Leukemia最新文献

{"title":"The long non-coding RNA CRNDE stabilises SIRT1 protein and influences Hedgehog signalling in multiple myeloma","authors":"Simone Zocchi, Pauline Trichet, Paloma Guernalec, Manal Agdada, Ana Alonso Bartolomé, Vincent Ogor, Caroline Choisy, Carine Vias, Xavier Sabaté-Cadenas, Jean-Christophe Bories, Michele Goodhardt, Alena Shkumatava, David Garrick","doi":"10.1038/s41375-025-02736-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02736-x","url":null,"abstract":"<p>Multiple myeloma (MM) is a malignancy of immunoglobulin-secreting plasma cells that represents 10% of all hematological cancers and remains essentially incurable, despite recent advances. Long non-coding RNAs (lncRNAs) are an important class of regulatory molecules that have been strongly implicated in the aetiology of MM. Colorectal Neoplasia Differentially Expressed (CRNDE) is one lncRNA that is upregulated in tumor plasma cells of MM patients and contributes to disease progression and outcome. In order to characterise the molecular mechanisms of CRNDE action in MM, here we have carried out a high-throughput screen to identify proteins interacting with this lncRNA inside cells. From the output of this screen, we demonstrate that in MM cells, CRNDE interacts with and stabilises the deacetylase protein SIRT1, previously identified as an important mediator of the Hedgehog (Hh) signalling pathway in MM. We further show that CRNDE exerts downstream effects on MM cell survival, tumorigenic potential, and stem-like properties via an effect on the SIRT1/Hh signalling axis. Our findings add to the molecular understanding of the pro-tumorigenic activity of CRNDE in MM and could have wider implications in other malignant diseases.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"17 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899232","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":"Retinoic acid disrupts an NPM1c/ROS/SENP3/ARF oncogenic axis in acute myeloid leukemia","authors":"Rita Hleihel, Hala Skayneh, Hsin-Chieh Wu, Maguy Hamie, Abdallah Kurdi, Jana Dakour, Charbel Machaalani, Marwan El-Sabban, Hugues de Thé, Ali Bazarbachi, Hiba El Hajj","doi":"10.1038/s41375-025-02731-2","DOIUrl":"https://doi.org/10.1038/s41375-025-02731-2","url":null,"abstract":"<p>Nucleophosmin-1 (NPM1) is a nucleolar chaperone protein frequently mutated in acute myeloid leukemia (AML). ARF and Sentrin/SUMO Specific Peptidase 3 (SENP3) control NPM1 functions through dynamic SUMOylation/de-SUMOylation. Mutated NPM1 is an oncoprotein that exhibits an aberrant cytoplasmic localization (NPM1c) and disrupts PML/P53 signaling. Studies reported increased survival of patients with NPM1c AML when retinoic acid (RA) was added to chemotherapy or hypomethylating agents. Ex vivo, RA initiates NPM1c degradation, P53 activation and cell death. Yet, the molecular mechanisms involved remain elusive. Here we show that in NPM1c AML cell lines or patients’ blasts, NPM1c-triggered mitochondrial dysfunction and oxidative stress drive NPM1c stabilization through SENP3 upregulation. RA decreases mitochondrial ROS production, driving degradation of SENP3, ARF stabilization, PML-dependent NPM1c hyperSUMOylation followed by RNF4-dependent ubiquitination and degradation. Thus, the feedback loop stabilizing NPM1c protein can be interrupted by RA-triggered enhanced mitochondrial fitness, mechanistically explaining the benefit of RA in chemotherapy or hypomethylating agents-treated AMLs.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"22 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899261","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 evolving nosology of myeloid neoplasms: the semi-centennial of the 1976 French-American-British classification","authors":"Shyam A. Patel, John M. Bennett","doi":"10.1038/s41375-025-02746-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02746-9","url":null,"abstract":"<p>The year 2026 marks the semi-centennial of the first iteration of the classification schema for myeloid neoplasms, namely the 1976 French-American-British (FAB) classification created by John M. Bennett and colleagues. The FAB classification of acute leukemia formed the biological framework of our current understanding of myeloid neoplasia. Reflecting from this historical lens, we have seen remarkable advances in diagnostics, prognostication, and therapeutics over the decades. Concerted efforts from various consensus groups have paved the way for these advances. Herein, we perform a historical analysis of the evolution of the nosology of myeloid neoplasms over the past 50 years, beginning with the landmark 1976 FAB classification. We discuss how the new nosology of myeloid neoplasms has been inspired by the widespread availability of next-generation sequencing technology as a critical adjunct to classical morphological assessment. We discuss evidence in support of a conceptual framework for categorizing myeloid neoplasms based on ontogeny, beginning from clonal hematopoiesis of indeterminate potential (CHIP). We review the foundational definitions of CHIP, including parallels with Darwinism at the cellular level, and the relevance of incorporation of precursor conditions into the most recent disease classification of myeloid neoplasms. We shed light onto patient-focused practical implications of classification schema, with emphasis on mutation-adapted therapeutic strategies. Finally, we discuss how emerging techniques such as single-cell sequencing and multi-omics may integrate into future revisions.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"50 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899262","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":"Quality of life and life satisfaction in long-term survivors of acute myeloid leukemia","authors":"Eva Telzerow, Dennis Görlich, Cristina Sauerland, Maja Rothenberg-Thurley, Anna Sophia Moret, Simon M. Krauß, Friederike H. A. Mumm, Susanne Amler, Wolfgang E. Berdel, Bernhard J. Wörmann, Utz Krug, Jan Braess, Pia Heußner, Wolfgang Hiddemann, Karsten Spiekermann, Klaus H. Metzeler","doi":"10.1038/s41375-025-02735-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02735-y","url":null,"abstract":"<p>We performed a questionnaire-based cross-sectional study to analyze Acute Myeloid Leukemia (AML) long-term survivor (LTS) outcomes, including psychosocial well-being and somatic health status. Four-hundred-twenty-seven former AML patients participated (response rate, 63%) ≥5 years[y] and up to 18.6 y past their leukemia diagnosis (median, 11.3 y). Median age at study participation was 61 y (range 28y–93y), 23% had experienced disease relapse, and 63% had received allogeneic hematopoietic stem cell transplantation (alloHSCT). Overall, quality of life (QoL) and general life satisfaction (gLS) summary scores were higher in AML LTS (<i>p</i> &lt; 0.001) compared to age-/sex-matched reference cohorts, although differences were small and likely not clinically relevant. However, we identified subgroups of survivors reporting impaired QoL (27%), gLS (13%) and health-related life satisfaction (hrLS; 17%). Using multivariable regression models, we identified predisposing and protective factors for each of these outcomes. Treatment with alloHSCT did not adversely impact QoL, gLS, or hrLS. In summary, global QoL and LS in AML LTS are comparable to the general population, irrespective of treatment modality, although some survivors report clinically significant impairment of global QoL and/or in specific domains. We identified factors associated with impaired outcomes (e.g., comorbidity and fatigue), delineating a subgroup of survivors with unmet needs ≥5 y after their AML diagnosis.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"13 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899200","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":"Predicting antigen-specific T-cell immunity against Wilms tumor 1 in hematologic cancer","authors":"Brittany L. Ford, Emmi Jokinen, Jani Huuhtanen, Sofia Forstén, Jay Klievink, Gabriella Antignani, Oscar Brück, Vincenzo Cerullo, Karita Peltonen, Satu Mustjoki","doi":"10.1038/s41375-025-02727-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02727-y","url":null,"abstract":"<p>Wilms tumor 1 (WT1) is a tumor-associated antigen expressed in solid tumors and hematological malignancies. T-cell immunotherapies targeting WT1 are currently under development. To analyze endogenous T-cell responses against WT1, we trained computational models capable of detecting WT1-specific T-cell responses from T-cell receptor (TCR) sequencing data. We peptide-pulsed healthy donor and acute myeloid leukemia (AML) patient samples with VLDFAPPGA (VLD, WT1_37-45) and RMFPNAPYL (RMF, WT1_126-134) peptides, then sequenced the WT1 dextramer-positive CD8 + T-cells with single-cell RNA + TCRαβ sequencing. The TCRGP machine-learning TCR-classification method was trained with epitope-specific and control TCR repertoires, and we obtained AUROC values of 0.74 (VLD) and 0.75 (RMF), allowing reliable identification of WT1-specific T-cells. In bulk TCRβ sequenced patient samples (AML n = 21, chronic myeloid leukemia (CML) n = 26, and myelodysplastic syndrome n = 25), the median WT1-specific T-cell abundance was similar to healthy controls, but their VLD and RMF-specific TCR repertoires exhibited higher clonality with two patients presenting up to 13% of WT1-specific T-cells. ScRNA+TCRαβ sequencing of AML bone marrow T-cells revealed that WT1-specific T-cells predominantly exhibit an effector or terminal effector memory phenotype. In conclusion, our novel computational models enable large-scale WT1-specific T-cell identification from TCR sequencing datasets and leukemia-antigen-specific immune response monitoring.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"22 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899306","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":"Unraveling the molecular landscape of Erdheim–Chester disease: new insights from methylome and transcriptome integration","authors":"Miriam Cerván-Martín, Francesco Pegoraro, Javier Martínez-López, Inmaculada Rodriguez-Martin, Ana Márquez, Lourdes Ortiz-Fernández, Marialbert Acosta-Herrera, Martin Kerick, Eduardo Andrés-León, Francesco Catamerò, Matthias Papo, Fleur Cohen-Aubart, Zahir Amoura, Julien Haroche, Augusto Vaglio, Javier Martín","doi":"10.1038/s41375-025-02742-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02742-z","url":null,"abstract":"<p>Erdheim–Chester Disease (ECD) is a rare histiocytosis characterized by a wide spectrum of clinical manifestations. Although somatic mutations have been involved in ECD, its etiology remains poorly understood. This study aimed to identify novel molecular mechanisms involved in ECD through the first integrated methylome and transcriptome analysis. Peripheral blood samples were collected from 137 ECD patients and 410 controls. Genome-wide DNA methylation and transcriptome analyses were performed, followed by functional in silico studies using different online bioinformatics tools. Subsequently, methylome and transcriptome data were integrated, and a drug repurposing approach was undertaken. Our results revealed 2511 differentially methylated positions and 1484 differentially expressed genes associated with ECD. The integrative analysis identified 46 alterations in DNA methylation patterns that regulate the expression levels of 29 altered genes in ECD patients, highlighting key genes involved in immune response and tumorigenesis. Remarkably, our results identified B cells and NF-kB signaling pathway as novel contributors of ECD pathogenesis. Finally, the drug repurposing analysis identified potential therapeutic options for ECD patients. In conclusion, this study represents an important advance in understanding the molecular basis of ECD, proposing novel cell types and pathways involved in ECD pathogenesis and suggesting new avenues for clinical management.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"36 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899309","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":"Germline Jak2-R1063H mutation interferes with normal hematopoietic development and increases risk of thrombosis and leukemic transformation","authors":"Veronika Zimolova, Monika Burocziova, Linda Berkova, Srdjan Grusanovic, Jan Gursky, Lubos Janotka, Petr Kasparek, Alena Pecinova, David Kundrat, Dusan Hrckulak, Jakub Onhajzer, Ivana Jeziskova, Lucie Nekvindova, Barbora Weinbergerova, Sarka Pospisilova, Michael Doubek, Meritxell Alberich-Jorda, Vladimir Korinek, Vladimir Divoky, Lucie Lanikova","doi":"10.1038/s41375-025-02737-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02737-w","url":null,"abstract":"<p>The acquired <i>JAK2</i>-V617F mutation plays a causal role in myeloproliferative neoplasms (MPN). Weakly activating <i>JAK2</i> germline variants have been associated with MPN risk, but the underlying mechanisms remain unclear. We previously identified the <i>JAK2</i>-R1063H germline variant, which contributes to hereditary MPN and increased disease severity in essential thrombocythemia. Here, we studied alterations in hematopoiesis in <i>Jak2</i>-R1063H knock-in mice. The <i>Jak2</i>-R1063H mouse cohort exhibited increased mortality, stimulated thrombopoiesis and elevated D-dimers levels, indicative of thrombotic complications. Bone marrow analysis revealed myeloid bias, enhanced megakaryopoiesis and activation of inflammatory signaling. Transcriptional and functional assays of hematopoietic stem cells suggested their accelerated aging and functional decline. The Egr1 transcriptional network, including the <i>Thbs1</i> gene, progressively increased in aging mice, reinforcing alterations initiated by Jak2/Stat signaling. In murine acute myelogenous leukemia models, the <i>Jak2</i>-R1063H cooperated with a driver oncogene in promoting leukemogenesis. Germline <i>JAK2</i>-R1063H was found in 10 of 200 MPN patients from local hematology centers, with a higher minor allele frequency compared to healthy controls. Patients harboring <i>JAK2</i>-R1063H variant exhibited an increased incidence of thrombotic complications and disease progression with shortened survival. In conclusion, our findings identify the <i>JAK2</i>-R1063H germline variant as a risk factor for MPN development, thrombotic complications, and leukemic transformation.</p><figure><p>Our study, which involves a mouse model and a cohort of 200 MPN patients, characterizes the <i>JAK2</i>-R1063H germline mutation as a risk factor for MPN development, thrombotic complications, and leukemic transformation. These findings may have important clinical implications for managing MPN patients carrying the <i>JAK2</i>-R1063H germline variant.</p></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"15 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899308","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":"Targeting p16INK4a-mediated cellular senescence as a therapeutic strategy for FLT3-ITD-driven acute myeloid leukemia","authors":"Jiarui Zheng, Linlin Jin, Yunlong Chen, Yongjuan Duan, Suyu Zong, Peng Wu, Xiaofan Zhu, Wenyu Yang, Tianyuan Hu, Yingchi Zhang","doi":"10.1038/s41375-025-02743-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02743-y","url":null,"abstract":"<p>Cellular senescence serves as a critical tumor-suppressive mechanism across various cancer types, yet its role in <i>FLT3</i>-ITD-positive acute myeloid leukemia (AML) remains poorly understood. Through the analysis of multiple sequencing datasets, we identified that <i>FLT3</i>-ITD-positive patients with low <i>p16</i>^<i>INK4a</i> expression have significantly worse prognoses. Consistent with these clinical findings, knockout of <i>p16</i>^<i>INK4a</i> in mice was shown to accelerate <i>FLT3</i>-ITD AML onset. Mechanistic investigations further revealed that the <i>FLT3</i>-ITD mutation suppresses <i>p16</i>^<i>INK4a</i> expression via the STAT5A-E2F3-EZH2 signaling axis. This downregulation of <i>p16</i>^<i>INK4a</i> allows cells to evade senescence, thereby promoting increased malignancy and establishing a positive feedback loop that exacerbates disease progression. This mechanism provides a molecular explanation for the poorer long-term survival observed in this patient subset. Furthermore, the <i>FLT3</i>-ITD-STAT5A/E2F3/EZH2-<i>p16</i>^<i>INK4a</i> axis identified in this study represents a promising therapeutic target for addressing refractory <i>FLT3</i>-ITD AML with low <i>p16</i>^<i>INK4a</i> expression.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"21 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899307","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":"Progressive T cell defects correlate with disease outcome in high-count monoclonal B-cell lymphocytosis","authors":"Sameer A. Parikh,&nbsp;Nikolaos Ioannou,&nbsp;Alan G. Ramsay,&nbsp;Justin C. Boysen,&nbsp;Saad S. Kenderian,&nbsp;Kari G. Rabe,&nbsp;Sutapa Sinha,&nbsp;Esteban Braggio,&nbsp;Kay L. Medina,&nbsp;Susan L. Slager,&nbsp;Tait D. Shanafelt,&nbsp;Neil E. Kay","doi":"10.1038/s41375-025-02689-1","DOIUrl":"10.1038/s41375-025-02689-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2551-2554"},"PeriodicalIF":13.4,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899092","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 scholar of blood and beauty: remembering Prof. Jacques-Louis Binet (1932–2024)","authors":"Thomas J. Kipps","doi":"10.1038/s41375-025-02726-z","DOIUrl":"10.1038/s41375-025-02726-z","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2309-2310"},"PeriodicalIF":13.4,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02726-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144857691","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}