Blood最新文献

{"title":"Project EVOLVE: an international analysis of postimmunotherapy lineage switch, an emergent form of relapse in leukemia.","authors":"Sara K Silbert, Alexander W Rankin, Chloe N Hoang, Alexandra Semchenkova, Regina M Myers, Elena Zerkalenkova, Hao-Wei Wang, Alexandra E Kovach, Constance M Yuan, Dana Delgado Colon, Loïc Vasseur, Alex Bataller, Samuel John, Kaylyn Utley Lyons, Barbara Friedes, Anna Alonso-Saladrigues, Hisham Abdel-Azim, Estelle Balducci, Ahmed Assim Aljudi, Marie Balsat, D Nathan Biery, Aghiad Chamdin, Bill H Chang, Raymund S Cuevo, Barbara De Moerloose, David S Dickens, Ulrich Duffner, Nicolas Duployez, Firas El Chaer, Michelle Ann Elliott, Gabriele Escherich, Sneha Fernandes, Mandi R Fitzjohn, Zhubin Gahvari, Stephan A Grupp, Rui Rochelle He, Cynthia Harrison, Christopher B Hergott, Emily M Hsieh, Annette S Kim, Dennis J Kuo, Daniel P Larson, Benjamin J Lee, Thibaut Leguay, R Coleman Lindsley, Abhishek A Mangaonkar, Kerstin Mezger, Holly L Pacenta, Jing Pan, Marlie Provost, Latika Puri, Sunil S Raikar, Armando Martinez, Isabella Bristol, Kyle Murphy, Lauren Reiman, Michele Redell, Kelly Reed, Gabrielle Roth-Guepin, Jeremy Rubinstein, Süreyya Savaşan, Kristian Schafernak, Alexandra Stevens, Aimee Talleur, Naomi Torres Carapia, Jacques Vargaftig, Anant Vatsayan, Matthias Wölfl, Liping Zhao, Susana Rives, Vanessa A Fabrizio, Koji Sasaki, Ibrahim Aldoss, Nicolas Boissel, Susan R Rheingold, Kara L Davis, Sara Ghorashian, Elad Jacoby, Alexander Popov, Adam J Lamble, Nirali N Shah","doi":"10.1182/blood.2024026655","DOIUrl":"10.1182/blood.2024026655","url":null,"abstract":"<p><strong>Abstract: </strong>Lineage switch (LS), defined as the immunophenotypic transformation of acute leukemia, has emerged as a mechanism of relapse after antigen-targeted immunotherapy, which is associated with dismal outcomes. Through an international collaborative effort, we identified cases of LS after a host of antigen-targeted therapies (eg, CD19, CD22, CD38, and CD7), described how LS was diagnosed, reviewed treatment approaches, and analyzed overall outcomes for this form of postimmunotherapy relapse. Collectively, 75 cases of LS were evaluated, including 53 (70.7%) cases of B-cell acute lymphoblastic leukemia (B-ALL) transforming to acute myeloid leukemia (AML), 17 (22.7%) cases of B-ALL transforming to mixed phenotypic acute leukemia (MPAL)/acute leukemias of ambiguous lineage (ALAL), and 5 (6.7%) cases of rare LS presentation (ie, T-cell ALL to AML). An additional 10 cases with incomplete changes in immunophenotype, referred to as \"lineage drift\" were also described. With a primary focus on the 70 cases of LS from B-ALL to AML or MPAL/ALAL, LS emerged at a median of 1.5 months (range, 0-36.5) after immunotherapy, with 81.4% presenting with LS within the first 6 months from the most proximal immunotherapy. Although most involved KMT2A rearrangements (n = 45, 64.3%), other rare cytogenetic and/or molecular alterations were uniquely observed. Treatment outcomes were generally poor, with remission rates of <40%. The median overall survival after LS diagnosis was 4.8 months. Outcomes were similarly poor for those with rare immunophenotypes of LS or lineage drift. This global initiative robustly categorizes lineage changes after immunotherapy and, through enhanced understanding, establishes a foundation for improving outcomes of LS.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"437-455"},"PeriodicalIF":21.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802462","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":"Cytolytic helper T cells: a new addition to myeloma immunity.","authors":"Tom Cupedo","doi":"10.1182/blood.2025028916","DOIUrl":"https://doi.org/10.1182/blood.2025028916","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"14 1","pages":"402-403"},"PeriodicalIF":20.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693516","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":"Relationship between immunogenicity and protein structure at amino acid substitution sites of blood group antigens.","authors":"John G Howe, Gary Stack","doi":"10.1182/blood.2024025071","DOIUrl":"10.1182/blood.2024025071","url":null,"abstract":"<p><strong>Abstract: </strong>Polypeptide blood group antigens, many of which are created by single exofacial amino acid substitutions, have varying immunogenicities. Why some amino acid substitutions are more immunogenic than others is little understood. Using AlphaFold2, an artificial intelligence system that predicts 3-dimensional protein structure, along with multiple other structure analysis programs, we investigated protein structure at sites of amino acid substitutions that create 9 clinically significant blood group antigens. Based on structure predictions, the amino acid substitutions that create the 4 most immunogenic of the 9 antigens (K, Jka, Lua, and E) were typically buried or partially buried in rigid, ordered protein regions, usually helices and β-strands. This was reflected by their lower mean relative solvent accessibility (RSA) than the 5 less immunogenic antigens (c, M, Fya, C, and S; 0.13 vs 0.81; P = .003) and higher mean AlphaFold2 confidence score (92.5 vs 48.3; P = .001; scores <50 predict protein disorder). Substitutions creating the 5 least immunogenic antigens (c, Fya, M, C, and S) were all predicted to be in flexible regions with high accessibility, either in surface-accessible loops (C, c) or disordered coils (Fya, M, and S). Scatter plots revealed a positive linear correlation of immunogenicity with confidence score (R2 = 0.826; P = .0007) and percent helix/β-strand in 15-mers centered around the substitution sites (R2 = 0.763; P = .0021) and a negative linear correlation with RSA (R2 = 0.688; P = .0057). Therefore, based on an informatics analysis, the protein secondary and tertiary structures at amino acid substitution sites that create blood group antigens are significant correlates and potential determinants of immunogenicity.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"504-517"},"PeriodicalIF":21.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751134","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":"TCA cycle mode switch determines the fate of pirtobrutinib-tolerant persister cells in mantle cell lymphoma.","authors":"Wei Wang,Qingsong Cai,Yang Liu,Lei Nie,Heng-Huan Lee,Fangfang Yan,Yue Fei,Yixin Yao,Yijing Li,Lin Tan,Philip L Lorenzi,Ying-Nai Wang,Jun Yao,Zhihong Chen,Joseph McIntosh,Cheng-Tai Yu,Preetesh Jain,Vivian Jiang,Jovanny Vargas,Xiaolin Li,Tianci Zhang,Shaoying Li,David Santos,Selvi Thirumurthi,Erin Heather Seeley,Lukas Mikolaj Simon,Christopher R Flowers,Chi Young Ok,Michael L Wang","doi":"10.1182/blood.2024026919","DOIUrl":"https://doi.org/10.1182/blood.2024026919","url":null,"abstract":"Bruton's tyrosine kinase inhibitors (BTKi) and cell therapy have successfully been used to treat mantle cell lymphoma (MCL); however, therapy resistance inevitably emerges. Cancer cells can progressively develop stable resistance by traversing through a transient drug-tolerant persister (DTP) state. The mechanisms enabling DTP cells to reversibly adapt to therapies and evolve to acquire heterogeneity remain poorly understood, and characterizing DTP cells in MCL continues to pose a challenge for clinic translation. Here using pirtobrutinib, a recently FDA-approved non-covalent BTKi, we identified pirtobrutinib-tolerant persister cells exhibiting morphological variability by presenting a unique population of enlarged cells (Giant cells) with reversible fate transitions. During treatment, Giant cells enter a non-proliferative, dedifferentiated state, addicted to an activated cytosolic tricarboxylic acid (TCA) cycle coupled with the malate-aspartate shuttle to engage in biosynthesis. Upon drug removal, the TCA cycle shifts to oxidative catabolism, promoting Giant cells to differentiate into regular-sized cells. Throughout the transition, acetyl-CoA modulates cell fate by fine-tuning stemness. Our biphasic model demonstrates that the metabolic switch governs the phenotypic plasticity of DTP cells in MCL, resulting a dynamic presence of DTP cells across various developmental states in response to systemic therapies. Targeting Giant cells prior to their differentiation offers a promising strategy to overcoming therapy resistance in MCL.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"115 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693226","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":"CircFUT8 promotes proplatelet formation by interacting with IGF2BP2 and stabilizing TNS1 mRNA in megakaryocytes.","authors":"Huang Wu,Yao Lu,Denglian Sun,Zeqing Miao,Siyuan Chen,Wenjun Xia,Yanhua Chen,Yun Yu,Weiwei Zhang,Wei Chen,David Stegner,Su Hao Lo,Aiqing Wen","doi":"10.1182/blood.2025028527","DOIUrl":"https://doi.org/10.1182/blood.2025028527","url":null,"abstract":"During thrombopoiesis, megakaryocytes (MKs) transform their cytoplasm into proplatelets through complex cytoskeletal rearrangements. The shear force of blood flow releases newly formed platelets from the proplatelets into the bloodstream. Defects at any phase of this process can impair platelet production. While various non-coding RNAs have been identified as regulators of platelet production, the regulatory mechanisms of thrombopoiesis remain to be further investigated. Despite the high abundance of circular RNAs (circRNAs) in platelets, their role in platelet production is unclear. In this study, using RNA-seq and bioinformatics analysis, we identified circFUT8 as a novel circRNA that increases as hematopoietic stem cells from human umbilical cord blood differentiate into mature MKs, showing high expression in these mature cells. Knockdown of circFUT8 led to diminished proplatelet formation (PPF) and abnormal demarcation membrane system (DMS) formation in human cultured MKs. Additionally, inhibition of circFut8 in vivo decreased murine platelet counts. CircFut8 deficiency reduced the number of MKs in contact with sinusoids. Mechanistically, we revealed that circFUT8 interacts with insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) to stabilize tensin 1 (TNS1) mRNA in an m6A-dependent manner. In human cultured MKs, TNS1 knockdown resulted in defective F-actin polymerization and assembly, impaired spreading on extracellular matrix proteins, and decreased proplatelet formation. Taken together, our research reveals the crucial functions of circRNAs in platelet production and has significant implications for the development of therapeutic strategies for thrombocytopenia and bleeding disorders.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"17 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693227","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":"CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis.","authors":"Yuanyuan Ji, Yi Huang, Toby Thomas, Eda Gozel Kapti, Reiko Tachibana, Jacob Alan Lark, Iryna Berezniuk, Liang Guo, Mohamed A E Ali, Karin Mims, Benjamin Kroger, Wenhuo Hu, Christopher Y Park, Stephen S Chung","doi":"10.1182/blood.2024026271","DOIUrl":"https://doi.org/10.1182/blood.2024026271","url":null,"abstract":"<p><p>Blood production is sustained by hematopoietic stem cells (HSCs), which are typically the only blood cells capable of long-term self-renewal. HSCs exhibit and depend on low levels of protein synthesis to self-renew. However, the mechanisms by which HSCs regulate protein synthesis to maintain their self-renewal capacity during proliferative stress and leukemogenesis remain unknown. Here we show CD99, a protein upregulated in leukemia stem cells (LSCs) in acute myeloid leukemia (AML), is required for the self-renewal of proliferating HSCs and LSCs. We found that loss of CD99 in HSCs and LSCs leads to increased protein synthesis and that their self-renewal capacity can be restored by translation inhibition. These data demonstrate a functional role for CD99 in constraining protein synthesis, which may promote the clonal expansion of HSCs and LSCs that leads to AML. Furthermore, these studies demonstrate that similar to HSCs, LSCs depend on maintenance of tightly regulated protein synthesis rates.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697630","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":"Fusion Oncoproteins and Cooperating Mutations Define Disease Phenotypes in NUP98-Rearranged Leukemia.","authors":"Masayuki Umeda, Ryan Lea Hiltenbrand, Nicole L Michmerhuizen, Juan M Barajas, Melvin E Thomas, Bright Arthur, Michael P Walsh, Guangchun Song, Jing J Ma, Tamara Westover, Amit Kumar, Petri Pölönen, Cristina Mecucci, Danika Di Giacomo, Franco Locatelli, Riccardo Masetti, Salvatore Nicola Bertuccio, Martina Pigazzi, Shondra M Pruett-Miller, Stanley B Pounds, Jeffrey Rubnitz, Hiroto Inaba, Kyriakos P Papadopoulos, Michael J Wick, Ilaria Iacobucci, Charles G Mullighan, Jeffery M Klco","doi":"10.1182/blood.2025028993","DOIUrl":"https://doi.org/10.1182/blood.2025028993","url":null,"abstract":"<p><p>Leukemias with NUP98 rearrangements exhibit heterogeneous phenotypes such as acute myeloid leukemia (AML), T-acute lymphoblastic leukemia (T-ALL), or myelodysplastic syndrome/neoplasms (MDS) associated with fusion partners, whereas the mechanism responsible for this heterogeneity is poorly understood. Through genome-wide mutational and transcriptional analyses of 177 NUP98-rearranged leukemias, we show that cooperating alterations are associated with differentiation status even among leukemias sharing the same NUP98 fusions, such as NUP98::KDM5A acute megakaryocytic leukemia (AMKL) with RB1 loss or T-ALL with NOTCH1 mutations. CUT&RUN profiling of in vitro cord blood CD34+ cell (cbCD34) models of major NUP98 fusions revealed that NUP98 fusion oncoproteins directly regulate differentiation-related genes contributing to the disease phenotypes, represented by NUP98::KDM5A binding to MEIS2 or GFI1B for megakaryocyte differentiation. In patient samples, NUP98-fusion oncoprotein binding patterns are heterogeneous, potentially shaped by somatic mutations and differentiation status. Using cbCD34 models and CRISPR/Cas9 gene editing, we show that RB1 loss cooperates with NUP98::KDM5A by blocking terminal differentiation toward platelets and expanding megakaryocyte-like cells, whereas WT1 frameshift mutations skew differentiation toward dormant lymphoid-myeloid primed progenitor cells and cycling granulocyte-monocyte progenitor cells, providing evidence for NUP98-rearranged leukemia phenotypes affected by cooperating alterations. NUP98::KDM5A cbCD34 models with RB1 or WT1 alterations have different sensitivities to menin inhibition, suggesting that cellular differentiation provides stage-specific menin dependencies and resistance mechanisms that can be leveraged for future treatment strategies for NUP98-rearranged leukemia.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697556","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":"Inflammasome-resistant IPSC-derived myeloid-derived suppressor cells ameliorate xenogeneic graft-versus-host disease.","authors":"Lie Ma,Brent H Koehn,Michael C Zaiken,Keli L Hippen,Kyle D Smith,Jeremy R Allred,Robin L Williams,Ke Yao,Jordan Fink,Asim Saha,Benjamin Kopp,Nathaniel Payne,Renata Widelak,Angela Panoskaltsis-Mortari,Megan J Riddle,Jakub Tolar,Cindy Eide,Lily Xia,Alec Drake Witty,Amit K Mehta,Matthew Denholtz,Mehrdad Hefazi,Sophia Hani,Saad S Kenderian,Jeffrey S Miller,Jeffrey J Molldrem,Leslie S Kean,Bahram Valamehr,Bruce R Blazar","doi":"10.1182/blood.2025028562","DOIUrl":"https://doi.org/10.1182/blood.2025028562","url":null,"abstract":"Front-line pharmaceutical treatment for treatment of acute graft-versus-host disease (aGVHD) is not uniformly effective and has toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro generated MDSCs has been limited by the need for high MDSC:T cell ratios, multiple infusions to reduce inflammation and a relatively low peripheral blood-derived MDSC (PB-MDSCs) yield. To circumvent these obstacles, we developed a methodology to generate MDSCs using human induced pluripotent stem cell (iPSC)-derived CD34+ cells. Compared to PB-MDSCs, iPSC-MDSCs (iMDSCs) shared similar morphology, phenotype, and suppressive function. We found that the CD14+ iMDSC subset possessed the highest suppressor function. In previous studies, we reported that MDSCs transferred on day 0 into mice undergoing GVHD lost suppressor function due to inflammasome activation and immature myeloid cell maturation1. In striking contrast to human PB-MDSCs, we show here that iMDSCs retained 95% of suppressor function in vitro despite exposure to LPS+ATP, danger-associated molecular patterns inflammasome activating stimuli released early post-transplant during conditioning and GVHD-induced injury. When transferred in vivo with PB mononuclear cells, iMDSCs significantly increased recipient survival without loss of anti-leukemia effects. iMDSC RNAseq and gene knockdown studies revealed that the maintenance of the purine metabolizing enzyme, phosphoglycerate dehydrogenase, during LPS+ATP was linked to iMDSC inflammasome resistance. Taken together, these data provide a platform for translating in vitro generated, off-the-shelf iMDSCs into the clinic for suppressing a spectrum of adverse immune responses including GVHD.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"105 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693228","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":"α-Ketoglutarate promotes amino acid depletion and suppresses B-cell lymphoma growth and development.","authors":"Carine Jaafar,Purushoth Ethiraj,Zhijun Qiu,An-Ping Lin,Pedro Simonis Seabra Martins Ferrari,Ricardo Aguiar","doi":"10.1182/blood.2024028069","DOIUrl":"https://doi.org/10.1182/blood.2024028069","url":null,"abstract":"Targeting metabolic dependencies and \"starving\" malignant cells have long been considered as potential strategies to treat cancer. However, with rare exceptions, the implementation of these maneuvers has been fraught with limited activity and lack of specificity. Multiple cytoplasmic and mitochondrial transaminases catalyze reactions that lead to amino acid catabolism. These enzymes use alpha-ketoglutarate (αKG) as a nitrogen acceptor, and accumulation of the competitive inhibitor metabolite D-2-HG perturbs their function. We postulated that exogenous αKG supplementation would influence the directionality of these reactions and deplete amino acids in cancer cells. Using B cell lymphoma as a model system, we found that αKG mediates a rapid and sustained amino acid depletion, principally of aspartate and branched-chain leucine, valine and isoleucine. The decrease in leucine levels influenced MTORC1 sub-cellular movement, suppressed its activity and associated with inhibition of B cell lymphoma growth in vitro and in vivo Increasing import of aspartate or leucine levels in the lymphoma cells, genetically forcing MTORC1 lysosomal localization or blocking leucine catabolism through BCAT2 deletion, all blunted the anti-lymphoma effects of αKG. In addition, long term dietary supplementation of αKG, a toxicity free strategy, significantly hindered lymphoma development in Eµ-Myc mice, in association with amino acid perturbation and impaired energy generation. We posit that αKG supplementation, which has been shown to improve health and lifespan in mice, also encodes marked anti-cancer properties.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"75 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693225","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":"A BCMA-mRNA vaccine is a promising therapeutic for multiple myeloma.","authors":"Debasmita Dutta,Jiye Liu,Kenneth Wen,Arghya Ray,Alessandro Salatino,Xiangdong Liu,Annamaria Gulla,Teru Hideshima,Yan Song,Kenneth C Anderson","doi":"10.1182/blood.2025028597","DOIUrl":"https://doi.org/10.1182/blood.2025028597","url":null,"abstract":"Cancer vaccines are emerging as promising therapies to not only prevent cancer but to treat cancer. Here, we developed a therapeutic vaccine for multiple myeloma (MM) using BCMA protein as a target. Given the remarkable efficacy of COVID 19 mRNA vaccines, we first packaged sequence- and base- optimized BCMA mRNA into lipid nanoparticles (LNPs) using next-generation ionizable lipid enhancing their accumulation in the spleen. A TLR3 agonist, polyinosinic:polycytidylic acid (Poly(I:C)), was also encapsulated in LNPs to further elicit BCMA-specific immune response. BCMA-mRNA LNPs were internalized by dendritic cells (DCs) in vitro, triggering proliferation and activation of BCMA-specific CD8+ cytolytic T cells (CTLs). Importantly, these CTLs lysed BCMA+ U266 MM cells and CD138+ patient MM cells, without affecting BCMA-knockout (KO) U266 or CD138- patient derived bone marrow cells. Vaccination of C57BL/6J mice with BCMA-mRNA LNPs activated splenic DCs and induced BCMA-specific CTLs, assessed by tetramer staining, which selectively killed murine 5TGM1 BCMA overexpressing (5TGM1-BCMA-OE) MM cells. Finally, vaccination of C57BL/KaLwRijHsd mice bearing BCMA-overexpressing 5TGM1 cells inhibited tumor growth associated with BCMA-specific CD8+ T cell responses. The combination treatment with Poly(I:C) further triggered the immune response induced by BCMA-mRNA LNPs in all instances. Our findings provide the framework for clinical evaluation of BCMA-mRNA LNP vaccines to improve patient outcome in MM.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"19 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693230","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}