Blood最新文献

{"title":"Ikaros degradation by mezigdomide reduces T-cell dysfunction and improves the efficacy of antimyeloma T-cell therapies.","authors":"Lucia Y Chen, Adolfo Aleman, Marta Larrayoz, Hsiling Chiu, Junfei Zhao, Oliver Van Oekelen, Geoffrey Kelly, Seunghee Kim-Schulze, Alessandro Lagana, Sundar Jagannath, Tracy T Chow, Teresa Lozano, Juan J Lasarte, Joseph C Hamley, Warren Baker, Benjamin L Ebert, Udo Oppermann, Michael D Amatangelo, Anita Krithivas Gandhi, Patrick Ryan Hagner, Jose A Martínez-Climent, Sarah Gooding, Thomas A Milne, Samir Parekh","doi":"10.1182/blood.2025030891","DOIUrl":"https://doi.org/10.1182/blood.2025030891","url":null,"abstract":"<p><p>T cell dysfunction is an important contributor to both multiple myeloma (MM) disease progression and failure of anti-myeloma chimeric antigen receptor (CAR) T cell and bispecific T cell engager (TCE) therapies. Overcoming T cell dysfunction is therefore key to improving MM patient outcomes. Immunomodulatory drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs) have been observed to activate T cells, and more recently reduce T cell dysfunction, however the underlying mechanisms behind this are incompletely understood. Here, using bone marrow samples from MM patients, we demonstrate a significant reduction in dysfunctional T cell populations expressing exhaustion markers such as TIGIT, upon treatment with Mezigdomide. We further demonstrate the ability of Mezigdomide to improve T cell function and cytotoxicity in primary T cell models of T cell dysfunction and bispecific TCE therapy in vitro. Using concurrent ATAC-seq, ChIP-seq, HiC and RNA-seq in primary T cells treated with Mezigdomide, we demonstrate the novel role of transcription factor Ikaros in regulating an important T cell exhaustion gene TIGIT. Finally, we demonstrate the ability of Mezigdomide to enhance survival outcomes from anti-BCMA CAR-T therapy in vivo. Overall, our data show that Mezigdomide treatment improves anti-myeloma T cell therapy efficacy and reduces T cell dysfunction by abrogating Ikaros-mediated upregulation of exhaustion genes.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855927","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":"Procr+ endothelial progenitor cells govern hematopoiesis through fine-tuning mesenchymal stem cell niche signals.","authors":"Chang Xu, Xue Lv, Shangda Yang, Yanling Lv, Yawei Zheng, Yu-Xiang Wang, Yan Hui, Guohuan Sun, Xiangnan Zhao, Lan-Yue Ma, Honglin Duan, Linmin Zhang, Shuangshuang Pu, Lu Sun, Xialin Li, Yicheng He, Wenjia Fang, Meng Yang, Toshio Suda, Qi Chen, Tao Cheng, Hui Cheng","doi":"10.1182/blood.2025031474","DOIUrl":"https://doi.org/10.1182/blood.2025031474","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) rely on specialized niche cells for maintenance, yet how these regulators functionally integrate to preserve hematopoiesis remains unknown. Here, we identified a subset of Procr+ endothelial cells (ECs) with progenitor-like properties in bone marrow (BM), which is critical for vascular homeostasis and injury regeneration. Endothelial-specific ablation of Procr severely compromises BM vascular integrity and function. Beyond serving as a stem cell marker, Procr serves dual biological functions as a functional signaling receptor in multicellular communication. Mechanistically, Procr binds HSPA8 to promote Foxc2 nuclear translocation, upregulating Dll4 transcription to sustain Dll4/Notch3 activation in mesenchymal stem cells (MSCs), revealing a Procr/HSPA8/Foxc2/Dll4 axis essential for EC and MSC crosstalk. Through the HSPA8/Foxc2/Dll4/Notch3 axis, Procr+ ECs instruct MSCs Notch signaling, coordinating their adipogenic-osteogenic differentiation to maintain HSC self-renewal and myeloid output. Building on this mechanism, we demonstrated conserved functionality of Procr+ EPCs in human BM. Human PROCR+ ECs were found to similarly enhance DLL4/Notch3 signaling in MSCs, consequently preserving HSC function, confirming their therapeutic relevance. Our work highlights Procr⁺ EPCs sustain vascular integrity and govern MSC-dependent HSC maintenance, offering targeted clinical strategies for niche regeneration.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855988","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":"Tfr2 is necessary for acute iron-dependent hepcidin induction in mice with Tfr1-deficient hepatocytes.","authors":"Siqi Liu, Sofiya Tsyplenkova, Edouard Charlebois, Daniel F Wallace, V Nathan Subramaniam, Carine Fillebeen, Kostas Pantopoulos","doi":"10.1182/blood.2025030054","DOIUrl":"10.1182/blood.2025030054","url":null,"abstract":"<p><strong>Abstract: </strong>In hepatocytes, transferrin receptor 1 (Tfr1) plays a limited role in iron acquisition but negatively regulates signaling to the iron hormone hepcidin (Hamp) through its interaction with the hemochromatosis protein Hfe. Its homolog, transferrin receptor 2 (Tfr2), operates as an iron sensor and direct positive regulator of hepcidin expression. We generated TfrcAlb-Cre;Tfr2Alb-Cre mice with hepatocyte-specific ablation of both Tfr1 and Tfr2 to study their effects on iron homeostasis. These animals are viable and develop systemic iron overload, recapitulating a key feature of Tfr2Alb-Cre mice, albeit with milder hepatic iron accumulation and relatively higher residual hepcidin expression, presumably driven by liberated Hfe. Only Tfr1-expressing primary hepatocytes from Tfrcfl/fl;Tfr2fl/fl and Tfr2Alb-Cre mice internalized fluorescent holo-transferrin (AF647-Tf), arguing against a significant contribution of Tfr2 or other receptors in transferrin-bound iron uptake. Under dietary iron restriction, Hamp mRNA suppression and hepatic iron depletion were comparable in Tfr2-deficient livers from TfrcAlb-Cre;Tfr2Alb-Cre and Tfr2Alb-Cre mice despite compensatory Tfr1 upregulation in the latter, which likely sequesters Hfe. Conversely, Tfr1-deficient but Tfr2-expressing livers from TfrcAlb-Cre mice displayed relatively elevated Hamp mRNA, as expected. Following an acute dietary iron challenge, Hamp mRNA induction and Smad1,5,9 phosphorylation occurred only in the liver of Tfr2-expressing TfrcAlb-Cre but not in TfrcAlb-Cre;Tfr2Alb-Cre mice, indicating that \"liberated\" Hfe requires Tfr2 to become functionally active. Collectively, these findings demonstrate that transferrin receptors are dispensable for hepatocellular iron supply, and Tfr2 and Hfe exhibit nonredundant functions under chronic iron loading but act cooperatively to induce hepcidin in response to an acute iron challenge.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2252-2260"},"PeriodicalIF":23.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149048","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":"Focusing a sPOTlight on POT1.","authors":"Lucy A Godley","doi":"10.1182/blood.2025033015","DOIUrl":"https://doi.org/10.1182/blood.2025033015","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"147 19","pages":"2163-2164"},"PeriodicalIF":23.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833455","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":"JMJD1C-mediated epigenetic control of autoimmunity and HIT antibody production.","authors":"Mei Yu, Lu Zhou, Yongguang Zhang, Yongwei Zheng, Yuhong Chen, David W Wang, Nan Zhu, Renren Wen, Demin Wang","doi":"10.1182/blood.2025029593","DOIUrl":"https://doi.org/10.1182/blood.2025029593","url":null,"abstract":"<p><p>Heparin-induced thrombocytopenia (HIT) is a common drug-induced immune disorder occurring in a subset of heparin-treated patients. Immune complexes comprising heparin, platelet factor 4 (PF4), and PF4/heparin-reactive antibodies are central to its pathogenesis. However, the role of epigenetic modification in HIT remains unexplored. Our study identified JMJD1C, a member of the lysine-specific histone demethylase 3 subfamily, as an essential regulator of PF4/heparin-specific antibody production. While JMJD1C was expressed throughout B-cell development and was dispensable for normal B-cell development, its deficiency disrupted immune tolerance and promoted production of self-reactive antibodies in systemic autoimmune diseases, including PF4/heparin-specific platelet-activating antibodies, a hallmark of pathogenic HIT antibodies. JMJD1C-deficient B cells were hyperresponsive, characterized by enhanced B-cell receptor (BCR)-induced proliferation. Transcriptomic analysis (RNA-Seq) revealed upregulation of pathways associated with BCR signaling, NF-kB activation, the cell cycle, and systemic lupus erythematosus (SLE). CUT&Tag profiling demonstrated that JMJD1C deficiency increased H3K36me1 modification at gene start sites in these pathways, indicating that epigenetic dysregulation drives B-cell hyperactivation. Importantly, transcriptional profiling and regulon analysis of B cells from HIT patients showed enrichment of BCR signaling, cell-cycle, NF-κB, and SLE-associated pathways, closely mirroring those in JMJD1C-deficient B cells. Epigenetic analyses further revealed enhanced promoter chromatin accessibility and elevated H3K36me1 deposition at promoter-TSS regions in HIT B cells. Together, these findings establish a strong molecular overlap between JMJD1C deficiency and human HIT B cells and reveal a previously unrecognized epigenetic mechanism underlying HIT pathogenesis. Our study provides the first evidence linking epigenetic regulation to HIT, offering new insights into its pathophysiology.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833520","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":"MRD testing in Hodgkin lymphoma: filling the knowledge gaps.","authors":"Izidore S Lossos","doi":"10.1182/blood.2026033163","DOIUrl":"https://doi.org/10.1182/blood.2026033163","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"147 19","pages":"2159-2160"},"PeriodicalIF":23.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833546","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":"Is gene therapy a cure for β-thalassemia?","authors":"Haydar Frangoul","doi":"10.1182/blood.2025032609","DOIUrl":"https://doi.org/10.1182/blood.2025032609","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"147 19","pages":"2160-2161"},"PeriodicalIF":23.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833518","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 utilize somatic alterations in the diagnosis, risk stratification, and therapy of hypocellular bone marrow failure.","authors":"Emma M Groarke, Fernanda Gutierrez-Rodrigues, Bhavisha A Patel","doi":"10.1182/blood.2025029923","DOIUrl":"https://doi.org/10.1182/blood.2025029923","url":null,"abstract":"<p><p>Hypocellular bone marrow failure (BMF) may be acquired due to immune-mediated disease, the prototype being immune aplastic anemia (IAA), or inherited, due to germline defects in genes important for hematopoietic stem cells' function and maintenance (inherited bone marrow failure syndromes [IBMFS]). Proper diagnosis of the underlying etiology of hypocellular bone marrow failure, particularly distinguishing immune AA, myelodysplastic syndrome (MDS) (most relevant in this setting, hypoplastic MDS [MDS-h]), and the IBMFS, is important given the differences in clinical management. Clonal hematopoiesis (CH), in this context comprising somatic mutations or chromosomal abnormalities, is incorporated into standard algorithms for classification, risk stratification, and treatment decisions for hematologic malignancies, but the clinical significance in BMF is not well established. Disease-specific clonal signatures have been reported across the BMF spectrum, and here we show how distinct patterns of CH can aid in distinguishing different etiologies of hypocellular BMF. Additionally, detection of somatic alterations in many BMF disorders can estimate risk for secondary myeloid neoplasms, guide surveillance and, in some instances, allow for early therapeutic intervention.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833543","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":"Bone Marrow Stem Cell Connexins: Misconceptions and New Insights.","authors":"Abhishek K Singh, Kathrine S Rallis, Jose A Cancelas","doi":"10.1182/blood.2025031836","DOIUrl":"https://doi.org/10.1182/blood.2025031836","url":null,"abstract":"<p><p>Hematopoietic regeneration requires coordinated activation of hematopoietic stem and progenitor cells (HSPCs) and adaptive remodeling of the bone marrow (BM) microenvironment to meet extreme metabolic and oxidative demands imposed by cytotoxic injury, transplantation, and inflammation. While soluble factors and cytokine signaling are central to this process, emerging evidence identifies direct intercellular communication as a critical regulatory layer in stress hematopoiesis. Connexins, particularly Connexin-43 (Cx43), form an evolutionarily conserved communication network that integrates metabolic coupling, redox buffering, and organelle dynamics across hematopoietic and stromal compartments. Beyond canonical gap junction channel activity, connexins exert non-junctional, compartment-specific functions through cytoplasmic, nuclear, and mitochondrial pools that regulate signaling scaffolds, transcriptional programs, cytoskeletal organization, mitochondrial dynamics, calcium homeostasis, and bioenergetics. In HSPCs, mitochondrial Cx43 functions as a metabolic checkpoint that preserves regenerative capacity by supporting oxidative phosphorylation, limiting chronic AMPK activation, maintaining fusion-fission balance, and preventing mitochondrial Ca²⁺ overload. In parallel, Cx43 enables mitochondrial transfer from donor HSPCs to stromal niche cells, restoring stromal metabolic competence and promoting effective niche repair and engraftment. Dysregulation of connexin networks contributes to marrow failure, clonal evolution, leukemic niche remodeling, and chemoresistance, highlighting their context-dependent roles in health and disease. This review synthesizes advances in connexin biology in hematopoiesis, reframes connexins as integrators of metabolic and regenerative signaling rather than passive conduits, and defines emerging translational opportunities. Isoform- and compartment-specific targeting of connexin pathways offers a therapeutic strategy to enhance hematopoietic recovery, preserve long-term stem cell function, and disrupt pathological niche support in hematologic malignancies.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833372","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":"Classic Hodgkin lymphoma with IGH::CCND1 rearrangement: evidence of clonal relation to preceding mantle cell lymphoma.","authors":"Ahmed A Ahmed, Saber Tadros","doi":"10.1182/blood.2025032107","DOIUrl":"https://doi.org/10.1182/blood.2025032107","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"147 19","pages":"2278"},"PeriodicalIF":23.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833486","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}