Leukemia最新文献

{"title":"Fixed-duration therapy of chronic lymphocytic leukemia with venetoclax and Bruton tyrosine kinase inhibitors: an insight into differences between ibrutinib and acalabrutinib.","authors":"Alessandra Tedeschi,Anna Maria Frustaci,Pierantonio Menna,Giorgio Minotti","doi":"10.1038/s41375-025-02778-1","DOIUrl":"https://doi.org/10.1038/s41375-025-02778-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"78 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209091","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":"Base edited \"universal\" donor CAR T-cell strategies for acute myeloid leukaemia.","authors":"Renuka Kadirkamanathan, Christos Georgiadis, Arnold Kloos, Akshay Joshi, Annie Etuk, Roland Preece, Oliver Gough, Axel Schambach, Martin Sauer, Michael Heuser, Waseem Qasim","doi":"10.1038/s41375-025-02720-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02720-5","url":null,"abstract":"<p><p>Acute myeloid leukaemia (AML) is often aggressive and life-threatening with limited curative options. Immunotherapies including chimeric antigen receptor (CAR) T-cell approaches are under investigation, but high levels of disease heterogeneity remain a major hurdle to achieving durable responses. Targeting of multiple antigens may ensure complete immunological coverage of leukaemic blast populations, but such antigens are often also present on healthy haematopoietic populations. To address likely aplasia, strategies can be designed to bridge CAR T-cell therapies to allogeneic stem-cell transplantation (allo-SCT), as demonstrated in recent anti-CD7 CAR T-cell studies. Here we report that monotherapy using base edited \"universal\" donor CAR T cells against CD33, CLL-1, or CD7 delivered inhibition of AML in immunodeficient mice when antigen expression was homogenous, but combined use of BE-CAR33 and BE-CARCLL-1 T cells was required to address heterogenous CLL-1^-/+CD33^-/+ disease. We also demonstrate that removal of shared CD7 antigens enabled compatibility of BE-CAR33 and BE-CARCLL-1 with BE-CAR7 T cells, including in a patient-derived xenograft (PDX) model of AML. Therapeutic strategies envisage 'pick and mix' applications of base edited \"universal\" CAR T cells in combination determined by patient-specific antigen profiles. Such approaches also offer the possibility of deep, cell-based, de-bulking and conditioning ahead of allo-SCT and subsequent donor-derived reconstitution.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206758","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":"Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis.","authors":"Tania Setiawan,Jabir Aliyu Muhammad,Nadya Marcellina,Lawrence Mario Wirawan,Nayoung Jun,Ita Novita Sari,Vivian G Oehler,Dong-Wook Kim,Hyog Young Kwon","doi":"10.1038/s41375-025-02768-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02768-3","url":null,"abstract":"Amino acid homeostasis is critical for leukemic cell survival, with the mTOR pathway playing a central role in sensing and responding to nutrient availability. DEPTOR, a component and negative regulator of mTOR complexes, has been extensively studied in solid tumors and multiple myeloma, but its role in acute myeloid leukemia (AML) remains unclear. Here, we identify DEPTOR as a key regulator of leukemia progression through its interaction with KIF11. DEPTOR expression is transcriptionally induced by ATF4 and post-transcriptionally stabilized by MSI2, which binds to DEPTOR mRNA and prevents its degradation. DEPTOR is highly expressed in leukemia stem cells (LSCs) and is associated with poor clinical outcomes. Functionally, DEPTOR loss impairs leukemogenesis in both AML and blast phase chronic myeloid leukemia (bpCML) models, without affecting normal hematopoietic stem cells. Mechanistically, DEPTOR stabilizes KIF11 by preventing its ubiquitination and proteasomal degradation, thereby ensuring proper mTORC1 localization and metabolic adaptation during nutrient stress. Collectively, our findings establish the MSI2/DEPTOR/KIF11 axis as a critical driver of leukemogenesis and a promising therapeutic target for aggressive myeloid leukemias.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203973","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 do ionizing radiations from inter-planetary travel cause leukaemia?","authors":"Christophe Badie,Robert Peter Gale","doi":"10.1038/s41375-025-02761-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02761-w","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"37 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189259","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":"Refining PET-based response in extramedullary multiple myeloma using total lesion glycolysis.","authors":"Saurabh Zanwar,Gokce Belge Bilgin,Stephen M Broski,Matthew Thorpe,Cem Bilgin,Wilson Gonsalves,Prashant Kapoor,Taxiarchis Kourelis,Suzanne Hayman,Nadine Abdallah,Moritz Binder,Joselle Cook,Angela Dispenzieri,David Dingli,Morie A Gertz,Nelson Leung,Yi Lin,Eli Muchtar,Rahma Warsame,Robert A Kyle,S Vincent Rajkumar,Shaji Kumar","doi":"10.1038/s41375-025-02776-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02776-3","url":null,"abstract":"Positron Emission Tomography (PET)-based assessments are an integral part of response assessment in patients with multiple myeloma (MM) with extramedullary disease (EMD), yet their utility in EMD remains to be systematically studied. We retrospectively evaluated 95 patients with EMD undergoing FDG PET/CT imaging for metabolic response assessment using visual Deauville Scores (DS) and total lesion glycolysis (TLG). TLG responses were categorized as complete metabolic response (CMR; 100% reduction), major metabolic response (MMR; <100% to ≥50% reduction), and non-significant metabolic response (NMR; <50% reduction). The median progression-free survival (PFS) differed significantly by DS (22.4 vs. 4.3 vs. 2.8 months for DS ≤ 3, =4, and =5, respectively; p < 0.0001) and by TLG response (36.5 vs. 5.4 vs. 2.2 months for CMR, MMR, NMR; p < 0.0001). TLG offered better discrimination than DS, with approximately one-third of patients in each DS stratum being reclassified by the TLG stratification. In a multivariable analysis, TLG response [HR 2.6 (95% CI: 1.8-3.8), p < 0.0001] remained independently prognostic after adjusting for cytogenetics, triple-class refractoriness, and de novo EMD status. The 18-month OS rates were 89%, 42% and 19% for the TLG CMR, MMR, and NMR cohorts (p < 0.001). These findings support the integration of TLG into response criteria for EMD.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"23 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182582","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":"Misclassification of TP53 germline variants: implications for survival analysis in AML transplant studies.","authors":"Léa Rodriguez,François Delhommeau,Thierry Soussi","doi":"10.1038/s41375-025-02772-7","DOIUrl":"https://doi.org/10.1038/s41375-025-02772-7","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"155 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182562","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":"Clinical and transcriptomic characterization of patients with chronic lymphocytic leukemia harboring t(14;19): an ERIC study.","authors":"Andrea Visentin,Enrico Gaffo,Moritz Fürstenau,Kerry A Rogers,Baliakas Panagiotis,Chenghua Cui,Cecelia Miller,Claudia Haferlach,Karla Plevova,David Oscier,Zadie Davis,Florence Nguyen-Khac,Eleonora Roncaglia,Gian Matteo Rigolin,Anastasia Athanasiadou,Fanny Baran-Marszak,Alberto Valiente,Maria José Terol,Pau Abrisqueta,Blanca Espinet,Anna Puiggros,Annalisa Martines,Laura Bonaldi,Francesca Romana Mauro,Lydia Scarfò,Thomas Chatzikonstantinou,Eugen Tausch,Karl-Anton Kreuzer,Arnon Kater,Francesc Bosch,Michael Doubek,Panagiotis Panagiotidis,Olga Kalashnikova,Federica Frezzato,Giulia Calabretto,Valeria Ruocco,Silvia Orsi,Alessandro Cellini,Francesco Angotzi,Andrea Serafin,Shuhua Yi,Barbara Eichhorst,Jennifer A Woyach,Antonio Cuneo,Paolo Ghia,Kostas Stamatopoulos,Livio Trentin,Stefania Bortoluzzi","doi":"10.1038/s41375-025-02755-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02755-8","url":null,"abstract":"In chronic lymphocytic leukemia (CLL), the role of complex karyotype (CK) for prognostic stratification remains a topic of debate, and the impact of specific cytogenetic abnormalities is still unclear. This study aims to investigate the clinical and biological features of CLL with t(14;19)(q32;q13) (tCLL) involving the BCL3 gene. Patients with tCLL were younger and more commonly presented unmutated IGHV gene, subset #8 stereotypy, trisomy of chromosome 12, and complex karyotype than other patients without t(14;19) (oCLL). The presence of t(14;19) was associated with a shorter time to treatment and overall survival compared to oCLL. Gene expression analysis revealed a unique transcriptome profile in tCLL, characterized by the upregulation of BCL3 and the activation of B-cell receptor, PI3K-Akt. Conversely, apoptosis-related pathways were suppressed in tCLL. While the BTK gene was upregulated, the BCL2L11 gene, coding for the pro-apoptotic protein BIM, was downregulated. Notably, patients with tCLL were characterized by a trend (p = 0.058) for a longer time to the next treatment with BTK inhibitors (BTKi) compared to those treated with a venetoclax-based (Ven-based) regimen. We underscore the adverse outcomes of tCLL, its distinct molecular features and gene expression patterns. Therefore, our data suggest that identifying tCLL could help tailor therapeutic approaches.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"29 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089801","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":"Multi-dimensional analysis of adult acute myeloid leukemia cross-continents reveals age-associated trends in mutational landscape and treatment outcomes (Acute Myeloid Leukemia Cooperative Group & Alliance for Clinical Trials in Oncology).","authors":"Monica Cusan,Karilyn Larkin,Deedra Nicolet,Vindi Jurinovic,Krzysztof Mrózek,Aarif M N Batcha,Maja Rothenberg-Thurley,Stephanie Schneider,Cristina Sauerland,Dennis Görlich,Utz Krug,Wolfgang E Berdel,Bernhard J Woermann,Wolfgang Hiddemann,Jan Braess,Karsten Spiekermann,Philipp A Greif,James S Blachly,Alice S Mims,Christopher J Walker,Michael C Walker,Christopher C Oakes,Shelley Orwick,Andrew J Carroll,William G Blum,Bayard L Powell,Jonathan E Kolitz,Joseph O Moore,Robert J Mayer,Richard A Larson,Richard M Stone,John C Byrd,Klaus H Metzeler,Tobias Herold,Ann-Kathrin Eisfeld","doi":"10.1038/s41375-025-02644-0","DOIUrl":"https://doi.org/10.1038/s41375-025-02644-0","url":null,"abstract":"The outcome of patients with acute myeloid leukemia (AML) worsens with increasing age. Dichotomization into \"younger\" and \"older\" patients is clinically routine and often dictates treatment options. We aimed to delineate whether molecular genetic features and/or outcome measures support assorting patient populations by age, including division into \"younger\" and \"older\" groups. We analyzed 2823 adult AML patients enrolled onto frontline chemotherapy-based clinical protocols of two cooperative study groups from USA and Germany who were profiled molecularly via targeted sequencing platforms. Frequencies of gene mutations and cytogenetic findings were depicted in 5-year age increments. Clinical outcomes of 2756 AML patients were analyzed with respect to molecular features, genetic-risk groups and age. Age-associated distributions of gene mutations and cytogenetic abnormalities were similar in both cohorts. There was almost linear shortening of overall survival with increasing age among all patients (P < 0.001) and within 2022 European LeukemiaNet-defined genetic-risk groups, with survival decreasing as age increased (favorable-risk, P < 0.001; intermediate-risk, P < 0.001; adverse-risk, P < 0.001). Although mutational profiles and outcomes of the youngest patients differed from those of older patients, there was no age cut-off identifying \"younger\" and \"older\" patients. These findings support more age-associated flexibility for drug approval and trial eligibility.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"90 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089803","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":"Epitranscriptomic advances in normal and malignant hematopoiesis.","authors":"Maria Eleftheriou,James Russell,Konstantinos Tzelepis","doi":"10.1038/s41375-025-02765-6","DOIUrl":"https://doi.org/10.1038/s41375-025-02765-6","url":null,"abstract":"RNA modifications, collectively termed the epitranscriptome, constitute a dynamic layer of post-transcriptional regulation that governs RNA splicing, stability, localization, translation, and decay. In the hematopoietic system, these chemical marks influence stem cell fate, lineage specification, immune surveillance, and malignant transformation through context-dependent regulation of mRNA, tRNA, rRNA, and non-coding RNAs. Here, we focus on RNA modifications and editing events with emerging mechanistic and translational relevance in normal and malignant hematopoiesis, highlighting those implicated in stem cell dynamics, leukemic progression, and therapeutic resistance. Specifically, we discuss N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), N⁷-methylguanosine (m⁷G), N⁴-acetylcytidine (ac⁴C), pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, and RNA glycosylation. Particular attention is given to enzymes such as METTL3, METTL1, ADAR1, and NAT10, whose dysregulation sustains leukemic stem cell programmes, promotes immune evasion, and confers treatment resistance. With the first-in-class METTL3 inhibitor STC-15 now in early-phase clinical trials in solid tumours (NCT05584111, NCT06975293), and additional RNA-modifying enzyme inhibitors advancing preclinically, these pathways are emerging as therapeutically tractable, including in hematological cancers. Furthermore, integrating epitranscriptomic profiles into genomic risk frameworks may also improve disease stratification, minimal residual disease (MRD) monitoring, and the identification of targetable vulnerabilities. Together, these insights position RNA modifications as central to blood cancer biology and support their integration into next-generation diagnostic, prognostic, and therapeutic strategies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089805","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":"The endogenous T cell landscape is reshaped by CAR-T cell therapy and predicts treatment response in multiple myeloma.","authors":"Julia Frede,Julia C Poller,Kayleen Shi,Hannah Stuart,Noori Sotudeh,Claire Havig,Klothilda Lim,Caroline R M Wiggers,Eugene Y Cho,Tushara Vijaykumar,Jianlin Liu,Johannes M Waldschmidt,Monica S Nair,Praveen Anand,Valeriya Dimitrova,Anna Montanaro,Andrew J Yee,Nikhil C Munshi,Kenneth C Anderson,Nathan Martin,Shari M Kaiser,Marc-Steffen Raab,Noopur S Raje,Birgit Knoechel,Jens G Lohr","doi":"10.1038/s41375-025-02766-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02766-5","url":null,"abstract":"While most patients initially respond to CAR-T cell treatment, responses often are not durable and subsequent lines of immunotherapy show diminishing success. In this study, we investigated the co-evolutionary dynamics between CAR-T cells and the immune microenvironment in myeloma patients undergoing anti-BCMA CAR-T cell therapy at single-cell resolution. Our findings highlight the transformative impact of CAR-T cell treatment on the endogenous T cell landscape. We identify a novel transitional CD8 + T cell population that is predictive of poor treatment outcomes. The emergence of this population coincides with the depletion of the endogenous T cell repertoire and compositional evolution of functional T cell subsets. These changes in the endogenous T cell compartment induced by CAR-T cell therapy may contribute to inadequate immune capacity and tumor control. Our findings highlight the potential of targeting TIM3/GAL9 interactions to mitigate T cell exhaustion, apoptosis and lack of persistence, offering promising avenues for optimizing T cell-based cancer immunotherapies. We provide a framework for assessing and manipulating the 'mileage' of the immune system as predictive marker and therapeutic opportunity to prevent repeated immunotherapies from becoming increasingly less successful, even when targeting distinct antigens.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"54 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089804","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}