Blood最新文献

{"title":"Clonal tracing of blood stem cells across mouse and human lifespans.","authors":"Alejo E Rodriguez-Fraticelli","doi":"10.1182/blood.2024028195","DOIUrl":"https://doi.org/10.1182/blood.2024028195","url":null,"abstract":"For over sixty years, blood researchers have been counting clones with every tool at their disposal. Inspired by phage and fly geneticists, Till and McCulloch irradiated mice to induce chromosomal aberrations. Using this labeling strategy, they demonstrated that different types of blood cells shared the same mutation in every spleen colony, thereby proving the existence of hematopoietic stem cells. Since their breakthrough, technological advances have enabled researchers to quantify hematopoiesis at single-cell resolution in increasingly complex samples across both mice and humans. With these modern sophisticated lineage tracing methods, our foundational understanding of the blood system is being reshaped. For instance, we now interpret hematopoietic architecture as arising from stem and progenitor cells of diverse developmental origins, each with distinct fate biases encoded by unique regulatory states. Interacting with this regulatory layer, genetic mutations and epimutations arise, expanding clonally and becoming pervasive with age. Together, clonal heterogeneity and age-driven clonal selection may underlie the perplexing diversity of therapy responses in cancer and beyond. As these paradigm-shifting insights gain traction, clonal tracing is being adopted across dozens of biological and clinical studies. Here, we review the modern toolbox of clonal tracking technologies, with a focus on next-generation sequencing-based approaches, and provide a practical guide for matching specific research questions with optimal experimental strategies.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"9 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116850","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":"INCREASED LEF1 PROTEIN LEVELS AND ISOFORM SWITCHING DRIVE CELL PROLIFERATION IN CHRONIC LYMPHOCYTIC LEUKEMIA.","authors":"Judith Mateos-Jaimez,Anna Vidal Crespo,Stella Charalampopoulou,Raul Fernandez Perez,Vicente Chapaprieta,Víctor Jiménez-Martínez,Liska Caviedes-Cárdenas,Martí Duran-Ferrer,Guadalupe Espadas,Eduard Sabido,Anne Largeot,Sophie A Herbst,Sascha Dietrich,Miguel Bastos Boente,Miguel Alcoceba,Ferran Nadeu,Ingo Ringshausen,Jerome Paggetti,Etienne Moussay,Dolors Colomer,Elías Campo,Alba Maiques-Diaz,Jose Ignacio Martin-Subero","doi":"10.1182/blood.2025030129","DOIUrl":"https://doi.org/10.1182/blood.2025030129","url":null,"abstract":"The transcription factor LEF1 is aberrantly expressed across all subtypes and stages of chronic lymphocytic leukemia (CLL), yet the molecular mechanisms underlying its contribution to CLL pathogenesis remain poorly defined. Here, we conducted a comprehensive mechanistic dissection of LEF1 function in CLL using extensive functional analyses of patient-derived samples. We identified that, although LEF1 mRNA levels remain stable, clinically aggressive cases show elevated LEF1 protein levels due to enhanced protein stability. LEF1 protein abundance is selectively modulated by lymph node-derived stimuli, including T-cell interactions and B-cell receptor (BCR) signaling. Importantly, we uncovered a dual, context-dependent role for LEF1 that is determined by its protein levels. Low LEF1 protein, characteristic of indolent cases, supports B-cell activation, while increased protein abundance in aggressive disease promotes proliferation through the binding and induction of cell cycle and metabolic gene networks. We further showed that LEF1 exon 6 skipping is enriched in proliferative and aggressive CLL. Both in vitro and in vivo experiments revealed that LEF1-driven proliferation is mediated by these short, alternative spliced isoforms. While all LEF1 isoforms bind to a core set of proliferation- and activation-related genes, they induce distinct transcriptional programs: full-length LEF1 promotes a quiescence gene signature and limits leukemic growth, whereas exon 6-skipping isoforms drive proliferation. Our findings establish LEF1 as an oncogenic transcription factor in CLL whose biological and clinical effects are modulated post-transcriptionally by both protein abundance and isoform composition.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"72 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117127","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":"Hematopoietic stem cell transplantation for purine nucleoside phosphorylase deficiency: an EBMT-IEWP retrospective study.","authors":"Uli S Herrmann,Matthias Felber,Austen Jj Worth,Sule Haskologlu,Figen Dogu,Victor Anthony Lewis,Brigitte Strahm,Andreas H Groll,Andrew R Gennery,Fabian Hauck,Robert Wynn,Mary Coussons,Isabelle Meyts,Caroline A Lindemans,M Victoria Bordon Cueto de Braem,Robbert Gm Bredius,Joern-Sven Kühl,Mirjam Völler,Felix Zirngibl,Irina Zaidman,Alexandra Laberko,Ulrike Zeilhofer,Mathias M Hauri-Hohl,Arjan C Lankester,Aydan Ikinciogullari,Gregory M T Guilcher,Annette Hackenberg,M Akif Yeşilipek,E Graham Davies,Michael Hershfield,Suhag H Parikh,Patrick Gilbert,Claudia Bettoni da Cunha Riehm,Michael H Albert,Ansgar S Schulz,Manfred Honig,Bénédicte Neven,Tayfun Güngör","doi":"10.1182/blood.2025029640","DOIUrl":"https://doi.org/10.1182/blood.2025029640","url":null,"abstract":"Purine nucleoside phosphorylase (PNP) deficiency causes inadequate purine metabolite detoxification, leading to combined immunodeficiency and variable neurological symptoms. Hematopoietic stem cell transplantation (HCT) cures the immunodeficiency, but large studies on long-term outcomes are lacking. In a retrospective EBMT study, we investigated 46 patients with PNP deficiency from 21 centers. We analyzed the presenting clinical signs and outcomes after HCT. Cognition (0-3), hearing (0-3), interaction (0-4), movement (0-4) and occupation (0-3) (CHIMO-score) were scored at last follow-up (FU) visit (no impairment: 17; mild: 15-16, moderate: 12-14, and severe impairment: <12). The median age at initial presentation was 7.5 (1-48) months, with 41% of cases involving infectious, 39% neurological, 15% infectious/neurological, and 5% autoimmune symptoms. At timepoint of HCT (median age: 26 (2-192) mo.), 88% of patients exhibited neurologic abnormalities. After a median FU of 7.9 (1.0-22.3) years, 40 patients were alive with a 3-year overall survival (OS)/event-free survival (EFS) probability of 86% (CI 77-97%)/75% (CI 64-89%), respectively. At FU, high-level donor chimerism (>50-100%) was observed in 85% of patients, and low-level (11-50%) in 15% of patients resulting in resolution of T lymphopenia. The median scores for cognition, hearing, interaction, movement, and occupation were 3 (0-3), 3 (1-3), 4 (1-4), 3 (1-4), and 2 (0-3), respectively, with a median CHIMO-score of 14 (6-17). Patients who underwent HCT <24 months after initial presentation demonstrated superior OS (p=0.049). Neurological symptoms occurring <11 months of age were associated with reduced OS (p=0.027). While the overall results were satisfactory, earlier diagnosis could further improve outcomes.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"53 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116851","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":"Determining telomere content and genomics of myeloid neoplasia by whole-genome sequencing.","authors":"Luca Guarnera,Adam Wahida,Carmelo Gurnari,Stephan Hutter,Sabine A Stainczyk,Nakisha Williams,Arda Durmaz,Yasuo Kubota,Carlos Bravo-Perez,Naomi Kawashima,Mark David Orland,Simona Pagliuca,Yimin Huang,Thomas LaFramboise,Valeria Visconte,Wencke Walter,Manja Meggendorfer,Wolfgang Kern,Frank Westermann,Lars Feuerbach,Torsten Haferlach,Jaroslaw P Maciejewski","doi":"10.1182/blood.2025028644","DOIUrl":"https://doi.org/10.1182/blood.2025028644","url":null,"abstract":"Telomere length shortening has been associated with genomic instability and acquisition of molecular lesions, but these processes have not been systematically studied across large cohorts of myeloid neoplasia (MN). As proof of concept for a novel, cross-validated WGS-based method of telomere content (TC) determination combined with mutations, transcriptomics, and functional assays, we studied TC in correlation with specific molecular features of a large cohort (n=1804) of MN patients including acute myeloid leukemia (AML) and myelodysplastic syndrome. When compared to healthy subjects and patients with non-clonal diseases such as persistent polyclonal B cell lymphocytosis, both MN and non-malignant controls with clonal disease, such as paroxysmal nocturnal hemoglobinuria and aplastic anemia, exhibited decreased TC. Furthermore, we show that TC is lowered in adult MN abrogating correlation with age with considerable TC diversification among certain morphologic and molecular subtypes. For instance, AML harbored the lowest TC. Furthermore, MN originating from a more mature cell of origin (e.g., APL), and those characterized by hyperproliferative driver mutations (e.g., RAS pathway genes) had lower TC, possibly indicating a loss of telomere maintenance capacity. In contrast, MN subtypes arising in a context of profound genetic alterations, such as TP53 mutations and complex karyotype, exhibited a relatively higher/preserved TC compared to other mutations. This phenomenon did not involve alternative lengthening processes but was rather consistent with an increased TC due to preserved activity of the telomerase complex. Our results describe a common and genotype-specific telomeric make-up of a large cohort of patients with MN providing a molecular benchmark for future therapeutic targeting of the telomere machinery.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"61 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116806","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":"Tissue transglutaminase drives fibrin β-chain cross-linking: a novel fibrin modification observed in trauma patients.","authors":"Nana Kwame Kwabi Boateng,Riley Marie Wimberley,Jacob P Rose,Angelo D'Alessandro,Mitchell J Cohen,Ernest E Moore,Lauren Schmitt,Lauren Poole,James P Luyendyk,Kirk C Hansen","doi":"10.1182/blood.2025029458","DOIUrl":"https://doi.org/10.1182/blood.2025029458","url":null,"abstract":"Covalent crosslinking of fibrin by the plasma transglutaminase coagulation factor XIII (FXIII) is a key determinant of blood clot stability and function. FXIII-catalyzed formation of ε-N-(γ-glutamyl)-lysyl crosslinks is restricted to the fibrin γ- and α-chains and follows thrombin driven fibrin polymerization. Fibrinogen is also crosslinked by tissue transglutaminase (TG2) in a reaction favoring intra- and intermolecular a-g crosslinking. Emerging evidence points to fibrinogen as a relevant substrate of TG2 in conditions of acute tissue damage. Remarkably, beyond detection of prototypical FXIII-directed crosslinks (i.e., a-a, g-g), we identified entirely novel covalent crosslinks involving the fibrinogen β chain (i.e., b-a, via FGB-Q82). Addition of TG2 to in vitro clotting reactions and analysis of fibrin(ogen) in reducing conditions revealed loss of β chain polypeptide paired with formation of high-molecular weight β chain species. Mass spectrometry-based crosslinking proteomic analysis of in vitro clots recapitulated the precise TG2-directed β chain crosslinks observed in clots made using the plasma of trauma patients. The results are the first to document in vitro and ex vivo crosslinking of the fibrin β chain and highlight a novel example of TG2 emerging as a relevant plasma transglutaminase.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"64 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116852","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":"Target antigen and plasma cell phenotype are critical factors for sensitivity to response-adapted daratumumab therapy.","authors":"Mark B Meads,Xiaohong Zhao,David R Noyes,Praneeth Sudalagunta,Alexandra Achille,Chaomei Zhang,Rafael Renatino Canevarolo,Maria Silva,Dario Magaletti,Danny DeAvila,Sonila Toska,Ashley Oates,Daniel Lastorino,Dietrich Werner Idiaquez,Jinming Song,Samer Sansil,Sean J Yoder,Ariel F Grajales-Cruz,Brandon J Blue,Ciara L Freeman,Jongphil Kim,Melissa Alsina,Jason Brayer,Ariosto Siqueira Silva,Xiaofei Song,Kenneth H Shain,Rachid C Baz","doi":"10.1182/blood.2025029921","DOIUrl":"https://doi.org/10.1182/blood.2025029921","url":null,"abstract":"In this response-adapted clinic trial with daratumumab monotherapy for elderly newly diagnosed multiple myeloma (MM), we identified target antigen expression, a plasma cell phenotype, and an activated immune microenvironment (iTME) as critical features associated with response to CD38 monoclonal antibody therapy. Here, patients achieving a partial response (PR) after 2 cycles continued daratumumab, otherwise lenalidomide or bortezomib was added. This strategy resulted in an overall response rate of 97% and low rates of adverse events, with 37% of patients able to continue daratumumab monotherapy. Importantly, we found that higher CD38 expression, plasma cell gene expression programming, and an activated iTME were associated with patients who were able to continue daratumumab therapy alone. In contrast, patients requiring the addition of lenalidomide or bortezomib had increased expression of adhesion, TNF signaling, KRAS signaling, and B cell programs as well as an immunosuppressed iTME. Tracking of clonal dynamics illustrated the selection of subclones enriched for de novo resistance gene expression programs after only two cycles of daratumumab monotherapy. Upon relapse, daratumumab refractory MM cells were characterized by the expansion of pre-existing minor subclones with mixed transcriptomic programs containing the plasma cell phenotype with decreased CD38 and maintenance of resistance programs, suggesting development of acquired resistance involves an uncoupling of transcriptional programs present in therapy naïve tumors. To our knowledge, this is the first study to demonstrate the effectiveness of response-adapted daratumumab treatment and describe critical biomarkers of single-agent daratumumab sensitivity in vulnerable, therapy naïve MM patients. NCT04151667.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"57 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117126","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":"Alternative AAV gene therapy for hemophilia A using expression of Bi8, a novel single-chain FVIII-mimetic antibody.","authors":"Vincent Muczynski,Olivier D Christophe,Lewis Tanner,Charlotte Vayssiere,Alice Guérin,Caterina Casari,Jenny Hazel McIntosh,Doyoung Lee,Gavin Ling,Satyen Harish Gohil,Peter J Lenting,Edward G Tuddenham,Amit C Nathwani","doi":"10.1182/blood.2024027709","DOIUrl":"https://doi.org/10.1182/blood.2024027709","url":null,"abstract":"The recent approval of adeno-associated virus (AAV)-based gene therapies for haemophilia A (HA) represents a major advancement in the management of this X-linked bleeding disorder, offering multi-year bleed protection and improved quality of life over factor VIII (FVIII) replacement. However, challenges remain-including concerns over long-term durability of expression and the difficulty of packaging the oversized FVIII transgene into AAV vectors. To address these limitations, we developed AAV8-Bi8, a liver-directed gene therapy encoding Bi8, a novel 54.5 kDa FVIII mimetic antibody. Bi8 is expressed as a compact, single-chain tandem scFv and is delivered via a 4.4 kb expression cassette packaged within AAV8 capsids-well within the vector packaging capacity. In vitro, Bi8 demonstrated FVIII mimetic activity and effectively corrected FVIII-deficient human plasma to levels comparable with emicizumab, the current market standard. In vivo, a single administration of AAV8-Bi8 in FVIII-deficient mice resulted in dose-dependent, durable expression of Bi8, complete phenotypic correction of bleeding, and therapeutic equivalence to both emicizumab-treated and wild-type animals. Importantly, no toxicity or anti-drug antibody responses were observed. This approach, based on delivering FVIII mimetic antibodies through AAV rather than truncated FVIII transgenes, could provide a more flexible and efficient platform for gene therapy in haemophilia A. AAV8-Bi8 has the potential to offer sustained, life-long haemostatic control, including in patients who have developed inhibitors to FVIII.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"24 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116805","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":"VEXAS syndrome anemia is a mosaic erythroblastopenia.","authors":"Francois Rodrigues,Giulia Hardouin,Sara El Hoss,Aya Ghoul,Emilie-Fleur Gautier,Michaël Dussiot,Maria A Lizarralde-Iragorri,Annalisa Santini,Sandy Peltier,Pascal Amireault,Vanessa Soldan,Annarita Miccio,Mounia Debili,Vincent Jachiet,Thiago Trovati Maciel,Julien Rossignol,Eric Allemand,Arsène M Mékinian,Sophie Anne Georgin-Lavialle,Mohammad Salma,Eric Soler,Pierre-Emmanuel Gleizes,Marie-Francoise O'Donohue,Olivier Kosmider,Manuel S Rodriguez,Olivier Hermine","doi":"10.1182/blood.2025029081","DOIUrl":"https://doi.org/10.1182/blood.2025029081","url":null,"abstract":"VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently discovered autoinflammatory disorder linked to somatic mutations in the UBA1 gene, resulting in a profound cytoplasm-restricted defect in ubiquitylation. The disease is characterized by a macrocytic anemia that remains poorly understood. To investigate the erythroid lineage in VEXAS, we conducted a comprehensive study combining in vivo assessments of patients' mature red cells and marrow erythroblasts, alongside in vitro base-editing models of erythropoiesis. Here we show that mature red cells do not exhibit ubiquitylation defects, and patient-derived bone marrow erythroblasts lack UBA1 mutations beyond the basophilic stage of erythroid differentiation. In vitro base editing of UBA1 variants in CD34+ primary cells resulted in high mortality during early erythroid differentiation, but not during monocytic differentiation. Edited erythroid precursors displayed TP53 overexpression linked to defective ubiquitylation and anomalies in ribosome biogenesis, reminiscent of Diamond-Blackfan anemia. We propose that VEXAS-associated anemia should be considered as a mosaic erythroblastopenia, where the severity of anemia is influenced by the quality and quantity of the UBA1-WT compartment. Our findings offer new insights into the physiopathology of VEXAS and may suggest new potential therapeutic options.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"18 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089776","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":"FLAG-IDA plus venetoclax for children, adolescents, and young adults with newly diagnosed AML.","authors":"Reeja Raj,Samanta Catueno,Amber Gibson,David McCall,Miriam B Garcia,Cesar Nunez,Michael E Roth,Koji Sasaki,Priti Tewari,Ghayas C Issa,Aziz Farhat,Jeremy S Connors,Irtiza Naseer Sheikh,Yuki Nishida,Joanna S Yi,Alexandra M Stevens,Alex Bataller,Kapil N Bhalla,Demetrios Petropoulos,Naval G Daver,Tapan M Kadia,Branko Cuglievan,Courtney D DiNardo","doi":"10.1182/blood.2025029391","DOIUrl":"https://doi.org/10.1182/blood.2025029391","url":null,"abstract":"FLAG-IDA with venetoclax shows promise as frontline therapy for pediatric AML. In 12 patients treated at MD Anderson, most achieved remission with good early survival outcomes and many proceeded to transplant. Common toxicities included cytopenias comparable to previous regimens.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"28 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089802","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":"Reprogramming glutamine metabolism enhances BCMA-CART cell fitness and therapeutic efficacy in multiple myeloma.","authors":"Flor Navarro,Teresa Lozano,Andrea Fuentes-García,Inés Sánchez-Moreno,Marta Larrayoz,Pedro Justicia,Beatriz Perucha,Maialen Martinez-Tabar,Rebeca Martinez-Turrillas,Noelia Casares,Celia Martín-Otal,Marta Gorraiz,Erin W Meermeier,Marta Chesi,Douglas Lake,Paul Leif Bergsagel,Eva Santamaría,Maria Erendira Calleja-Cervantes,Patxi San Martín-Úriz,Lorea Jordana-Urriza,Xabier Agirre,Sandra Hervas-Stubbs,Juan Roberto Rodriguez-Madoz,Jose A Martínez-Climent,Felipe Prosper,Juan J Lasarte","doi":"10.1182/blood.2024027496","DOIUrl":"https://doi.org/10.1182/blood.2024027496","url":null,"abstract":"Glutamine-dependence of cancer cells reduces local glutamine availability, which hinders anti-tumor T-cell functionality and facilitates immune evasion. We thus speculated that glutamine deprivation might be limiting efficacy of CAR T-cell therapies in cancer patients. We have seen that antigen-specific T cells are unable to proliferate or produce IFN-γ in response to antigen stimulation when glutamine concentration is limited. Using multiple myeloma (MM) as a glutamine-dependent disease model, we found that murine CAR-T cells selectively targeting BCMA in MM cells were sensitive to glutamine deprivation. However, CAR-T cells engineered to increase glutamine uptake by expression of the glutamine transporter Asct2 exhibited enhanced proliferation and responsiveness to antigen stimulation, increased production of IFN-γ, and heightened cytotoxic activity, even under conditions of low glutamine concentration. Mechanistically, Asct2 overexpression reprogrammed CART cell metabolic fitness of CART cells by upregulating the mTORC1 gene signature, modifying the Solute Carrier transporter (SLC) repertoire, and improving both basal oxygen consumption rate and glycolytic function thereby enhancing CART cell persistence in vivo. Accordingly, expression of Asct2 increased the efficacy of BCMA-CART cells in syngeneic and genetically-engineered mouse models of MM, which prolonged mouse survival. In patients, reduced expression of Asct2 by MM cells predicted poor outcome to combined immunotherapy and BCMA-CAR T-cell therapy. Our results indicate that reprogramming glutamine metabolism may enhance anti-tumor CAR T-cell functionality in MM. This approach may also be effective for other cancers that depend on glutamine as a key energy source and metabolic hallmark.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"29 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089844","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}