LeukemiaPub Date : 2025-08-04DOI: 10.1038/s41375-025-02721-4
Simone Cesaro, Per Ljungman, Malgorzata Mikulska, Hans H. Hirsch, David Navarro, Catherine Cordonnier, Varun Mehra, Jan Styczynski, Francesco Marchesi, Jose Luis Pinana, Gernot Beutel, Herman Einsele, Johan Maertens, ECIL-10, Rafael de la Camara
{"title":"Author’s Reply to the correspondence: ECIL-10 guidelines for COVID-19 should take convalescent plasma into proper consideration by Focosi et al.","authors":"Simone Cesaro, Per Ljungman, Malgorzata Mikulska, Hans H. Hirsch, David Navarro, Catherine Cordonnier, Varun Mehra, Jan Styczynski, Francesco Marchesi, Jose Luis Pinana, Gernot Beutel, Herman Einsele, Johan Maertens, ECIL-10, Rafael de la Camara","doi":"10.1038/s41375-025-02721-4","DOIUrl":"10.1038/s41375-025-02721-4","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2304-2305"},"PeriodicalIF":13.4,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778086","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}
LeukemiaPub Date : 2025-08-01DOI: 10.1038/s41375-025-02712-5
Yun Wang, Shuzhao Chen, Zhijian Liang, Robert Peter Gale, Shutong Liu, Xiaoqin Chen, Peidong Chi, Yiling Song, Yingchun Zhang, Weida Wang, Juan Li, Zhongjun Xia, Yang Liang, Xiaojun Huang
{"title":"The bone marrow immune ecosystem shapes daratumumab acquired resistance in plasma cell myeloma","authors":"Yun Wang, Shuzhao Chen, Zhijian Liang, Robert Peter Gale, Shutong Liu, Xiaoqin Chen, Peidong Chi, Yiling Song, Yingchun Zhang, Weida Wang, Juan Li, Zhongjun Xia, Yang Liang, Xiaojun Huang","doi":"10.1038/s41375-025-02712-5","DOIUrl":"10.1038/s41375-025-02712-5","url":null,"abstract":"Daratumumab, an anti-CD38 monoclonal antibody, is an effective therapy for plasma cell myeloma (PCM). However, many initial responders relapse. We compared paired samples from subjects pre-therapy and then acquired resistance to daratumumab. We first used single-cell RNA sequencing and digital spatial profiler (DSP). The proportion of cytotoxic CD8-positive T-cells with an exhaustion phenotype and an IFN-γ signature increased in resistance compared with pre-therapy samples, whilst the proportion of NK-cells decreased and had an increased inhibitory phenotype. Transcription of CD38 in neoplastic plasma cells decreased. Numbers of immune cells in cancer centre defined by DSP were significantly decreased in parallel with an increased exhaustion signature. The acquired resistance signature and elevated PCM subset phenotype were associated with worse prognosis in 4 external cohorts (GSE24080, GSE136337, GSE57317, and coMMpass). Using single-cell regulatory network inference, we identified MYC regulation as a key activated factor for acquired resistance in neoplastic plasma cells by intersecting the top 20 upregulated regulons and upregulated genes in acquired resistance. Furthermore, data from in vitro and in vivo experiments indicate that IFN-γ secreted by cells of bone marrow immune ecosystem activates MYC, which correlates with acquired daratumumab resistance. Our data provide insights into acquired daratumumab resistance and suggest potential therapeutic strategies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2504-2515"},"PeriodicalIF":13.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02712-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-08-01DOI: 10.1038/s41375-025-02703-6
Sylvain Moinard, Benjamin Lebecque, Tom Lachaise, Hyacinthe Johnson-Ansah, Charlotte Doublet, Gabrielle Roth-Guepin, Françoise Rigal-Huguet, Lydia Roy, Anne Parry, Mathieu Meunier, Amélie Penot, Laurence Legros, Vanessa Pante, Martine Escoffre-Barbe, Philippe Rousselot, Guillaume Denis, Hélène Monjanel, Dalil Hamroun, Abdessattar Khlaifia, Joévin Besombes, Bruno Pereira, Céline Bourgne, Marc G. Berger
{"title":"Evaluating a predictive model of tyrosine kinase inhibitor therapy failure in a European-type cohort: a step towards population-specific tools","authors":"Sylvain Moinard, Benjamin Lebecque, Tom Lachaise, Hyacinthe Johnson-Ansah, Charlotte Doublet, Gabrielle Roth-Guepin, Françoise Rigal-Huguet, Lydia Roy, Anne Parry, Mathieu Meunier, Amélie Penot, Laurence Legros, Vanessa Pante, Martine Escoffre-Barbe, Philippe Rousselot, Guillaume Denis, Hélène Monjanel, Dalil Hamroun, Abdessattar Khlaifia, Joévin Besombes, Bruno Pereira, Céline Bourgne, Marc G. Berger","doi":"10.1038/s41375-025-02703-6","DOIUrl":"10.1038/s41375-025-02703-6","url":null,"abstract":"Predicting therapeutic failure in patients with chronic phase-chronic myeloid leukemia (CP-CML) treated with tyrosine kinase inhibitors (TKI) remains a major challenge for personalized care management. The Sokal and EUTOS long-term survival scores were designed to predict CML-related mortality, but are also used to guide therapeutic choices, despite their poor performance for this purpose. A recent study proposed a refined predictive model of therapy failure specifically tailored for patients treated with imatinib and second-generation TKIs that showed promising results in a Chinese cohort. The present study evaluated the performance and applicability of this predictive model in a real-world, multicenter cohort from the French CML Observatory. The key differences identified between the Chinese and French cohorts (age, baseline hemoglobin levels, and treatment regimens) likely influenced the model performance. Specifically, the new model did not allow for discriminating risk groups effectively in the French cohort. However, the model reconstruction using this cohort identified other predictive variables (sex, leukocytosis, comorbidities, high-risk additional chromosomal abnormalities) that better stratified patients at risk of therapy failure. Our findings highlight the influence of demographic and clinical differences on predictive models and emphasize the need for local or population-specific tools to optimize risk stratification and therapeutic decision-making in CP-CML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2375-2383"},"PeriodicalIF":13.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02703-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-07-30DOI: 10.1038/s41375-025-02697-1
Tayla B. Heavican-Foral, Felix Korell, Irene Scarfò, Caroline R. M. Wiggers, Allen Thayakumar B, Zachary Eisenbies, Foster Powers, Justin Hegel, Jianlin Liu, Steffen Kulp, Harrison Silva, Gongwei Wu, Anthony Letai, Kimberly Stegmaier, Jens G. Lohr, David M. Weinstock, Marcela V. Maus, Birgit Knoechel
{"title":"Combining MCL-1 inhibition and CD37-directed chimeric antigen receptor T cells as an effective strategy to target T-cell lymphoma","authors":"Tayla B. Heavican-Foral, Felix Korell, Irene Scarfò, Caroline R. M. Wiggers, Allen Thayakumar B, Zachary Eisenbies, Foster Powers, Justin Hegel, Jianlin Liu, Steffen Kulp, Harrison Silva, Gongwei Wu, Anthony Letai, Kimberly Stegmaier, Jens G. Lohr, David M. Weinstock, Marcela V. Maus, Birgit Knoechel","doi":"10.1038/s41375-025-02697-1","DOIUrl":"10.1038/s41375-025-02697-1","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy has not yet been realized for T-cell lymphomas (TCL), partially due to challenges in identifying tumor-specific antigens. We previously reported selective expression of CD37 on malignant T cells in a subset of TCL. Herein, we demonstrate CAR-37 T cells specifically target CD37-positive TCL in part by activating the intrinsic apoptotic pathway. To maximize therapeutic index, we identified selective/targetable BH3 dependences in individual TCL models and combined with CAR-37 T cells. We show that BH3 mimetics do not alter CD37 antigen binding capacity on TCL and have minimal effects on CAR-37 T-cell phenotype or function. In TCL models with dependence on MCL-1, combining CAR-37 T cells and the MCL-1 inhibitor AZD5991 increases anti-TCL response and prolongs survival of xenografted mice. These findings suggest that personalized selection of BH3 mimetic/CAR-T combinations could maximize the therapeutic index for patients with TCL and possibly other diseases.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2452-2464"},"PeriodicalIF":13.4,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02697-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-07-29DOI: 10.1038/s41375-025-02718-z
Juan Zhang, Dongmei Wang, Mengfan Luan, Xiaomin Liu, Nana Wang, Xue Sheng, Shuying Li, Boya Li, Tao Sun, Daoxin Ma, Jingjing Ye, Fei Lu, Chunyan Ji
{"title":"Liquid-liquid phase separation of ZHX2 protects DLBCL cells against ferroptosis through induction of SLC3A2","authors":"Juan Zhang, Dongmei Wang, Mengfan Luan, Xiaomin Liu, Nana Wang, Xue Sheng, Shuying Li, Boya Li, Tao Sun, Daoxin Ma, Jingjing Ye, Fei Lu, Chunyan Ji","doi":"10.1038/s41375-025-02718-z","DOIUrl":"10.1038/s41375-025-02718-z","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL), the most common B-cell non-Hodgkin lymphoma (B-NHL), is characterized by strong aggression, high heterogeneity, and poor prognosis. Consequently, there is an urgent need to identify crucial therapeutic targets. Here, we found that the transcription factor zinc-finger and homeobox 2 (ZHX2) was highly expressed in DLBCL. Subsequently, ZHX2 was proven to be critical for promoting DLBCL cell proliferation by inhibiting ferroptosis. Mechanistically, ZHX2 bound to the promoter region of the solute carrier family 3-member 2 (SLC3A2) gene through liquid-liquid phase separation (LLPS) and activated its function to negatively regulate ferroptosis. Furthermore, we constructed lipid nanoparticles ZHX2-siRNA@LNP targeting DLBCL, which effectively inhibited the growth of the tumors in vivo. In summary, our study indicated that the LLPS of ZHX2 protected DLBCL against ferroptosis through induction of SLC3A2, and disturbing it with ZHX2-siRNA@LNP could significantly repress DLBCL, providing a promising therapeutic strategy for DLBCL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2442-2451"},"PeriodicalIF":13.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02718-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144736787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-07-28DOI: 10.1038/s41375-025-02713-4
Gilad Itchaki, Harrison Bai, Grace Tiao, Reina Improgo, Ben E. Oppenheimer, Siddha Kasar, Bethany Tesar, Stacey M. Fernandes, Nathalie Pochet, John-Hanson Machado, Emily M. Thrash, Arnold S. Freedman, Gad Getz, Jennifer R. Brown
{"title":"Rare germline variant in NFATC4 associated with familial CLL","authors":"Gilad Itchaki, Harrison Bai, Grace Tiao, Reina Improgo, Ben E. Oppenheimer, Siddha Kasar, Bethany Tesar, Stacey M. Fernandes, Nathalie Pochet, John-Hanson Machado, Emily M. Thrash, Arnold S. Freedman, Gad Getz, Jennifer R. Brown","doi":"10.1038/s41375-025-02713-4","DOIUrl":"10.1038/s41375-025-02713-4","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2547-2550"},"PeriodicalIF":13.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715613","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":"Transcriptomic landscape of CD8+ and CD4 + T-LGL leukemia revealed the distinct impact of STAT3 and STAT5B activating mutations","authors":"Giulia Calabretto, Andrea Binatti, Antonella Teramo, Alessia Buratin, Gregorio Barilà, Vanessa Rebecca Gasparini, Cristina Vicenzetto, Enrico Gaffo, Elisa Rampazzo, Silvia Orsi, Elena Buson, Valentina Trimarco, Barbara Mariotti, Monica Facco, Flavia Bazzoni, Livio Trentin, Gianpietro Semenzato, Renato Zambello, Stefania Bortoluzzi","doi":"10.1038/s41375-025-02708-1","DOIUrl":"10.1038/s41375-025-02708-1","url":null,"abstract":"The biological basis of the high clinical heterogeneity of T-LGL Leukemia (T-LGLL) is not completely understood and effective therapies for this disease are lacking. Through RNA-Sequencing of purified T-LGLs we reveal gene expression profiles and pathway dysregulations in the major patient subgroups, defined by CD8+ or CD4+ phenotype and STAT3/STAT5B mutational status. Overall, T-LGLL patients exhibited a marked transcriptome dysregulation compared to controls. This was more pronounced in the most symptomatic CD8 + STAT3-mutated patients, which emerged as a distinct biological entity, separated from the other disease subgroups. Particularly, CD8 + STAT3-mutated cases displayed extensive down-regulation of genes, ultimately resulting in the de-repression of proliferation and cell cycle pathways. Among genes up-regulated in CD8 + STAT3-mutated cases we found VCAM1, the transcriptional repressor EZH2 and the p53-regulator MDM2 proto-oncogene, as well as the leukemogenesis-associated PVT1 up-regulation, representing the first report of a long-non-coding RNA alterations in leukemic T-LGLs. The impact of STAT5B mutations on T-LGLs transcriptome was more limited and the overexpression of the PIM1 serine/threonine kinase proto-oncogene was identified as one of the most relevant features of STAT5B-mutated CD4 + T-LGLL. This study significantly advances our understanding of T-LGLL pathogenesis, uncovering new oncogenic mechanisms within the distinct molecular subtypes of the disease.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2364-2374"},"PeriodicalIF":13.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02708-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-07-28DOI: 10.1038/s41375-025-02715-2
Denise Toscani, Oxana Lungu, Martina Chiu, Chiara Maccari, Vincenzo Raimondi, Giuseppe Taurino, Massimiliano G. Bianchi, Matteo Scita, Benedetta Dalla Palma, Nicolas Thomas Iannozzi, Rosanna Vescovini, Mattia Dessena, Camilla Sitzia, Paola Storti, Roberta Andreoli, Ovidio Bussolati, Nicola Giuliani
{"title":"High glutamate levels in the bone marrow of multiple myeloma patients promote osteoclast formation: a novel target for osteolytic bone disease","authors":"Denise Toscani, Oxana Lungu, Martina Chiu, Chiara Maccari, Vincenzo Raimondi, Giuseppe Taurino, Massimiliano G. Bianchi, Matteo Scita, Benedetta Dalla Palma, Nicolas Thomas Iannozzi, Rosanna Vescovini, Mattia Dessena, Camilla Sitzia, Paola Storti, Roberta Andreoli, Ovidio Bussolati, Nicola Giuliani","doi":"10.1038/s41375-025-02715-2","DOIUrl":"10.1038/s41375-025-02715-2","url":null,"abstract":"Multiple Myeloma (MM) is a glutamine (Gln)-addicted cancer. Consequently, the MM bone microenvironment (BM) is characterized by lower Gln and higher glutamate (Glu) levels than those in pre-malignant monoclonal gammopathies. Such MM-dependent metabolic perturbation impairs osteoblast differentiation in the bone microenvironment, but its effect on osteoclast (OCL) bone resorption is still unknown. We first show that bone marrow mononuclear cells from MM patients release higher levels of Glu compared to those from patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). This increased Glu production correlates with elevated bone resorption activity. We then demonstrate that Glu stimulates OCL differentiation via the activation of NF-κB-NFATc1 pathway in low-Glu BM samples from pre-malignant patients but not in high-Glu samples of MM patients. Secondly, the early phase of OCL formation was associated with high Glu intracellular content and induction of the Glu transporter EAAT1. Consistently, the pharmacological inhibition of EAAT1 hinders OCL differentiation by blocking the RANKL-dependent signaling pathway and actin cytoskeleton reorganization. Overall, our data indicate that high Glu levels in MM bone marrow are involved in OCL formation, suggesting that targeting Glu transport may represent a novel approach for the prevention of osteolytic lesions in MM patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2492-2503"},"PeriodicalIF":13.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02715-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-07-28DOI: 10.1038/s41375-025-02722-3
Michael R. Lieber, Chih-Lin Hsieh
{"title":"On the mechanism of NPM1 mutations in acute myeloid leukemia","authors":"Michael R. Lieber, Chih-Lin Hsieh","doi":"10.1038/s41375-025-02722-3","DOIUrl":"10.1038/s41375-025-02722-3","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2340-2343"},"PeriodicalIF":13.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02722-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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