Leukemia最新文献

{"title":"A novel role for transcription factor NFE2 in redox regulation and chemotherapy resistance in acute myeloid leukemia","authors":"Anne Marie Staehle, Florian Perner, Hans Felix Staehle, Katharina Gellrich, Fiona Preiß, Annika Grafemeyer, Jana Schulze, Jean-Luca Funk, Albert Gründer, Julia Berner, Sander Bekeschus, Christoph Koellerer, Heike L. Pahl","doi":"10.1038/s41375-026-03095-x","DOIUrl":"https://doi.org/10.1038/s41375-026-03095-x","url":null,"abstract":"Elevated activity of transcription factor NFE2 is sufficient to cause leukemic transformation in absence of a classical leukemic driver. However, the molecular mechanism promoting NFE2-driven leukemogenesis is not known. Here we report a previously unrecognized role for NFE2 as a key regulator of the oxidative stress response in leukemic cells. Through a comprehensive analysis of NFE2 genomic occupancy and its effect on chromatin accessibility and transcription, we demonstrate that NFE2 regulates glutathione homeostasis as well as the expression of central detoxifying enzymes. NFE2 constituted one of the highest scoring gene dependencies in MLL-AF9-transformed primary leukemic cells under redox stress, substantially more significant than the universally recognized redox regulator NRF2. Consequently, NFE2 knockdown sensitized leukemic cells to GSH depletion, ferroptosis induction, as well as to cytarabine treatment. Deriving an NFE2 RedOx score, we demonstrate that increased NFE2 activity constitutes an independent predictor of inferior outcome in AML patients at diagnosis.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"2 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769250","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":"Next-generation synthetic trials in hematology with generative artificial intelligence","authors":"Jan-Niklas Eckardt, Martin Bornhäuser, Jan Moritz Middeke","doi":"10.1038/s41375-026-03116-9","DOIUrl":"10.1038/s41375-026-03116-9","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 10","pages":"1-4"},"PeriodicalIF":8.8,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-026-03116-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795172","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}

{"title":"mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia","authors":"Agnieszka Dąbkowska, Martyna Janowska, Agata Pastorczak, Krzysztof Domka, Zuzanna Nowicka, Zuzanna Urbanska, Weronika Zając, Mikołaj Bugajewski, Julia Grzybowska, Pola Pruchniak, Klaudyna Fidyt, Wojciech Fendler, Jason Taslim, Nicholas T. Crump, Alexey Ushmorov, Elzbieta Patkowska, Malgorzata Firczuk","doi":"10.1038/s41375-026-03093-z","DOIUrl":"https://doi.org/10.1038/s41375-026-03093-z","url":null,"abstract":"B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by impaired B-cell maturation and poor prognosis in relapsed/refractory (R/R) cases. While CD20-targeted immunotherapies offer clinical benefit, their efficacy is limited by low and heterogeneous CD20 expression on BCP-ALL cells. In this study, we demonstrate that overexpression of wild-type IKZF1, a tumor suppressor frequently mutated in high-risk BCP-ALL, upregulates CD20 and promotes leukemic B cell maturation. Using a transcriptional mimicry approach, we identified mTORC1 inhibitors as compounds showing similarity to selected IKZF1-induced transcriptional signatures, including convergence on B-cell maturation and induction of CD20 expression both in vitro and in vivo. mTORC1 inhibition enhanced the antitumor efficacy of anti-CD20 monoclonal antibodies and promoted B-lineage antigen expression, while downregulating immature markers. Mechanistically, CD20 upregulation was mediated via the AKT–FOXO1 axis, with AKT phosphorylation being essential for this effect. Importantly, this phenotypic shift was observed in BCP-ALL models with IKZF1 deletions, highlighting the relevance to high-risk disease. Our findings support the use of mTORC1 inhibitors to sensitize BCP-ALL cells to CD20-directed immunotherapies and provide a strong rationale for their clinical evaluation as adjuncts to anti-CD20 immunotherapy in BCP-ALL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769253","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":"Daratumumab plus bortezomib, lenalidomide, and dexamethasone in transplant-deferred newly diagnosed multiple myeloma: Frailty subgroup analysis of CEPHEUS","authors":"Sonja Zweegman, Saad Z. Usmani, Vania Hungria, Nizar J. Bahlis, Christopher P. Venner, Marc Braunstein, Ludek Pour, Josep M. Marti, Supratik Basu, Yael C. Cohen, Morio Matsumoto, Kenshi Suzuki, Cyrille Hulin, Sebastian Grosicki, Wojciech Legiec, Angelo Maiolino, Mai Ngo, Lorena Lopez-Masi, Fredrik Borgsten, Melissa Rowe, Robin L. Carson, Thierry Facon","doi":"10.1038/s41375-026-03111-0","DOIUrl":"https://doi.org/10.1038/s41375-026-03111-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"34 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769251","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":"Modeling KRAS mutations in KMT2A::MLLT3 acute myeloid leukemia promotes leukemic progression and transcriptional rewiring","authors":"Nayeli Esparza, Joan Defrêne, Eva Bresson, Anne-Cécile Soufflet, Martha María Juárez-Rodríguez, Veronique Lisi, Alberto Hernández-Sánchez, Lars Bullinger, Vincent-Philippe Lavallée, Brian T. Wilhelm, Frédéric Barabé","doi":"10.1038/s41375-026-03112-z","DOIUrl":"https://doi.org/10.1038/s41375-026-03112-z","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"23 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769254","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":"Mutant TP53 allelic states in human hematopoietic stem and progenitor cells","authors":"Karin Lind, Sayantanee Dutta, Marco Raffaele Cosenza, Thomas Eder, Johannes Foßelteder, Gabriel Pabst, Wolfgang Schöll, Andreas Prokesch, Holger W. Auner, Albert Wölfler, Armin Zebisch, Andreas Reinisch, Florian Grebien, Jan O. Korbel, Heinz Sill","doi":"10.1038/s41375-026-03106-x","DOIUrl":"https://doi.org/10.1038/s41375-026-03106-x","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"60 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769357","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":"Immunotherapeutic targeting of calreticulin mutant myeloproliferative neoplasms","authors":"Charles Hertz, Nikolaos Spyrou, Ronald Hoffman, Cansu Cimen Bozkus, Nina Bhardwaj, Douglas Tremblay, Marina Kremyanskaya, John Mascarenhas","doi":"10.1038/s41375-026-03115-w","DOIUrl":"10.1038/s41375-026-03115-w","url":null,"abstract":"Calreticulin (CALR) frameshift mutations drive the majority of JAK2/MPL-wild-type cases of essential thrombocythemia and myelofibrosis, producing a shared novel C-terminus that activates the thrombopoietin receptor and leads to constitutive Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. CALR mutations transform the multifunctional endoplasmic reticulum (ER)-resident protein into an oncogenic driver that aberrantly traffics to the cell surface, activates the thrombopoietin receptor, MPL, and promotes MF megakaryocytic proliferation and hemopoietic stem cell fitness. Clinically, CALR-mutated MPNs affect younger patients, exhibit thrombocytosis and progressive anemia, and, in MF patients, are associated with a superior survival compared with JAK2- or MPL-mutated disease, yet responses to hydroxyurea and ruxolitinib remain inferior. The C-terminal motif shared between CALR mutations is presented extracellularly on major histocompatibility complex (MHC) Class I molecules and in complex with the thrombopoietin receptor enabling targeting with vaccination and antibody based therapeutic platforms, respectively. Mutant CALR peptide vaccines induce T cell responses but have failed to result in hematologic or molecular responses. Mutant CALR-specific monoclonal antibodies, such as Fc-silent antagonists, can block mutant-CALR–MPL signaling, suppress hematopoietic stem and progenitor cells (HSPC) proliferation and megakaryopoiesis, and achieve rapid, durable hematologic remissions with minimal toxicity in early-phase trials. Preclinical antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor T cell (CAR-T) cells also show potent, selective mutant-cell killing. Here we review the basis and ongoing translational and clinical efforts in the development of CALR-targeted immunotherapies that offer a potential shift from symptom management to disease-modifying treatment in this molecularly defined MPN subset.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 10","pages":"2107-2117"},"PeriodicalIF":8.8,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-026-03115-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795188","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}

{"title":"Clinical outcomes of newly diagnosed myeloma patients with SLIM criteria : a subgroup analysis of the CASSIOPEIA study","authors":"Cyrille Touzeau, Aurore Perrot, Cyrille Hulin, Mammoun Dib, Gedeon Agbetsivi, Laure Vincent, Thierry Facon, Xavier Leleu, Niels W.C.J. van de Donk, Annemiek Broijl, Sonja Zweegman, Michel Delforge, Jill Corre, Pieter Sonneveld, Ariane Boumendil, Philippe Moreau","doi":"10.1038/s41375-026-03094-y","DOIUrl":"https://doi.org/10.1038/s41375-026-03094-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"13 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148728883","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 role for the protease MALT1 in EBV-mediated B-cell transformation by Latent Membrane Proteins 1 and 2","authors":"Mélanie Juilland, Laurence Romy, Harun-Or Rashid, Sara Escudeiro Lopes, Silvia Podavini, David Vallois, Manhui Luo, Montserrat Gonzalez, Katerina Pandeva, Frédéric Frête, Chantal Décaillet, Laurence de Leval, Sylvia Rothenberger, Margot Thome","doi":"10.1038/s41375-026-03109-8","DOIUrl":"https://doi.org/10.1038/s41375-026-03109-8","url":null,"abstract":"Epstein-Barr virus (EBV) is a human herpesvirus that causes a variety of hematological malignancies, in particular B-, T- and NK-cell lymphomas. Latency proteins of the virus contribute to lymphomagenesis by activating the transcription factor NF-κB, however, the molecular mechanism underlying EBV-driven NF-κB activation remains incompletely understood. Here we show that EBV latent membrane proteins LMP1 and LMP2A or LMP2B synergize to activate the protease MALT1, a key driver of NF-κB-mediated lymphocyte proliferation. EBV-positive B-cell lines co-expressing LMP1 and LMP2 proteins exhibited constitutive MALT1 activity, and treatment with a MALT1 inhibitor or silencing of latent membrane protein-1 (LMP1) or LMP2 impaired MALT1-dependent substrate cleavage. LMP1 physically interacted with the MALT1-binding partner BCL10, while LMP2A and LMP2B interacted with MALT1. LMP1 also colocalized with LMP2 in dotted structures, suggesting that LMP1 and LMP2 synergize via the coordinated formation of LMP-BCL10-MALT1 (LBM) complexes. Finally, MALT1 protease inhibition led to reduced expression of a set of NF-κB-driven genes, and reduced tumor growth in an EBV-positive lymphoma xenograft model. These findings establish a key role for the protease MALT1 in LMP1/2-mediated, NF-κB-driven cellular transformation and provide a rationale for inhibiting MALT1 to treat EBV-positive B-cell lymphomas that co-express LMP1 and LMP2.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"13 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148728875","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":"Do FLT3 and KIR3DL1 converge on a common immune surveillance axis in treatment-free remission of chronic myeloid leukemia?","authors":"Mai Fujita, Hiroshi Ureshino","doi":"10.1038/s41375-026-03113-y","DOIUrl":"10.1038/s41375-026-03113-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 9","pages":"2097-2098"},"PeriodicalIF":8.8,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148726598","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}