{"title":"Divergent molecular pathways drive monomorphic epitheliotropic and enteropathy-associated intestinal T-cell lymphoma.","authors":"David Vallois,Edoardo Missiaglia,Luis Veloza,Anja Fischer,Doriane Cavalieri,Vimel Rattina,Bettina Bisig,Vincent Roh,Laura Wiehle,Rita Sarkis,Emmanuel Bachy,Christophe Bonnet,Julie Bruneau,Anne Cairoli,Roland De Wind,Fanny Drieux,Romain Dubois,Jean-François Emile,Virginie Fataccioli,Kamel Laribi,Albane Ledoux-Pilon,François Lemonnier,Francisco Llamas-Gutierrez,Pierre Morel,Marie Parrens,Elsa Poullot,Leticia Quintanilla-Martinez,Jeremy Sandrini,Joan Somja,Luc Xerri,Olivier Tournilhac,Philippe Gaulard,Reiner Siebert,Laurence de Leval","doi":"10.1038/s41375-025-02777-2","DOIUrl":"https://doi.org/10.1038/s41375-025-02777-2","url":null,"abstract":"Enteropathy-associated intestinal T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) have distinctive clinical context, morphology, and immunophenotype. To characterize their genetic and molecular specificities, we compared 30 EATLs and 52 MEITLs by whole-exome, RNA and miRNA sequencing and DNA methylation profiling. Highly recurrent SETD2 loss-of-function alterations and frequent mutations of H3-3A/B consistently altering H3R2, implying deregulation of histone marks, were selectively found in MEITL. EATL instead harbored frequent mutations in TET2, ARID1A, and KMT2D. Highly prevalent JAK-STAT pathway mutations preferentially affected JAK3 and STAT5B in MEITL, and JAK1 and STAT3 in EATL. Half of EATLs contained disruptive mutations in HLA class I genes, impacting class I molecule expression. EATL containing more abundant macrophages was enriched in inflammatory response signatures, with upregulation of CD274, CXCL13, and IDO1 transcripts, suggesting an immunosuppressive tumor microenvironment. CpGs hypomethylated in MEITL compared to EATL were enriched in promoter regions. Unsupervised analyses of mutations, transcription, and methylation profiles concordantly segregated EATLs from MEITLs. In summary, the distinctive genetic, epigenetic, and expression footprints of EATL and MEITL established by this study expand disease-defining features, have diagnostic implications, and provide a rationale for targeted therapies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"21 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240935","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":"Genetic and epigenetic alterations at secondary resistance after continued decitabine-based treatment of acute myeloid leukemia in the randomized phase II DECIDER trial.","authors":"Inga Hund,Maria Elena Hess,Geoffroy Andrieux,Julia Stomper,Gabriele Greve,Christoph Niemöller,Tobias Ma,David Uhl,Olga Grishina,Felicitas Thol,Michael Heuser,Gesine Bug,Martina Crysandt,Andreas Neubauer,Justus Duyster,Hartmut Döhner,Melanie Boerries,Michael Lübbert,Heiko Becker","doi":"10.1038/s41375-025-02780-7","DOIUrl":"https://doi.org/10.1038/s41375-025-02780-7","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"56 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240960","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 : 2025-10-07DOI: 10.1038/s41375-025-02774-5
Rebecca K Voss,Victor B Pastor Loyola,Maria F Cardenas,Priya Kumar,Jamie L Maciaszek,Maria Namwanje,Jing Ma,Jennifer L Neary,Meiling Jin,Masayuki Umeda,Mark R Wilkinson,Debbie Payne-Turner,Mohammad K Eldomery,Jingqun Ma,Jiali Gu,Jim Dalton,Samantha Melton,Yen-Chun Liu,Scott Foy,Michael Rusch,David A Wheeler,Jinghui Zhang,Kim E Nichols,Seth E Karol,Hiroto Inaba,Raul Ribeiro,Jeffrey E Rubnitz,Jeffery M Klco,Lu Wang
{"title":"Clinical experience of using integrated whole genome and transcriptome sequencing as a framework for pediatric and adolescent acute myeloid leukemia diagnosis and risk assessment.","authors":"Rebecca K Voss,Victor B Pastor Loyola,Maria F Cardenas,Priya Kumar,Jamie L Maciaszek,Maria Namwanje,Jing Ma,Jennifer L Neary,Meiling Jin,Masayuki Umeda,Mark R Wilkinson,Debbie Payne-Turner,Mohammad K Eldomery,Jingqun Ma,Jiali Gu,Jim Dalton,Samantha Melton,Yen-Chun Liu,Scott Foy,Michael Rusch,David A Wheeler,Jinghui Zhang,Kim E Nichols,Seth E Karol,Hiroto Inaba,Raul Ribeiro,Jeffrey E Rubnitz,Jeffery M Klco,Lu Wang","doi":"10.1038/s41375-025-02774-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02774-5","url":null,"abstract":"Pediatric acute myeloid leukemia (AML) exhibits distinct genetic characteristics, including unique driver alterations and mutations with prognostic and therapeutic implications. Cytogenetics study, along with Next Generation Sequencing (NGS) panel testing, have long been the standard for molecular diagnosis of AML. While these approaches enable diagnosis and prognosis determination in most cases, they have limitations-particularly in detecting emerging rare, recurrent genetic abnormalities. In this study, we systematically reviewed our real-time clinical experience with the diagnostic workup of pediatric AML using an integrated whole genome and whole transcriptome sequencing (iWGS-WTS) approach and compared the test results obtained from various methodologies, including whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome sequencing (WTS), iWGS-WTS, cytogenetics, and targeted panel NGS. Our findings demonstrate that the iWGS-WTS approach improves the identification of clinically relevant genetic alterations, enhancing precise disease classification and risk assessment. Additionally, the iWGS-WTS approach streamlines sample acquisition and reduces testing redundancy, positioning it as a practical and superior alternative to traditional diagnostic methods in pediatric AML management.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"107 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240936","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":"Combined treatment with amlexanox and cytarabine induces apoptosis via the S100A6-Akt pathway in KMT2A::AFF1-positive acute lymphoblastic leukemia.","authors":"Hayato Tamai,Koichi Miyake,Noriko Miyake,Junko Asano,Ayaka Ohashi,Ayako Arai","doi":"10.1038/s41375-025-02782-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02782-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"107 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235745","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 : 2025-10-02DOI: 10.1038/s41375-025-02778-1
Alessandra Tedeschi,Anna Maria Frustaci,Pierantonio Menna,Giorgio Minotti
{"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}
LeukemiaPub Date : 2025-10-01DOI: 10.1038/s41375-025-02720-5
Renuka Kadirkamanathan, Christos Georgiadis, Arnold Kloos, Akshay Joshi, Annie Etuk, Roland Preece, Oliver Gough, Axel Schambach, Martin Sauer, Michael Heuser, Waseem Qasim
{"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<sup>-/+</sup>CD33<sup>-/+</sup> 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}
LeukemiaPub Date : 2025-10-01DOI: 10.1038/s41375-025-02768-3
Tania Setiawan,Jabir Aliyu Muhammad,Nadya Marcellina,Lawrence Mario Wirawan,Nayoung Jun,Ita Novita Sari,Vivian G Oehler,Dong-Wook Kim,Hyog Young Kwon
{"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}
LeukemiaPub Date : 2025-09-29DOI: 10.1038/s41375-025-02761-w
Christophe Badie,Robert Peter Gale
{"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}
LeukemiaPub Date : 2025-09-28DOI: 10.1038/s41375-025-02776-3
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
{"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}
LeukemiaPub Date : 2025-09-28DOI: 10.1038/s41375-025-02772-7
Léa Rodriguez,François Delhommeau,Thierry Soussi
{"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}