Blood最新文献

{"title":"The interleukin-33 receptor (ST2) is a novel therapeutic target to attenuate the progression of hemophilic arthropathy.","authors":"Heike C Hawerkamp,Aoife Yeow,Ciara Byrne,Anne Chevalier,Laura Matarazzo,Alexander George Lawrence,Daniel Ivers,Tatenda Murangi,Niamh Helen O'Dowd,Anne-Marije Hulshof,Ferdows Atiq,Jamie M O'Sullivan,Vincent Patrick Kelly,Conor M Finlay,Henry McSorley,Bagirath M Gangadharan,Birgit M Reipert,James O'Donnell,Peter L Turecek,Padraic G Fallon","doi":"10.1182/blood.2024027578","DOIUrl":"https://doi.org/10.1182/blood.2024027578","url":null,"abstract":"Haemophilia A is an X-linked bleeding disorder caused by a blood clotting protein factor VIII deficiency. Patients with haemophilia develop recurrent bleeding episodes. When bleeding occurs in the joints, haemophilic arthropathy (HA) may develop, resulting in hemarthroses and joint deformation. A novel congenic mouse model of severe haemophilia A was generated using CRISPR/Cas9 targeting of exon-1 of the F8 gene (F8em1-/-) to explore changes in the bleeding and inflammation during HA. F8em1-/- mice have a high penetrance of spontaneous bleeding, with joint bleeds progressing to arthropathy. F8em1-/- mice were subjected to needle-induced damage to the knee to assess synchronised joint bleeding, and the development of HA and synovial inflammation was assessed. The synovium of injured joints of F8em1-/- mice had differential and temporal expression of inflammatory genes after injury. Pathway analysis identified upregulation of the IL-1 family cytokines, IL-1b and IL-33, and respective receptors IL-1RAP and T1/ST2 (ST2) in the synovium of mice after needle-induced HA. Soluble ST2 and IL-33 levels were elevated in the plasma of F8em1-/- mice in acute stages after needle injury to the joints. Dual ST2 deficient F8em1-/- mice were generated, with ST2 deficient haemophilic mice developing significantly reduced joint damage after needle injury relative to F8em1-/- mice. Using a therapeutic intervention, blocking ST2 following joint injury significantly ameliorated joint damage during HA in haemophilic mice. These studies in a new mouse model of HA identify a crucial role of ST2 in HA pathogenesis and highlight its potential as a novel therapeutic target.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"24 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661847","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":"---RGI-2001 for the Prophylaxis of Acute Graft-Versus-Host Disease Following Allogeneic HCT.","authors":"Zachariah DeFilipp,Hannah K Choe,Yvonne A Efebera,Ayman Saad,Shatha Farhan,Lazaros J Lekakis,Jean A Yared,Gary J Schiller,Markus Y Mapara,Amer Assal,Ted A Gooley,Jack D Bui,Dana D Lee,Hayley Lane,Yi-Bin Chen","doi":"10.1182/blood.2025029584","DOIUrl":"https://doi.org/10.1182/blood.2025029584","url":null,"abstract":"RGI-2001, a liposomal glycolipid that binds CD1d receptor of antigen-presenting cells, can activate invariant natural killer T cells and stimulate cytokine-dependent proliferation of regulatory T-cells (Tregs). This open-label, single-arm, multicenter phase 2b trial evaluated the safety and efficacy of RGI-2001 in combination with standard graft-versus-host disease (GVHD) prophylaxis in participants receiving myeloablative allogeneic hematopoietic cell transplantation (HCT) for hematologic malignancies. RGI-2001 was infused at a dose of 100 ug/kg for six weekly doses starting on Day 0 of HCT. The primary endpoint was grades II-IV acute GVHD by Day 100 after HCT. Forty-nine participants received RGI-2001 in combination with tacrolimus and methotrexate. RGI-2001 was well tolerated, with no serious infusion reactions. Sixteen participants experienced grade ≥3 treatment-related adverse events, with the most common being decreased appetite, leukopenia, thrombocytopenia and stomatitis. The estimated probability of grades II-IV and III-IV acute GVHD were 24.9% and 4.1%, respectively. Compared to controls from the Center for International Blood and Marrow Research Transplant registry, participants receiving RGI-2001 experienced superior clinical outcomes, including Day-180 grades II-IV acute GVHD-free survival (70.8% vs 50.7%, adjusted hazard ratio 0.45, 95% CI 0.30-0.68). Increasing NKT and Treg populations were observed after HCT, consistent with the proposed action of RGI-2001. In conclusion, RGI-2001 was well tolerated and was associated with low rates of acute GVHD and encouraging survival after myeloablative HCT. These results support strategies that target NKT and Treg cell populations to augment immunological changes in allogeneic HCT recipients. This trial was registered at www.clinicaltrials.gov as NCT04014790.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"13 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661842","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":"Weathering the HLH storm and redesigning clinical trials.","authors":"Adi Zoref-Lorenz,Martin Ellis","doi":"10.1182/blood.2025029715","DOIUrl":"https://doi.org/10.1182/blood.2025029715","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"14 1","pages":"263-265"},"PeriodicalIF":20.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645857","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: a hidden talent?","authors":"Samithamby Jeyaseelan","doi":"10.1182/blood.2025029739","DOIUrl":"https://doi.org/10.1182/blood.2025029739","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"146 3","pages":"271-273"},"PeriodicalIF":21.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648436","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":"Proteostasis disruption in inherited bone marrow failure syndromes.","authors":"Helena Yu, Robert A J Signer","doi":"10.1182/blood.2024024956","DOIUrl":"10.1182/blood.2024024956","url":null,"abstract":"<p><strong>Abstract: </strong>Inherited bone marrow failure syndromes (IBMFS) are genetic disorders of impaired hematopoiesis that manifest in childhood with both cytopenias and extrahematologic findings. Although several IBMFS are categorized as ribosomopathies owing to shared underlying ribosomal dysfunction, there is a broader disruption of the protein homeostasis (proteostasis) network across both classic and emerging IBMFS. Precise regulation of the proteostasis network, including mechanisms of protein synthesis, folding, trafficking, and degradation and associated stress response pathways, has emerged as essential for maintaining hematopoietic stem cell function, providing new potential mechanistic insights into IBMFS pathogenesis. Furthermore, the varied clinical trajectories of patients with IBMFS with possible divergent outcomes of malignancy and spontaneous remission may reflect developmental and temporal changes in proteostasis activity and be driven by strong selective pressures to restore proteostasis. These new insights are spurring fresh therapeutic approaches to target proteostasis. Thus, further evaluation of proteostasis regulation and the consequences of proteostasis disruption in IBMFS could aid in developing new biomarkers, therapeutic agents, and preventive approaches for patients.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"304-317"},"PeriodicalIF":21.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639665","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":"HNRNPC and m6A RNA methylation control oncogenic transcription and metabolism in T-cell leukemia.","authors":"Jonas De Kesel, Igor Fijalkowski, Tim Pieters, Cristina Borin, Kasper Thorhauge Christensen, Manou Wittouck, Jolien Van Laere, Laura Guerrero, Lindy Reunes, Marino Caruso, Bijal Thakkar, Wouter Sleeckx, Luyao Kevin Xu, Filip Van Nieuwerburgh, Dieter Deforce, Kim De Keersmaecker, Tim Lammens, Steven Goossens, Tom Taghon, Cuijuan Han, Giulia Veltri, Valentina Serafin, Bruno Palhais, Nitesh D Sharma, Hao Huang, Hudan Liu, Ksenia Matlawska-Wasowska, Ana Milovanovic, Eva Maria Novoa, Eric Wang, Panagiotis Ntziachristos","doi":"10.1182/blood.2024026848","DOIUrl":"10.1182/blood.2024026848","url":null,"abstract":"<p><strong>Abstract: </strong>RNA homeostasis is dysregulated in cancer and affects disease progression and therapy resistance. N6-methyladenosine (m6A), the most abundant epitranscriptomic modification in eukaryotic messenger RNA, plays a pivotal role in RNA biology, affecting transcript stability, translation, and splicing. Our study uncovers the extensive m6A changes in patients with T-cell acute lymphoblastic leukemia (T-ALL), to our knowledge, for the first time. It reveals m6A's regulatory role in the oncogenic MYC and cholesterol biosynthesis pathways. In addition, we discovered that T-ALL is highly dependent on the m6A reader heterogeneous nuclear ribonucleoprotein C (HNRNPC). HNRNPC is transcriptionally controlled by MYC and is an essential regulator of m6A-modified transcripts. Consequently, transcriptional silencing of HNRNPC profoundly impairs oncogenic pathways and critically diminishes leukemia cell growth. In addition, the levels of the m6A demethylase fat mass and obesity-associated protein (FTO) are significantly elevated in T-ALL cells compared with normal cells, and to other types of leukemia. Targeting FTO shows therapeutic potential in preclinical disease models and synergizes with clinically relevant therapeutics. Our findings underscore the integral role of RNA methylation in orchestrating cancer cell oncogene expression and metabolism and highlight promising novel therapeutic avenues for the treatment of T-cell leukemia.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"275-290"},"PeriodicalIF":21.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172462","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":"Unusual suspects: a surprise cast in making blood stem cells.","authors":"Brandon Hadland","doi":"10.1182/blood.2025029369","DOIUrl":"https://doi.org/10.1182/blood.2025029369","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"16 1","pages":"265-266"},"PeriodicalIF":20.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645849","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":"Efficacy of a novel BCL-xL degrader, DT2216, in preclinical models of JAK2-mutated post-MPN AML.","authors":"Zhe Wang, Anna Skwarska, Gowri Poigaialwar, Sovira Chaudhry, Alba Rodriguez-Meira, Pinpin Sui, Emmanuel Olivier, Yannan Jia, Varun Gupta, Warren Fiskus, Cassandra L Ramage, Guangrong Zheng, Alexandra Schurer, Kira Gritsman, Eirini P Papapetrou, Kapil Bhalla, Daohong Zhou, Adam J Mead, Raajit K Rampal, Jeffrey W Tyner, Hussein A Abbas, Naveen Pemmaraju, Qi Zhang Tatarata, Marina Konopleva","doi":"10.1182/blood.2024027117","DOIUrl":"10.1182/blood.2024027117","url":null,"abstract":"<p><strong>Abstract: </strong>Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments do not significantly extend survival beyond 12 months. B-cell lymphoma-extra large (BCL-xL) has been found to be overexpressed in leucocytes from patients with MPN, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera, in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in patients with post-MPN AML than in those with de novo AML. Single-cell multiomics analysis revealed that leukemia cells harboring both MPN-driver and TP53 mutations exhibited higher BCL2L1 expression and elevated scores for leukemia stem cell, megakaryocyte development, and erythroid progenitor than wild-type cells. BH3 profiling confirmed a strong dependence on BCL-xL in post-MPN AML cells. DT2216 alone, or in combination with standard AML/MPN therapies, effectively degraded BCL-xL, reduced the apoptotic threshold, and induced apoptosis in post-MPN AML cells. DT2216 effectively eliminated viable cells in JAK2-mutant AML cell lines, induced pluripotent stem cell-derived hematopoietic progenitor cells, primary samples, and reduced tumor burden in cell line-derived xenograft model in vivo by degrading BCL-xL. DT2216, either as a single agent or in combination with azacytidine, effectively inhibited the clonogenic potential of CD34+ leukemia cells from patients with post-MPN AML. In summary, our data indicate that the survival of post-MPN AML is BCL-xL dependent, and DT2216 may offer therapeutic advantage in this high-risk leukemia subset with limited treatment options.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"341-355"},"PeriodicalIF":21.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751117","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":"Secondary blastoid plasma cell leukemia: can an old dog learn new tricks?","authors":"Jinjun Cheng,Jiehao Zhou","doi":"10.1182/blood.2025029282","DOIUrl":"https://doi.org/10.1182/blood.2025029282","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"52 1","pages":"396"},"PeriodicalIF":20.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645850","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":"PROTACtion against BCL-xL in post-MPN AML.","authors":"Nicole S Arellano,Shannon E Elf","doi":"10.1182/blood.2025029273","DOIUrl":"https://doi.org/10.1182/blood.2025029273","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"30 1","pages":"266-267"},"PeriodicalIF":20.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645851","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}