Pub Date : 2026-03-05DOI: 10.1182/blood.2025032407
Ghassan Zammar,Chan Y Cheah
{"title":"Pretransplant promise for PD-1 in Hodgkin lymphoma.","authors":"Ghassan Zammar,Chan Y Cheah","doi":"10.1182/blood.2025032407","DOIUrl":"https://doi.org/10.1182/blood.2025032407","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"245 1","pages":"1015-1017"},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350496","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2026033208
{"title":"Burger JA, Barr PM, Robak T, et al. Final analysis of the RESONATE-2 study: up to 10 years of follow-up of first-line ibrutinib treatment for CLL/SLL. Blood. 2025;146(18):2168-2176.","authors":"","doi":"10.1182/blood.2026033208","DOIUrl":"https://doi.org/10.1182/blood.2026033208","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"12 1","pages":"1136"},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350577","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2025031756
Moua Yang,Osamede Clinton Owegie,Anika Patel,Quinn Patrick Kennedy,James T Flaumenhaft,Mathivanan Chinnaraj,Nathan Ponzar,Emmy M Fulcidor,Mario C Rico,Amit Bhowmik,Kate S Carroll,Diane E Handy,Joseph Loscalzo,David W Essex,Nicola Pozzi,Robert Flaumenhaft
Protein disulfide isomerase (PDI) functions in thrombus formation in vivo and represents a viable target for antithrombotic therapy. PDI is a redox sensor that can either reduce or oxidize substrates depending on the redox environment. Yet whether PDI functions primarily as a reductase or an oxidase in the context of thrombus formation is unknown. We have used pharmacological approaches and PDI mutants to determine how the redox state of PDI affects thrombus formation. LOC14, which inhibits PDI reductase activity and induces PDI oxidation, promoted thrombus formation in arteries exposed to FeCl3 and enhanced injury-induced platelet accumulation and fibrin formation in cremaster arterioles. Substitution of a single sulfur atom with oxygen in LOC14 reversed these prothrombotic effects. Blocking antibodies targeting PDI also reversed the effect of LOC14. Evaluation of sulfenylation-mediated PDI oxidation using C53A, C56A, R120D and T101A PDI mutants showed that the sulfenylation mechanism of PDI resembles that of H2O2 reduction by peroxiredoxins. These studies identified PDI mutants that failed to undergo H2O2-mediated oxidation, but showed normal reductase activity. When tested in vivo, either wild-type PDI or the R120D mutant fully restored normal thrombus formation following morphilino-induced knockdown of PDI. In contrast, the R120D mutant PDI was unable to fully restore thrombus formation in the setting of oxidative stress induced in mice with genetic deletion of glutathione peroxidase 3 null (GPx3-/-). These studies show that PDI-catalyzed oxidization drives thrombus formation in vivo and demonstrate a mechanism of peroxide-mediated oxidation of PDI that contributes to the prothrombotic response of oxidative stress.
{"title":"Oxidized PDI promotes thrombus formation in oxidative stress.","authors":"Moua Yang,Osamede Clinton Owegie,Anika Patel,Quinn Patrick Kennedy,James T Flaumenhaft,Mathivanan Chinnaraj,Nathan Ponzar,Emmy M Fulcidor,Mario C Rico,Amit Bhowmik,Kate S Carroll,Diane E Handy,Joseph Loscalzo,David W Essex,Nicola Pozzi,Robert Flaumenhaft","doi":"10.1182/blood.2025031756","DOIUrl":"https://doi.org/10.1182/blood.2025031756","url":null,"abstract":"Protein disulfide isomerase (PDI) functions in thrombus formation in vivo and represents a viable target for antithrombotic therapy. PDI is a redox sensor that can either reduce or oxidize substrates depending on the redox environment. Yet whether PDI functions primarily as a reductase or an oxidase in the context of thrombus formation is unknown. We have used pharmacological approaches and PDI mutants to determine how the redox state of PDI affects thrombus formation. LOC14, which inhibits PDI reductase activity and induces PDI oxidation, promoted thrombus formation in arteries exposed to FeCl3 and enhanced injury-induced platelet accumulation and fibrin formation in cremaster arterioles. Substitution of a single sulfur atom with oxygen in LOC14 reversed these prothrombotic effects. Blocking antibodies targeting PDI also reversed the effect of LOC14. Evaluation of sulfenylation-mediated PDI oxidation using C53A, C56A, R120D and T101A PDI mutants showed that the sulfenylation mechanism of PDI resembles that of H2O2 reduction by peroxiredoxins. These studies identified PDI mutants that failed to undergo H2O2-mediated oxidation, but showed normal reductase activity. When tested in vivo, either wild-type PDI or the R120D mutant fully restored normal thrombus formation following morphilino-induced knockdown of PDI. In contrast, the R120D mutant PDI was unable to fully restore thrombus formation in the setting of oxidative stress induced in mice with genetic deletion of glutathione peroxidase 3 null (GPx3-/-). These studies show that PDI-catalyzed oxidization drives thrombus formation in vivo and demonstrate a mechanism of peroxide-mediated oxidation of PDI that contributes to the prothrombotic response of oxidative stress.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"283 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359443","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}
Abstract: Sickle cell disease (SCD) and β-thalassemia, caused by mutations or deletions in the β-globin gene, are among the most prevalent genetic disorders worldwide, significantly affecting global health and mortality. Recently, reactivation of δ-globin gene expression has been proposed as a potential therapeutic strategy for these conditions. In this study, we found that interferon gamma (IFN-γ) and IFN-β significantly enhance δ-globin expression and activate the JAK/STAT signaling pathway in erythroid cells, with IFN-γ exerting a stronger effect than IFN-β. In erythroid cells derived from CD34+ progenitors, IFN-γ not only increased δ-globin expression but also promoted differentiation, as confirmed by quantitative polymerase chain reaction, western blotting, high-performance liquid chromatography, and flow cytometry. Inhibition of the JAK/STAT pathway, either through a JAK1/2 inhibitor (AZD1840 or ruxolitinib) or via small interfering RNAs targeting JAK1, JAK2, STAT1, or STAT3, significantly decreased both basal and IFN-γ-induced δ-globin expression in HBD-HiBiT knockin HUDEP2 cells. Mutation or removal of the putative IRF-1/STAT2 binding site (-265 to -242) and the adjacent STAT binding site (-243 to -231) in the δ-globin promoter impaired IFN-γ-induced δ-promoter activity. Chromatin immunoprecipitation assays confirmed enhanced binding of interferon regulatory factor 1 (IRF-1) and STAT1 upon IFN-γ treatment. Our elucidation of the mechanism by which a specific molecule induces δ-globin expression suggests that IFN-γ may hold therapeutic potential for patients with SCD, and that screening for compounds that can induce δ-globin could offer a novel pharmaceutical strategy for treating β-hemoglobinopathies.
{"title":"IFN-γ increases δ-globin gene expression through activation of the JAK/STAT pathway in erythroid cells.","authors":"Jianqiong Zhu, Kyung Chin, Jizhong Zou, Wulin Aerbajinai, Wan-Chi Lin, Hongzhen Li, Griffin P Rodgers","doi":"10.1182/blood.2025029969","DOIUrl":"10.1182/blood.2025029969","url":null,"abstract":"<p><strong>Abstract: </strong>Sickle cell disease (SCD) and β-thalassemia, caused by mutations or deletions in the β-globin gene, are among the most prevalent genetic disorders worldwide, significantly affecting global health and mortality. Recently, reactivation of δ-globin gene expression has been proposed as a potential therapeutic strategy for these conditions. In this study, we found that interferon gamma (IFN-γ) and IFN-β significantly enhance δ-globin expression and activate the JAK/STAT signaling pathway in erythroid cells, with IFN-γ exerting a stronger effect than IFN-β. In erythroid cells derived from CD34+ progenitors, IFN-γ not only increased δ-globin expression but also promoted differentiation, as confirmed by quantitative polymerase chain reaction, western blotting, high-performance liquid chromatography, and flow cytometry. Inhibition of the JAK/STAT pathway, either through a JAK1/2 inhibitor (AZD1840 or ruxolitinib) or via small interfering RNAs targeting JAK1, JAK2, STAT1, or STAT3, significantly decreased both basal and IFN-γ-induced δ-globin expression in HBD-HiBiT knockin HUDEP2 cells. Mutation or removal of the putative IRF-1/STAT2 binding site (-265 to -242) and the adjacent STAT binding site (-243 to -231) in the δ-globin promoter impaired IFN-γ-induced δ-promoter activity. Chromatin immunoprecipitation assays confirmed enhanced binding of interferon regulatory factor 1 (IRF-1) and STAT1 upon IFN-γ treatment. Our elucidation of the mechanism by which a specific molecule induces δ-globin expression suggests that IFN-γ may hold therapeutic potential for patients with SCD, and that screening for compounds that can induce δ-globin could offer a novel pharmaceutical strategy for treating β-hemoglobinopathies.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1111-1124"},"PeriodicalIF":23.1,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596014","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2025032278
Christian Récher
{"title":"MRD is a new therapeutic target in AML.","authors":"Christian Récher","doi":"10.1182/blood.2025032278","DOIUrl":"https://doi.org/10.1182/blood.2025032278","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"15 1","pages":"1012-1013"},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350490","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}
The molecular classification of T-cell acute lymphoblastic leukemia (T-ALL) remains incomplete, limiting risk stratification and the development of targeted therapies. Enhancer hijacking is a critical oncogenic mechanism that deregulates proto-oncogenes by repositioning cis-regulatory regions via structural variants. Here, we performed an integrated analysis of pediatric and adult T-ALL and mixed phenotype acute leukemias (MPALs), using whole-genome and whole-transcriptome sequencing. This analysis identified a group of 14 patients with predominantly T-lineage neoplasms driven by a t(14;16)(q32;q24) translocation, harboring universal GATA3 mutations and CDKN2A/B deletions. Mechanistically, this translocation repositions the ThymoD locus downstream of BCL11B, causing monoallelic, ectopic overexpression of FENDRR and mesenchymal transcription factor genes FOXF1 and FOXC2, activating epithelial-mesenchymal transition (EMT) transcription signatures. Immunophenotypic and single-cell RNA-seq analyses revealed marked lineage ambiguity with myeloid and B-cell differentiation potentials specific to this subtype. Furthermore, functional analyses in CD34-positive cord blood cells demonstrated that FOXF1 overexpression promotes myeloid differentiation while suppressing T-cell differentiation, serving as a key factor for lineage specification. Clinically, this subtype was detected in 0.15-4.0% of T-ALL/MPAL cases depending on the cohort, showing a median age of 15 years and enrichment in adolescents and young adults (AYA). Importantly, patients with t(14;16)(q32;q24) have an extremely poor prognosis, showing a trend toward worse outcomes than high-risk groups such as KMT2A-rearranged early T-cell progenitor (ETP)-like, SPI1-rearranged, and LMO2 γδ-like T-ALLs. The unique molecular landscape and poor prognosis of patients with the t(14;16)(q32;q24) translocation underscore the need for the development of novel subtype-specific therapeutic approaches.
{"title":"BCL11B enhancer hijacking by t(14;16)(q32;q24) translocation defines a novel high-risk subtype of T-ALL.","authors":"Kaito Mimura,Akira Kaino,Yotaro Ochi,Yu-Hsuan Chang,Masafumi Seki,June Takeda,Saori Katayama,Hidetaka Niizuma,Yoji Sasahara,Yoko Mizoguchi,Maiko Shimomura,Ryosuke Koyamada,Rintaro Ono,Daisuke Hasegawa,Kazuki Mitani,Hirohito Kubota,Satoshi Yoshihara,Nobuhiro Hiramoto,Akihito Otsuki,Yasunobu Okamura,Fumiki Katsuoka,Kengo Kinoshita,Masataka Hasegawa,Marina Togo-Ohno,Hirona Maeda,Nobuyuki Kakiuchi,Mai Takeuchi,Aiko Sato-Otsubo,Shota Kato,Kentaro Watanabe,Kotoe Katayama,Seiya Imoto,Yuichi Shiraishi,Katsuyoshi Koh,Souichi Suenobu,Eiso Hiyama,Susumu Goyama,Atsuo Kikuchi,Seishi Ogawa,Motohiro Kato,Yasuhito Nannya,Junko Takita,Kenichi Yoshida","doi":"10.1182/blood.2025031466","DOIUrl":"https://doi.org/10.1182/blood.2025031466","url":null,"abstract":"The molecular classification of T-cell acute lymphoblastic leukemia (T-ALL) remains incomplete, limiting risk stratification and the development of targeted therapies. Enhancer hijacking is a critical oncogenic mechanism that deregulates proto-oncogenes by repositioning cis-regulatory regions via structural variants. Here, we performed an integrated analysis of pediatric and adult T-ALL and mixed phenotype acute leukemias (MPALs), using whole-genome and whole-transcriptome sequencing. This analysis identified a group of 14 patients with predominantly T-lineage neoplasms driven by a t(14;16)(q32;q24) translocation, harboring universal GATA3 mutations and CDKN2A/B deletions. Mechanistically, this translocation repositions the ThymoD locus downstream of BCL11B, causing monoallelic, ectopic overexpression of FENDRR and mesenchymal transcription factor genes FOXF1 and FOXC2, activating epithelial-mesenchymal transition (EMT) transcription signatures. Immunophenotypic and single-cell RNA-seq analyses revealed marked lineage ambiguity with myeloid and B-cell differentiation potentials specific to this subtype. Furthermore, functional analyses in CD34-positive cord blood cells demonstrated that FOXF1 overexpression promotes myeloid differentiation while suppressing T-cell differentiation, serving as a key factor for lineage specification. Clinically, this subtype was detected in 0.15-4.0% of T-ALL/MPAL cases depending on the cohort, showing a median age of 15 years and enrichment in adolescents and young adults (AYA). Importantly, patients with t(14;16)(q32;q24) have an extremely poor prognosis, showing a trend toward worse outcomes than high-risk groups such as KMT2A-rearranged early T-cell progenitor (ETP)-like, SPI1-rearranged, and LMO2 γδ-like T-ALLs. The unique molecular landscape and poor prognosis of patients with the t(14;16)(q32;q24) translocation underscore the need for the development of novel subtype-specific therapeutic approaches.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"407 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368257","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2025032749
Helen E Heslop,Jorge Di Paola
{"title":"Introduction to a review series on hemophagocytic lymphohistiocytosis.","authors":"Helen E Heslop,Jorge Di Paola","doi":"10.1182/blood.2025032749","DOIUrl":"https://doi.org/10.1182/blood.2025032749","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"48 1","pages":"1005-1006"},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350781","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}
Pub Date : 2026-03-05DOI: 10.1182/blood.2025032329
Carlos Fernández de Larrea
{"title":"Targeting BCMA: a double-edged sword for infection risk.","authors":"Carlos Fernández de Larrea","doi":"10.1182/blood.2025032329","DOIUrl":"https://doi.org/10.1182/blood.2025032329","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"52 1","pages":"1010-1011"},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350491","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}
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