia (sWM) with an annual 1.5-12% risk of progression. Although clinical prognostic models exist for risk stratification, it remains challenging to distinguish asymptomatic patients who will eventually progress from those who will not. Hence, the characterization of genomic features that shape disease progressors could potentially improve risk stratification. We performed whole-exome sequencing on 232 samples from 139 patients, including 9 patients with sequential samples. We observed an increasing mutation burden through the stages of disease evolution. Genes such as CD79B, ARID1A and CREBBP were more often mutated in the aWM progressed (aWMpr) compared to the non-progressor aWM group (aWMst) while MYD88L265 variant allele frequency (VAF) was significantly higher in aWMpr compared to aWMst patients. In addition, IgM-MGUS patients with MYD88WT genotype showed a distinct genomic profile compared to the MYD88MUT patients. Furthermore, the presence of more aneuploidies showed a significant association with a higher risk of progression to the symptomatic disease. Overall, our study shows that genomic profiling of patients' tumor at the time of aWM diagnosis might represent an improved strategy for identifying patients at high risk to progression who could benefit from earlier intervention.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"41 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140358","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":"Fusion Gene Depletion Eliminates Stemness and Induces Bidirectional Differentiation of Acute Myeloid Leukemia.","authors":"Polina K Derevyanko,Laura E Swart,L Daniel Mata Casimiro,Anita van Oort,Manisha Du Plessis,Luca van den Brink,Minoo Ashtiani,C Michel Zwaan,Anja Krippner-Heidenreich,Constanze Bonifer,Ray Michel Schiffelers,Josef Josef Vormoor,Sophie Kellaway,Olaf Heidenreich","doi":"10.1182/blood.2025028988","DOIUrl":"https://doi.org/10.1182/blood.2025028988","url":null,"abstract":"Chromosomal rearrangements that generate novel fusion genes are a hallmark of acute myeloid leukemia (AML). Depletion experiments in cell line models have suggested that their continued expression is required for maintaining their leukemic phenotype and that fusion genes therefore represent ideal cancer-specific therapeutic targets. However, to which extent this result holds true for the different stages of hematopoietic development in primary cells and whether therapeutic agents can be efficiently delivered to those cells is still unclear. In this study, we demonstrate that primary AML cells harboring the chromosomal translocation t(8;21) are critically dependent on the corresponding fusion gene, RUNX1::RUNX1T1, to suppress differentiation and maintain stemness. Silencing RUNX1::RUNX1T1 expression using siRNA-loaded lipid nanoparticles induces substantial changes in chromatin accessibility, thereby redirecting the leukemia-associated transcriptional network towards a myeloid differentiation program. Single-cell analyses reveal that this transcriptional reprogramming is associated with the depletion of immature stem and progenitor-like cell populations, accompanied by an expansion of granulocytic and eosinophilic/mast cell-like populations with impaired self-renewal capacity. These findings underscore the essential role of RUNX1::RUNX1T1 in sustaining AML and highlight the therapeutic potential of targeting fusion gene expression in primary AML cells.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"3 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134081","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 value of premaintenance FDG PET/CT response in patients with newly diagnosed myeloma from the CASSIOPEIA trial.","authors":"Françoise Kraeber-Bodere,Bastien Jamet,Sonja Zweegman,Aurore Perrot,Cyrille Hulin,Denis Caillot,Thierry Facon,Xavier Leleu,Karim Belhadj,Emmanuel Itti,Lionel Karlin,Clement Bailly,Mark-David Levin,Monique C Minnema,Caroline Bodet-Milin,Bart de Keizer,Jill Corre,Pieter Sonneveld,Philippe Moreau,Thomas Carlier,Cyrille Touzeau","doi":"10.1182/blood.2025030084","DOIUrl":"https://doi.org/10.1182/blood.2025030084","url":null,"abstract":"The CASSIOPEIA trial (NCT02541383) demonstrated superior progression-free survival (PFS) with the addition of daratumumab to bortezomib, thalidomide, and dexamethasone (D-VTd) induction/consolidation and with daratumumab maintenance versus observation in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients. The companion study, CASSIOPET, assessed the prognostic value of pre-maintenance (PM) PET/CT response based on the standardized Deauville score on PFS and overall survival (OS) in addition to bone marrow (BM) minimal residual disease (MRD) detection by multiparameter flow cytometry (MFC) at 10-5 level. PM PET/CT was available for 225 patients: 112 patients treated with daratumumab after D-VTd (59) or VTd (53) and 113 patients followed by observation after D-VTd (56) or VTd (57). At PM, 92% of the 175 baseline PET-positive patients achieved PET-negativity, with a longer PFS in univariate analysis (HR, 0.48; P = 0.019) and a major trend of prolonged OS (HR, 0.37; P = 0.056). In univariate analysis, patients who achieved both PET and MFC negativity were found to have a better PFS (HR, 0.39; P<0.0001) than those who had at least one positive result. In daratumumab-treated patients, PM PET-negativity was associated with prolonged PFS and OS in univariate analysis (HR, 0.35; P = 0.0023 and HR, 0.32, P = 0.033, respectively) and double MFC and PET-negativity was independently associated with PFS by multivariate analysis (HR, 0.39, P = 0.0006). This study confirms the prognostic relevance of a PM PET response in NDMM patients treated with daratumumab in addition to MRD detection by MFC at the BM level.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"64 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134079","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":"High-risk genomic consensus validation for patients with newly diagnosed multiple myeloma using next-generation sequencing.","authors":"Anaïs Schavgoulidze,Aurore Perrot,Xavier Leleu,Titouan Cazaubiel,Marie-Lorraine Chretien,Pierre Feugier,Karim Belhadj,Salomon Manier,Murielle Roussel,Sabine Brechignac,Frederique Orsini Piocelle,Mohamad Mohty,Jean Marc Schiano de Colella,Margaret Macro,Didier Adiko,Mamoun Dib,Jean Fontan,Carine Motard,Didier Bouscary,Laurent Pascal,Virginie Roland,Francois Lifermann,Jana Armelle Bakala,Lydia Montes,Celine Kennel,Philippe Rey,Valentine Richez,Faiza Keddar,Laurent Frenzel,Claire Calmettes,Carine Chaleteix,Isabelle Plantier,Emilie Chalayer,Anna Schmitt,Christophe Roul,Hélène Demarquette,Chloe Cerutti,Luka Pavageau,Laure Derrier,Hervé Avet-Loiseau,Jill Corre","doi":"10.1182/blood.2025029999","DOIUrl":"https://doi.org/10.1182/blood.2025029999","url":null,"abstract":"The prognostic heterogeneity of multiple myeloma is mainly driven by genomic features of myeloma cells. The International Myeloma Society (IMS) / International Myeloma Working Group (IMWG) recently proposed a high-risk (HR) genomic model in order to have a consensus definition of genomic risk. We performed NGS panel in 6528 new diagnosed myeloma patients (NDMM) and 1583 patients at first relapse, between 2019 and 2024. We observed that 22.4% of patients at diagnosis and 36.7% at first relapse were HR according to the Consensus Genomic Staging (CGS). Clinical data were available for 2695 patients at diagnosis. After a median follow-up of 35 months, the median PFS was 30 months for HR NDMM patients, vs 51 months for standard-risk (SR) (p<0.0001). HR cytogenetic criteria from the Revised-ISS score were not able to discriminate patients in HR nor SR IMS/IMWG genomic subgroups. Looking at each criteria independently, we found that the presence of del(17p), TP53 mutation, biallelic del(1p32), or the combination of intermediate risk cytogenetics (gain 1q, del(1p32), t(4;14), t(14;16), t(14;20)) significantly reduces the PFS compared with standard-risk patients. Moreover, patients cumulating several criteria had an even worse prognosis. Among SR patients according to the genomic definition with normal creatinine, median PFS of those with high beta2-microglobulin was not significantly different from patients with normal beta2-microglobulin level. This study validates the IMS/IMWG genomic definition of high-risk myeloma in a large cohort of patients diagnosed from 2019.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"57 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134043","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":"CEBPA repression by MECOM blocks differentiation to drive aggressive leukemias.","authors":"Travis Fleming, Mateusz Antoszewski, Sander Lambo, Michael Gundry, Riccardo Piussi, Lara Wahlster, Sanjana B Shah, Fiona Reed, Kevin Dong, Joao A Paulo, Steven Gygi, Claudia A Mimoso, Seth Goldman, Karen Adelman, Jennifer A Perry, Yana Pikman, Kimberly Stegmaier, Maria N Barrachina, Kellie R Machlus, Volker Hovestadt, Andrea Arruda, Mark D Minden, Richard A Voit, Vijay G Sankaran","doi":"10.1182/blood.2025028954","DOIUrl":"10.1182/blood.2025028954","url":null,"abstract":"<p><p>Acute myeloid leukemias (AMLs) have an overall poor prognosis with many high-risk cases co-opting stem-cell gene regulatory programs, yet the mechanisms through which this occurs remain poorly understood. Increased expression of the stem-cell transcription factor, MECOM, underlies one key driver mechanism in largely incurable AMLs. How MECOM results in such aggressive AML phenotypes remains unknown. To address existing experimental limitations, we engineered and applied targeted protein degradation with functional genomic readouts to demonstrate that MECOM promotes malignant stem-cell-like states by directly repressing pro-differentiation gene regulatory programs. Remarkably and unexpectedly, a single node in this network, a MECOM-bound cis-regulatory element located 42 kb downstream of the myeloid differentiation regulator CEBPA is both necessary and sufficient for maintaining MECOM-driven leukemias. Importantly, targeted activation of this regulatory element promotes differentiation of these aggressive AMLs and reduces leukemia burden in vivo. These findings suggest a broadly applicable approach for functionally dissecting oncogenic gene regulatory networks to inform improved therapeutic strategies.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136439","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":"Talquetamab plus daratumumab for the treatment of relapsed or refractory multiple myeloma in the TRIMM-2 study.","authors":"Ajai Chari,Niels W C J van de Donk,Bhagirathbhai Dholaria,Katja C Weisel,Maria-Victoria Mateos,Hartmut Goldschmidt,Tom G Martin,Daniel Morillo,Donna Reece,Paula Rodriguez-Otero,Manisha Bhutani,Anita D'Souza,Albert Oriol,Laura Rosiñol,Nizar J Bahlis,Deeksha Vishwamitra,Sheri Skerget,Raluca I Verona,Kalpana K Bakshi,Lijuan Kang,Thomas J Prior,Lien Vandenberk,Jaszianne Tolbert,Sangmin Lee,Damiette Smit,Ralph Wäsch","doi":"10.1182/blood.2025029360","DOIUrl":"https://doi.org/10.1182/blood.2025029360","url":null,"abstract":"Talquetamab, a GPRC5D-targeting bispecific antibody for relapsed/refractory multiple myeloma (RRMM), plus daratumumab may lead to deeper and more durable responses than either therapy alone. In the phase 1b TRIMM-2 study, patients with RRMM (at least 3 prior lines of therapy or double refractory to a proteasome inhibitor and an immunomodulatory drug) received subcutaneous talquetamab 0.4 mg/kg weekly (QW; \"QW cohort\") or 0.8 mg/kg every other week (Q2W; \"Q2W cohort\") plus daratumumab 1800 mg per the approved schedule. The primary end point was safety. Secondary end points included overall response and duration of response. Progression-free survival was an exploratory end point. Sixty-five patients (median 5 prior lines of therapy; 61.5% triple-class refractory; 24.6% bispecific antibody-exposed) received talquetamab plus daratumumab (QW, n = 14; Q2W, n = 51; median follow-up: 18.6 months). Most common adverse events were oral events, skin events, cytokine release syndrome, and infections. Grade 3/4 events occurred in 81.5%. Two patients had dose-limiting toxicities, both in the Q2W cohort (grade 3 stomatitis/oral mucositis and grade 3 maculopapular rash). Responses occurred in 71.4% (QW cohort) and 82.4% (Q2W cohort) of patients. Median progression-free survival was 23.3 and 21.2 months, respectively, in each cohort. Pharmacodynamic results suggest the immunomodulatory action of daratumumab contributes to a conducive environment for talquetamab by reducing immunosuppressive cells. Talquetamab plus daratumumab demonstrated promising efficacy outcomes in heavily pretreated patients, with a safety profile consistent with each agent as monotherapy. ClinicalTrials.gov ID: NCT04108195.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"41 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116804","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}