Blood最新文献

{"title":"Surface pTα expression predicts LCK activation and preclinical synergy of LCK and JAK coinhibition in adult T-ALL.","authors":"Lucien Courtois, Antoine Pinton, Aurelie Cabannes-Hamy, Mathieu Simonin, Guillaume P Andrieu, Mélodie Queri, Charlotte Smith, Guillaume Charbonnier, Marie-Emilie Dourthe, Marianne Courgeon, Grégoire Huré, Nicolas Gaidot, Elizabeth A Macintyre, Hervé Dombret, André Baruchel, Nicolas Boissel, Aurore Touzart, Ludovic Lhermitte, Philippe Rousselot, Vahid Asnafi","doi":"10.1182/blood.2024027982","DOIUrl":"https://doi.org/10.1182/blood.2024027982","url":null,"abstract":"<p><p>Refractory and/or relapsing T-cell acute lymphoblastic leukemia (T-ALL) remains a major therapeutic challenge. The pre-TCR pathway has recently emerged as a therapeutic target via LCK inhibition in this context. However, there is a need for simple and quickly assessable biomarkers to predict sensitivity to LCK inhibitors. Moreover, targeting LCK alone by tyrosine kinase inhibitors, such as Dasatinib, often results in transient clinical responses, emphasizing the need for efficient combination strategies. Here, we assessed pre-TCR alpha chain (pTα) surface expression by flow cytometry in a unique series of 50 adult T-ALL patient-derived xenografts (PDX). We show that cases displaying a cortical phenotype often express high levels of surface pTα (pre-TCR+ T-ALL) and that the latter associates with LCK activation. Furthermore, we show that ectopic interleukin-7 receptor (IL-7R) expression can rescue pre-TCR+ T-ALL from Dasatinib cytotoxicity (5 PDX). We tested whether co-inhibition of pre-TCR and IL-7R signaling pathways could be synergetic in pre-TCR+ IL-7R+ T-ALL (11 PDX). Combination of JAK-inhibitors, Ruxolitinib or Tofacitinib, with Dasatinib elicited strong and specific synergy in IL-7R+ pre-TCR+ T-ALL in vitro, including in the relapse setting (4/28 patient-derived primary samples). Using 3 adult-PDX models, we show that in vivo treatment with this combination significantly delayed leukemic progression and prolonged survival compared to either monotherapy. This preclinical study thus proposes the use of pTα as a biomarker of LCK-inhibitor sensitivity in T-ALL, and suggests that dual targeting of IL-7R and pre-TCR signaling pathways may be a relevant therapeutic strategy in a substantial proportion of adult T-ALL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466939","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 treat quantitative fibrinogen disorders.","authors":"Alessandro Casini","doi":"10.1182/blood.2024025712","DOIUrl":"10.1182/blood.2024025712","url":null,"abstract":"<p><strong>Abstract: </strong>Quantitative fibrinogen disorders, including afibrinogenemia and hypofibrinogenemia, are defined by the complete absence or reduction of fibrinogen, respectively. The diagnosis is based on the measurement of fibrinogen activity and antigen levels, which define the severity of this monogenic disorder. Afibrinogenemia is the result of homozygosity or combined heterozygosity for the causative mutations, whereas monoallelic mutations lead to hypofibrinogenemia. The bleeding phenotype varies in accordance with fibrinogen levels, ranging generally from frequent and often life-threatening bleeding in afibrinogenemia to the absence of symptoms, or mild bleeding symptoms in mild hypofibrinogenemia. The main treatment for quantitative fibrinogen disorders is fibrinogen supplementation. Despite low fibrinogen levels, a tendency for thrombosis is a characteristic of these disorders and may be exacerbated by fibrinogen supplementation. The management of surgery and pregnancy presents significant challenges regarding the amount of fibrinogen replacement and the need for thromboprophylaxis. The objective of this article is to present 4 clinical scenarios that illustrate common clinical challenges and to propose strategies for managing bleeding, thrombosis, surgery, and pregnancy.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"801-810"},"PeriodicalIF":21.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863352","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":"Inflammation-driven NF-κB signaling represses ferroportin transcription in macrophages via HDAC1 and HDAC3.","authors":"Oriana Marques, Natalie K Horvat, Laura Zechner, Silvia Colucci, Richard Sparla, Stefan Zimmermann, Christopher J Neufeldt, Sandro Altamura, Ruiyue Qiu, Katja Müdder, Günter Weiss, Matthias W Hentze, Martina U Muckenthaler","doi":"10.1182/blood.2023023417","DOIUrl":"10.1182/blood.2023023417","url":null,"abstract":"<p><strong>Abstract: </strong>Anemia of inflammation is a prevalent comorbidity in patients with chronic inflammatory disorders. Inflammation causes hypoferremia and iron-restricted erythropoiesis by limiting ferroportin (FPN)-mediated iron export from macrophages that recycle senescent erythrocytes. Macrophage cell surface expression of FPN is reduced by hepcidin-induced degradation and/or by repression of FPN (Slc40a1) transcription via cytokine and Toll-like receptor (TLR) stimulation. Although the mechanisms underlying hepcidin-mediated control of FPN have been extensively studied, those inhibiting Slc40a1 messenger RNA (mRNA) expression remain unknown. We applied targeted RNA interference and pharmacological screens in macrophages stimulated with the TLR2/6 ligand FSL1 and identified critical signaling regulators of Slc40a1 mRNA repression downstream of TLRs and NF-κB signaling. Interestingly, the NF-κB regulatory hub is equally relevant for Slc40a1 mRNA repression driven by the TLR4 ligand lipopolysaccharide, the cytokine tumor necrosis factor β/lymphotoxin-alpha (LTA), and heat-killed bacteria. Mechanistically, macrophage stimulation with heat-killed Staphylococcus aureus recruits the histone deacetylases (HDACs) HDAC1 and HDAC3 to the antioxidant response element (ARE) located in the Slc40a1 promoter. Accordingly, pretreatment with a pan-HDAC inhibitor abrogates Slc40a1 mRNA repression in response to inflammatory cues, suggesting that HDACs act downstream of NF-κB to repress Slc40a1 transcription. Consistently, recruitment of HDAC1 and HDAC3 to the Slc40a1 ARE after stimulation with heat-killed S aureus is dependent on NF-κB signaling. These results support a model in which the ARE integrates the transcriptional responses of Slc40a1 triggered by signals from redox, metabolic, and inflammatory pathways. This work identifies the long-sought mechanism of Slc40a1 transcriptional downregulation upon inflammation, paving the way for therapeutic interventions at this critical juncture.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"866-880"},"PeriodicalIF":21.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799084","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":"Oral inflammation and microbiome dysbiosis exacerbate chronic graft-versus-host disease.","authors":"Yui Kambara, Hideaki Fujiwara, Akira Yamamoto, Kazuyoshi Gotoh, Shuma Tsuji, Mari Kunihiro, Tadashi Oyama, Toshiki Terao, Ayame Sato, Takehiro Tanaka, Daniel Peltier, Keisuke Seike, Hisakazu Nishimori, Noboru Asada, Daisuke Ennishi, Keiko Fujii, Nobuharu Fujii, Ken-Ichi Matsuoka, Yoshihiko Soga, Pavan Reddy, Yoshinobu Maeda","doi":"10.1182/blood.2024024540","DOIUrl":"10.1182/blood.2024024540","url":null,"abstract":"<p><strong>Abstract: </strong>The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in graft-versus-host disease (GVHD) pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients after hematopoietic cell transplantation (HCT) associated with increased chronic GVHD (cGVHD), even in patients receiving posttransplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut, with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes both before and after transplantation activated antigen-presenting cells, thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increase in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"881-896"},"PeriodicalIF":21.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852713","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":"Oral pathogens exacerbate chronic GVHD.","authors":"","doi":"10.1182/blood.2025028355","DOIUrl":"https://doi.org/10.1182/blood.2025028355","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 8","pages":"899"},"PeriodicalIF":21.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456706","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":"Long-term efficacy and safety of danicopan as add-on therapy to ravulizumab or eculizumab in PNH with significant EVH.","authors":"Austin Kulasekararaj, Morag Griffin, Caroline Piatek, Jamile Shammo, Jun-Ichi Nishimura, Christopher Patriquin, Hubert Schrezenmeier, Wilma Barcellini, Jens Panse, Anna Gaya, Yogesh Patel, Peng Liu, Gleb Filippov, Flore Sicre de Fontbrune, Antonio Risitano, Jong Wook Lee","doi":"10.1182/blood.2024026299","DOIUrl":"10.1182/blood.2024026299","url":null,"abstract":"<p><strong>Abstract: </strong>Complement C5 inhibitor treatment with ravulizumab or eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) improves outcomes and survival. Some patients remain anemic due to clinically significant extravascular hemolysis (cs-EVH; hemoglobin [Hb] ≤9.5 g/dL and absolute reticulocyte count [ARC] ≥120 × 109/L). In the phase 3 ALPHA trial, participants received oral factor D inhibitor danicopan (150 mg 3 times daily) or placebo plus ravulizumab or eculizumab during the 12-week, double-blind treatment period 1 (TP1); those receiving placebo switched to danicopan during the subsequent 12-week, open-label TP2 and continued during the 2-year long-term extension (LTE). There were 86 participants randomized in the study, of whom 82 entered TP2, and 80 entered LTE. The primary end point was met, with Hb improvements from baseline at week 12 (least squares mean change, 2.8 g/dL) with danicopan. For participants switching from placebo to danicopan at week 12, improvements in mean Hb were observed at week 24. Similar trends were observed for the proportion of participants with ≥2 g/dL Hb increase, ARC, proportion of participants achieving transfusion avoidance, and Functional Assessment of Chronic Illness Therapy-Fatigue scale scores. Improvements were maintained up to week 72. No new safety signals were observed. The breakthrough hemolysis rate was 6 events per 100 patient-years. These long-term data demonstrate sustained efficacy and safety of danicopan plus ravulizumab/eculizumab for continued control of terminal complement activity, intravascular hemolysis, and cs-EVH in PNH. This trial was registered at www.clinicaltrials.gov as #NCT04469465.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"811-822"},"PeriodicalIF":21.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863365","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 treat patients who are refractory to platelet transfusions.","authors":"Susan Nahirniak, Veera Sekaran Nadarajan, Simon J Stanworth","doi":"10.1182/blood.2023022883","DOIUrl":"https://doi.org/10.1182/blood.2023022883","url":null,"abstract":"<p><p>Patients with thrombocytopenia requiring on-going platelet transfusion support may develop inadequate platelet count increments, referred to as Platelet Refractoriness (PR), which further complicates their care. The underlying etiologies of PR can be broadly divided into immune and non-immune causes. A high index of suspicion is required to initiate testing for alloimmunization and t leading culprit in immune PR is development of Class I Human Leukocyte Antigens (HLA) antibodies. The approach to diagnosis of immune PR has changed over the recent years with new technologies but questions regarding clinical significance and interpretation of these methods have not been conclusively answered. The provision of HLA-matched platelets requires close and timely co-ordination between transfusion services and clinical teams; however, the true impact of their provision on clinical outcomes is not clear. This paper will review diagnostic and management challenges, appraise the existing data available to support treatment options, and identify research gaps.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456672","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":"Clinical-genomic profiling of MDS to inform allo-HSCT:Recommendations from an international panel on behalf of the EBMT.","authors":"Carmelo Gurnari, Marie Robin, Lionel Adès, Mahmoud Aljurf, Antonio M Almeida, Fernando Barroso Duarte, Elsa Bernard, Corey S Cutler, Matteo Giovanni Della Porta, Theo M de Witte, Amy E DeZern, Joanna Drozd-Sokolowska, Eric J Duncavage, Pierre Fenaux, Nico Gagelmann, Guillermo Garcia-Manero, Claudia Haferlach, Torsten Haferlach, Robert P Hasserjian, Eva S Hellstrom-Lindberg, Meagan A Jacoby, Austin G Kulasekararaj, R Coleman Lindsley, Jaroslaw P Maciejewski, Hideki Makishima, Luca Malcovati, Moshe Mittelman, Anders Eivind Myhre, Seishi Ogawa, Francesco Onida, Elli Papaemmanuil, Jakob R Passweg, Uwe Platzbecker, Lisa Pleyer, Kavita Raj, Valeria Santini, Anna Sureda, Magnus Tobiasson, Maria Teresa Voso, Ibrahim Yakoub-Agha, Amer M Zeidan, Matthew J Walter, Nicolaus Kröger, Donal P McLornan, Mario Cazzola","doi":"10.1182/blood.2024025131","DOIUrl":"https://doi.org/10.1182/blood.2024025131","url":null,"abstract":"<p><p>For patients with myelodysplastic neoplasm/syndrome (MDS), allogeneic hematopoietic cell transplantation (allo-HCT) represents the only potentially curative treatment, capable of eradicating disease-related mutant hematopoietic cells and establishing normal donor hematopoiesis. Biologic-assignment clinical trials have indicated that in eligible patients, allo-HCT is associated with superior clinical outcomes compared to non-transplant therapy. However, this therapeutic option is only available to a subset of patients, and the outcome is influenced by multiple factors inherent to the patient, the MDS subtype, and the allo-HCT procedure itself. In 2017, the EBMT published recommendations for allo-HCT in MDS to guide practical decision-making. In the contemporary era, genomic profiling has become routine clinical practice in many centers, and the most recent classification systems include MDS entities that are defined by genetic abnormalities. In particular, the Molecular International Prognostic Scoring System (IPSS-M) offers more precise prognostication across all clinical endpoints and currently represents the standard tool for estimating patient survival in the absence of disease-modifying treatment. Evidence from multiple sources increasingly indicates that allo-HCT should be considered at the time of diagnosis in all eligible MDS patients. Therefore, genomic profiling for somatic mutations and testing for germline predisposition variants are integral to determining a patient's eligibility for transplantation. While all patients with higher-risk MDS are potential candidates for immediate transplantation, a subset of those with lower-risk MDS may also derive benefit from this procedure at an earlier disease stage. Comprehensive recommendations on behalf of an expert international panel for clinical practice and future clinical studies of relevance are presented.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456670","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":"Immunoactinopathies revisited: Understanding clinical manifestations and biological pathways.","authors":"Fleur Hiensch, Loic Dupre, Elisabeth Salzer","doi":"10.1182/blood.2024026763","DOIUrl":"https://doi.org/10.1182/blood.2024026763","url":null,"abstract":"<p><p>Immune cell functionality is highly dependent on the actin cytoskeleton. The actin cytoskeleton is regulated by a complex molecular machinery, involving multiple genes. Mutations in these genes can cause inborn errors of immunity, also termed immunoactinopathies, of which Wiskott Aldrich Syndrome is the best-characterized entity. At present, mutations in 23 genes can be considered causative of immunoactinopathies. Immunoactinopathies are rare disease entities with complex combinations of clinical manifestations, including immunodeficiency, immune dysregulation, malignancies, atopy, thrombocytopenia and bleeding, skin involvement or congenital defects. Prompt diagnosis is of crucial importance, as HSCT in an early phase can offer cure and prevent further complications. This review provides a detailed summary of the clinical experience with immunoactinopathies so far, elaborates on the most distinguishing features among immunoactinopathies by providing a clinical categorization, and links this information to the biological pathways that are involved. This information may be of help for clinicians to diagnose patients and eventually improve patient care.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456674","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 mantle cell lymphoma: sands shifting in the darkness.","authors":"Philippe Armand","doi":"10.1182/blood.2024027684","DOIUrl":"https://doi.org/10.1182/blood.2024027684","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 7","pages":"653-654"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405568","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}