Leukemia最新文献

{"title":"Fabp4 is essential for the maintenance of leukemia stem cells while sparing hematopoietic stem cells","authors":"Cheng Xing, Huifang Zhang, Mengqiu Zheng, Qian Lu, Yujia Tao, Shina Xu, Yang Xiao, Long Liang, Haodong Xu, Shuqian Xu, Hongling Peng, Yue Sheng","doi":"10.1038/s41375-025-02568-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02568-9","url":null,"abstract":"<p>Fatty Acid Binding Protein 4 (FABP4) is a key player among the fatty acid-binding protein family. It exhibits a high level of expression specifically in adipocytes, immune cells, and endothelial cells. Serving as a lipid chaperone, FABP4 is essential for the metabolic processing of fatty acids, including their breakdown, transport, and storage [1, 2]. Additionally, it significantly contributes to the development of various metabolic disorders [3]. Extensive research has shown that FABP4 is instrumental in the pathogenesis of conditions such as diabetes, non-alcoholic fatty liver disease, and atherosclerosis [4,5,6]. In the realm of oncology, recent findings have revealed that FABP4 is frequently upregulated in numerous malignant tumors. It exerts a substantial influence on tumorigenesis, metastasis, and the acquisition of drug resistance [7]. Despite advancements, the role of FABP4 in hematopoietic and leukemia stem cells remains unexplored, highlighting a significant gap in current scientific literature.</p><p>Single-cell RNA sequencing (scRNA-seq) was conducted on BM cells harvested from primary recipient mice of MA9-WT, MA9-HET, and MA9-KO to investigate Fabp4’s role in LSCs. The gene set machine annotation, complemented by manual curation, pinpointed cluster 10 as enriched for LSCs (Fig. S5A-E). Analysis of the sequencing data indicated a significant decrease in the presence of LSCs among MA9-HET and MA9-KO mice when compared with their MA9-WT counterparts, with a concurrent increase in mature cell clusters (Fig. 2F–H). A stark divergence in the transcriptome profile was evident of all BM cells between WT and HET_KO groups, with tumor development-associated genes such as Ikzf2, Igkc, Satb1, Mt1, Pbx3, etc., being significantly downregulated in the HET_KO cohort (Fig. S6A). Notably, pathways essential for hematopoietic cell maturation, including hematopoietic cell lineage, Th1, Th2, and Th17 cell differentiation, were upregulated in HET_KO compared to WT (Fig. S6B). Conversely, the transcriptional misregulation in cancers was notably downregulated (Figure S6C). In our comparative analysis of differentially expressed genes between HET_KO and WT, the heatmap in Fig. S6D depicted a significant downregulation of tumor progression-related genes, including TCF4, Gadd45b, Mt1, Gtf2b, etc., in the LSCs of from HET and KO recipient mice. Gene set enrichment analysis (GSEA) revealed notable downregulation of oxidative phosphorylation (OXPHOS) and arginine biosynthesis in LSCs from HET and KO mice (Fig. S6E-F). Extensive research has implicated OXPHOS upregulation in leukemia, with OXPHOS inhibition shown to selectively target dormant LSCs [11]. Arginine, central to tumor growth, invasion, angiogenesis, and immune modulation, serves as a crucial intermediate in the production of compounds associated with cancer [12]. These findings suggest that Fabp4 deficiency induces LSC dysfunction, thereby impeding the progression of AML.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"25 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813753","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 effect of ibrutinib on the myeloid cell compartment in CNS lymphoma","authors":"Julia C. Kuehn, Nicolas N. Neidert, Junyi Zhang, Jurik Mutter, Stefan Alig, Christian Klingler, Fabian Hummel, Lavanya Ranganathan, Sabine Bleul, Jürgen Beck, Marco Prinz, Maximilian Diehn, Ash Alizadeh, Justus Duyster, Roman Sankowski, Dieter H. Heiland, Florian Scherer","doi":"10.1038/s41375-025-02600-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02600-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"2 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813701","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":"Asciminib monotherapy in patients with chronic myeloid leukemia in chronic phase without BCR::ABL1T315I treated with at least 2 prior TKIs: Phase 1 final results","authors":"Andreas Hochhaus, Dong-Wook Kim, Jorge E. Cortes, Koji Sasaki, Michael J. Mauro, Timothy P. Hughes, Massimo Breccia, Moshe Talpaz, Hironobu Minami, Yeow Tee Goh, Daniel J. DeAngelo, Fabian Lang, Oliver Ottmann, Michael C. Heinrich, Valle Gomez Garcia de Soria, Philipp le Coutre, Gessami Sanchez-Olle, Meng Cao, Nathalie Pognan, Shruti Kapoor, Matthias Hoch, Delphine Rea","doi":"10.1038/s41375-025-02578-7","DOIUrl":"https://doi.org/10.1038/s41375-025-02578-7","url":null,"abstract":"<p>Asciminib is the first approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP). The present final analysis of the phase 1, open-label, nonrandomized trial (NCT02081378) assessed the long-term safety, tolerability, and antileukemic activity of asciminib in 115 patients with chronic myeloid leukemia in chronic phase without the <i>BCR::ABL1</i>^T315I mutation who received asciminib 10–200 mg twice daily (BID) or 80–200 mg once daily (cutoff: March 14, 2023). Median exposure duration was 5.9 (range, 0–8.4) years; 60.9% of patients continued receiving asciminib through post-trial access. Grade ≥3 adverse events (AEs) occurred in 88 patients (76.5%). AEs led to treatment discontinuation, dose adjustment/interruption, or additional therapy in 15 (13.0%), 74 (64.3%), and 106 (92.2%) patients, respectively. Most first-ever AEs, particularly hematologic AEs, presented within the first year and no new safety signals emerged. Of 56 patients who achieved major molecular response, 50 maintained the response by cutoff; the Kaplan-Meier-estimated probability of maintaining this response for ≥432 weeks ( ≈ 8.3 years) was 88% (95% confidence interval, 78.2–97.0%). The recommended dose for expansion was determined at 40 mg BID. With up to 8.4 years of treatment, asciminib continued to demonstrate long-term safety and efficacy in this population.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"183 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805669","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":"Guiding clinical management of patients with CNS lymphomas by minimal-invasive detection of ctDNA in cerebrospinal fluid","authors":"S. Weinschenk, U. Philipp, J. C. Kuehn, K. Mueller, J. Fauser, D. Boeckle, I. Gebhard, M. Hinz, N. Neidert, S. Bleul, E. M. Lauer, J. A. Mutter, S. K. Alig, D. M. Kurtz, J. Finke, R. Marks, M. Diehn, A. A. Alizadeh, P. C. Reinacher, J. Wehrle, U. Keller, D. Wolf, F. Kocher, B. Chapuy, J. Beck, M. Prinz, L. von Baumgarten, E. Schorb, J. Duyster, F. Scherer","doi":"10.1038/s41375-025-02583-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02583-w","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"14 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805664","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":"Asciminib in combination with imatinib, nilotinib, or dasatinib in patients with chronic myeloid leukemia in chronic or accelerated phase: phase 1 study final results","authors":"Jorge E. Cortes, Fabian Lang, Delphine Rea, Andreas Hochhaus, Massimo Breccia, Yeow Tee Goh, Michael C. Heinrich, Timothy P. Hughes, Jeroen J. W. M. Janssen, Philipp le Coutre, Hironobu Minami, Koji Sasaki, Daniel J. DeAngelo, Gessami Sanchez-Olle, Nathalie Pognan, Meng Cao, Matthias Hoch, Michael J. Mauro","doi":"10.1038/s41375-025-02592-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02592-9","url":null,"abstract":"<p>Data from in vitro and animal studies suggest that asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), synergizes with adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) to prevent emergence of and overcome resistance. Combination therapy may provide new treatment options for patients with chronic myeloid leukemia (CML) with suboptimal responses to ATP-competitive TKI monotherapy. Preliminary analysis of asciminib combined with nilotinib, imatinib, or dasatinib in a phase 1 dose-escalation study suggested promising efficacy and safety for patients with CML in chronic phase or accelerated phase treated with prior ATP-competitive TKIs; herein, we present final results from the 3 combination therapy arms. Asciminib, in combination with ATP-competitive TKIs, demonstrated rapid efficacy offset by a decreased tolerability compared with asciminib monotherapy. Based on these safety, tolerability, and preliminary efficacy results, asciminib 40 mg twice daily (BID) plus nilotinib 300 mg BID, asciminib 40 or 60 mg once daily (QD) plus imatinib 400 mg QD, and asciminib 80 mg QD plus dasatinib 100 mg QD were identified as recommended doses for expansion. The maximum tolerated dose was reached at asciminib 60 mg QD plus imatinib 400 mg QD and was not reached with asciminib plus nilotinib or dasatinib.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"32 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805665","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":"DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes","authors":"Fadimana Kaya, Findlay Bewicke-Copley, Juho J. Miettinen, Pedro Casado, Eve Leddy, Özgen Deniz, Vincent-Philippe Lavallée, Celine Philippe, Jiexin Zheng, Florian Grebien, Naeem Khan, Szilvia Krizsán, Joseph Saad, Alexis Nolin-Lapalme, Josée Hébert, Sébastien Lemieux, Eric Audemard, Janet Matthews, Marianne Grantham, Doriana Di Bella, Krister Wennerberg, Alun Parsons, John Gribben, James D. Cavenagh, Sylvie D. Freeman, Csaba Bödör, Guy Sauvageau, Jun Wang, Pilar Llamas-Sillero, Jean-Baptiste Cazier, David C. Taussig, Dominique Bonnet, Pedro R. Cutillas, Caroline A. Heckman, Jude Fitzgibbon, Kevin Rouault-Pierre, Ana Rio-Machin","doi":"10.1038/s41375-025-02593-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02593-8","url":null,"abstract":"<p>The t(6;9)(p22.3;q34.1) translocation/DEK::NUP214 fusion protein defines a distinct subgroup of younger AML patients classified as a separate disease entity by the World Health Organization. DEK is a nuclear factor with multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK::NUP214 drives leukemia remains unclear. A comprehensive multi-omics comparison of 57 AML primary samples (including whole genome sequencing, targeted sequencing, transcriptomics, and drug screening with &gt;500 compounds) revealed that t(6;9) cases display a selective response to XPO1 inhibitors (Selinexor &amp; Eltanexor) and a distinct transcriptomic signature characterized by the overexpression of <i>FOXC1</i> and <i>HOX</i> genes that are key leukemia mediators. CUT&amp;RUN experiments demonstrated the direct binding of DEK::NUP214 to the promoters of <i>FOXC1</i> and <i>HOXA/B</i> clusters. Strikingly, the expression of these genes and the binding of DEK::NUP214 to their regulatory regions were selectively reduced upon XPO1 inhibition in t(6;9) cells. Altogether, these results identified a novel function of DEK::NUP214 as an XPO1-dependent transcriptional activator of key leukemia drivers and provide a rationale to explore the use of XPO1 inhibitors in this patient population.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"86 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805935","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":"Primary antifungal prophylaxis in hematological malignancies. Updated clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL)","authors":"Livio Pagano, Georg Maschmeyer, Frederic Lamoth, Ola Blennow, Alienor Xhaard, Manuela Spadea, Alessandro Busca, Catherine Cordonnier, Johan Maertens","doi":"10.1038/s41375-025-02586-7","DOIUrl":"https://doi.org/10.1038/s41375-025-02586-7","url":null,"abstract":"<p>At the 10th European Conference on Infections in Leukaemia (ECIL), the guidelines for antifungal prophylaxis in pediatric and adult patients with hematological malignancies (HM) were updated and some changes introduced. Regarding acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients undergoing remission induction chemotherapy, a B-II grading has been assigned to isavuconazole, micafungin, and caspofungin, based on non-randomized studies that have shown efficacy in preventing invasive fungal diseases (IFD). Regarding high-risk MDS patients treated with azacytidine, prophylaxis with posaconazole during the first four cycles of treatment is supported in the literature. Prophylaxis is not indicated in patients treated for myeloproliferative neoplasms (NPM), acute lymphoid leukemia (ALL), and Hodgkin lymphoma (HL). For patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), prophylaxis is not generally indicated. For patients with multiple myeloma (MM), prophylaxis is not indicated and the limited epidemiological data available do not support the use of prophylaxis in subjects treated with bispecific antibodies. For patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT), no substantial changes were made, apart from the addition of isavuconazole with grading B-II in the post-engraftment period. In patients undergoing auto-HSCT, antifungal prophylaxis is not indicated. Previous ECIL guidelines did not include CAR-T cells. The expert panel proposes to endorse the use of anti-mold prophylaxis in high-risk patients during pre-infusion and post-infusion, while in low-risk patients, anti-yeast prophylaxis can be recommended (B-II). For pediatric hematology patients, based on newly published data, caspofungin received a B-I grading as mold-active prophylaxis. Moreover, patients with ALL with insufficient treatment response during induction therapy, and children older than 12 y.o are now considered at high risk for IFD and are recommended to receive antifungal prophylaxis.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"74 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805667","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":"Cell polarity: cell type-specific regulators, common pathways, and polarized vesicle transport","authors":"Soumen Bera, Dirk Loeffler","doi":"10.1038/s41375-025-02601-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02601-x","url":null,"abstract":"<p>Cell polarity, the asymmetric organization of cellular components, is evolutionarily conserved from unicellular and multicellular organisms and is crucial for many biological processes. Polarity is required to maintain cell and tissue integrity by regulating cell division, migration, orientation, cell-cell interactions, and morphogenesis. Impaired polarity leads to dysregulation of cellular functions and is associated with disease. Understanding how polarity is established, maintained, and regulated is thus critical to improving our knowledge of pathologies and devising novel therapies. Here, we explore the various manifestations of cell polarity across different model systems, tissues, and cell types and focus on known polarity mechanisms in hematopoietic stem and progenitor cells. We discuss how cells with vastly different functions utilize conserved molecular complexes to establish cell polarity while adapting polarity proteins to unique cell-type-specific functions. In this discussion, we attempt to extract common themes and concepts to improve our understanding of cell polarity in hematological malignancies and other diseases. Finally, we summarize, compare, and evaluate classical as well as recently developed methods to quantify cell polarity, highlight important advances in imaging and analytical techniques, and suggest critical next steps required to move the field forward.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"217 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805934","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":"Current landscape of vector safety and genotoxicity after hematopoietic stem or immune cell gene therapy","authors":"Giorgio Ottaviano, Waseem Qasim","doi":"10.1038/s41375-025-02585-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02585-8","url":null,"abstract":"<p>Malignant transformation of gene modified haematopoietic stem cells caused anxiety following adverse events in early clinical trials using gamma-retroviral vectors (γRV) to correct haematopoietic stem cells (HSC) in monogenic immune disorders. Adoption of HIV-derived lentiviral vectors (LV) with SIN (self-inactivating) configurations greatly reduced risks and subsequently hundreds of patients have been dosed with HSC gene therapy for blood, immune and metabolic conditions. Nevertheless, as experience builds, it’s now well recognised that vector integration can drive clonal expansions and these may carry long term safety risks. Documented cases of haematological malignancy after SIN-LV gene therapy have recently emerged, in particular where heterologous retroviral promoters were employed and there are concerns around certain insulator elements and other possible contributors to clonal expansions. Similarly, tens of thousands of subjects have now received engineered T cell products, and longstanding dogma that mature T cells cannot be transformed is being questioned, with reports of a small number of malignant transformation events and wider concerns around secondary malignancies in some groups of patients. We summarize current clinical information and revisit genotoxicity risks following ex-vivo gene modification of HSC and T cells.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"24 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805668","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":"Emerging T-cell lymphomas after CAR T-cell therapy","authors":"Till Braun, Florian Kuschel, Kristin Reiche, Maximilian Merz, Marco Herling","doi":"10.1038/s41375-025-02574-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02574-x","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"18 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790132","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}