Leukemia最新文献

{"title":"Zanubrutinib in Bing Neel syndrome: efficacy and tolerability","authors":"Anne-Marie L. Becking, Johannes P. M. van de Mortel, Oliver Tomkins, Thijs W. H. Flinsenberg, Nicole Japzon, Marie José Kersten, Jahanzaib Khwaja, Saskia Kuipers, Henriette Levenga, Sean McKeague, Stephen Opat, Ross T. Salvaris, Sherif Seif, Sheeba K. Thomas, Alexander F. J. E. Vrancken, Shirley D’Sa, Monique C. Minnema, Josephine M. I. Vos","doi":"10.1038/s41375-025-02581-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02581-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"34 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736596","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":"Senescence profiling of monoclonal gammopathies reveals paracrine senescence as a crucial defense against disease progression","authors":"Gabriel Alvares Borges, Marta Diaz-delCastillo, Angelo J. Guilatco, Bilal Mohamad El-Masri, Fatima A. Mustapha, Michael T. Gundesen, Maja Hinge, Thomas Lund, Nadine Abdallah, Linda B. Baughn, Ming Xu, Anne Gingery, Tamar Tchkonia, James L. Kirkland, Taxiarchis Kourelis, Matthew T. Drake, Thomas Levin Andersen, Megan M. Weivoda","doi":"10.1038/s41375-025-02572-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02572-z","url":null,"abstract":"<p>Multiple myeloma (MM) is a plasma cell (PC) malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). MGUS and SMM PCs exhibit the same primary oncogenic abnormalities as MM but lack the end-organ damage that defines proliferative disease, suggesting that clonal PCs in these precursor conditions could exhibit senescence or senescence-like growth arrest. Herein we identified monoclonal gammopathy patient-derived PCs that exhibit senescence features and found that senescent PCs were significantly increased in MGUS patients compared to SMM or MM. Spatial analysis of senescent PCs in stable MGUS and SMM patient biopsies demonstrated the activation of local paracrine senescence in the bone marrow microenvironment. Stable MGUS and SMM patients also exhibited disease-specific senescence-associated secretory phenotype (SASP) signatures that significantly correlated with PC burden and clonal antibody. In contrast, progressing MGUS, SMM, and new MM patients lacked local paracrine senescence responses and robust activation of disease specific SASP signatures. Overall, these data suggest that failure to activate tumor-specific paracrine senescence responses is key to disease progression in monoclonal gammopathies.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"72 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736624","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":"Whole-genome sequencing of myeloproliferative neoplasms revealed dynamic clonal changes in the fibrotic or leukemic transformation and novel FOXP1 mutations in the fibrotic transformation","authors":"Hiroyuki Takamori, Ying-Jung Huang, Hidehito Fukushima, Kazuaki Yokoyama, Ting-Yu Huang, Ming-Chung Kuo, Seishi Ogawa, Yasuhito Nannya, Lee-Yung Shih","doi":"10.1038/s41375-025-02576-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02576-9","url":null,"abstract":"<p>Myeloproliferative neoplasms (MPNs) are characterized by clonal proliferation of hematopoietic stem cells, which can lead to secondary myelofibrosis or acute myeloid leukemia. We explored the changes in genomic alterations during MPN transformation using whole-genome sequencing of samples from both the chronic and fibrotic or leukemic phases of 20 patients. We identified <i>FOXP1</i> mutations in 3 of 14 (21.4%) patients with secondary myelofibrosis. This novel mutation was identified in another 5 of the 35 patients (14.3%) in an independent cohort. All these 8 patients with <i>FOXP1</i> mutations did not experience leukemic transformation after a median follow-up of 5.1 years. The acquisition of non-canonical <i>MPL</i>^Y591 mutations was detected in the fibrotic or leukemic phase. Clonal expansion, involving both known and unknown driver genes (in 18 and 2 patients, respectively), was observed in all patients. We determined the patterns of clonal evolution based on myeloid driver mutations in 18 patients: linear clonal evolution in 11 patients and branched clonal evolution in 7 patients. Our results suggested that MPN patients carrying <i>FOXP1</i> mutations are unlikely to have leukemia transformation and emphasized that the acquisition of specific genetic mutations and dynamic changes in clonal architecture underlie the pathogenesis in patients undergoing MPN transformation.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"72 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736623","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":"Discrete genetic subtypes and tumor microenvironment signatures correlate with peripheral T-cell lymphoma outcomes","authors":"Yasuhito Suehara, Kana Sakamoto, Manabu Fujisawa, Kota Fukumoto, Yoshiaki Abe, Kenichi Makishima, Sakurako Suma, Tatsuhiro Sakamoto, Keiichiro Hattori, Takeshi Sugio, Koji Kato, Koichi Akashi, Kosei Matsue, Kentaro Narita, Kengo Takeuchi, Joaquim Carreras, Naoya Nakamura, Kenichi Chiba, Yuichi Shiraishi, Satoru Miyano, Seishi Ogawa, Shigeru Chiba, Mamiko Sakata-Yanagimoto","doi":"10.1038/s41375-025-02563-0","DOIUrl":"https://doi.org/10.1038/s41375-025-02563-0","url":null,"abstract":"<p>Peripheral T-cell lymphoma (PTCL) exhibits a diverse clinical spectrum, necessitating methods to categorize patients based on genomic abnormalities or tumor microenvironment (TME) profiles. We conducted an integrative multiomics study in 129 PTCL patients, performing whole-exome sequencing and identifying three genetic subtypes: C1, C2, and C3. C2 was characterized by loss of tumor suppressor genes and chromosomal instability, while C1 and C3 shared T follicular helper (TFH)-related genomic alterations, with C3 also showing a high incidence of <i>IDH2</i> mutations and chromosome 5 gain. Compared to C1, survival was significantly worse in C2 (HR 2.52; 95% CI, 1.37–4.63) and C3 (HR 2.14; 95% CI, 1.17–3.89). We also estimated the proportions of immune cell fractions from the bulk RNA sequencing data using CIBERSORTx and classified TME signatures into the following hierarchical clusters: TME1 (characterized by increased B and TFH cells), TME2 (macrophages), and TME3 (activated mast cells). TME2 was associated with shorter survival (HR 3.4; 95% CI, 1.6–7.5) and was more frequent in C2 (64.3%) than in C1 (7.7%), whereas C1 had more TME3 signatures (80.8% vs. 28.6%). These findings highlight a significant relationship between genetic subtypes and TME signatures in PTCL, with important implications for clinical prognosis.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"18 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736631","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":"Correction: Correlation of progression-free survival and overall survival after treatment for relapsed Hodgkin lymphoma: individual patient data analysis of randomized German Hodgkin Study Group (GHSG) Trials.","authors":"P J Bröckelmann, H Müller, M Fuchs, S Gillessen, D A Eichenauer, S Borchmann, A S Robertz, K Behringer, J Welters, J Ferdinandus, B Böll, H Tharmaseelan, X Yang, C Kobe, H T Eich, C Baues, W Klapper, P Borchmann, B von Tresckow","doi":"10.1038/s41375-025-02597-4","DOIUrl":"10.1038/s41375-025-02597-4","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753484","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":"DYRK1A inhibition results in MYC and ERK activation rendering KMT2A-R acute lymphoblastic leukemia cells sensitive to BCL2 inhibition","authors":"V. S. S. Abhinav Ayyadevara, Gerald Wertheim, Shikha Gaur, John A. Chukinas, Joseph P. Loftus, Sung June Lee, Anil Kumar, Srividya Swaminathan, Rahul S. Bhansali, Wayne Childers, Huimin Geng, Thomas A. Milne, Xianxin Hua, Kathrin M. Bernt, Thierry Besson, Junwei Shi, John D. Crispino, Martin Carroll, Sarah K. Tasian, Christian Hurtz","doi":"10.1038/s41375-025-02575-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02575-w","url":null,"abstract":"<p>Unbiased kinome-wide CRISPR screening identified DYRK1A as a potential therapeutic target in <i>KMT2A</i>-rearranged (<i>KMT2A-</i>R) B-acute lymphoblastic leukemia (ALL). Mechanistically, we demonstrate that <i>DYRK1A</i> is regulated by the KMT2A fusion protein and affects cell proliferation by regulating MYC expression and ERK phosphorylation. We further observed that pharmacologic DYRK1A inhibition markedly reduced human <i>KMT2A</i>-R ALL cell proliferation in vitro and potently decreased leukemia proliferation in vivo in drug-treated patient-derived xenograft mouse models. DYRK1A inhibition induced expression of the proapoptotic factor BIM and reduced the expression of BCL-XL, consequently sensitizing <i>KMT2A</i>-R ALL cells to BCL2 inhibition. Dual inhibition of DYRK1A and BCL2 synergistically decreased <i>KMT2A</i>-R ALL cell survival in vitro and reduced leukemic burden in mice. Taken together, our data establishes DYRK1A as a novel therapeutic target in <i>KMT2A</i>-R ALL and credential dual inhibition of DYRK1A and BCL2 as an effective translational therapeutic strategy for this high-risk ALL subtype.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"95 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723169","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":"XPO1-dependency of DEK::NUP214 leukemia","authors":"Fiorella Charles Cano, Arnold Kloos, Rucha Y. Hebalkar, Thomas Plenge, Robert Geffers, Hanna Kirchhoff, Nadine Kattre, Kerstin Görlich, Guntram Büsche, Halyna R. Shcherbata, Michaela Scherr, Konstanze Döhner, Razif Gabdoulline, Michael Heuser","doi":"10.1038/s41375-025-02570-1","DOIUrl":"https://doi.org/10.1038/s41375-025-02570-1","url":null,"abstract":"<p>The nuclear export protein XPO1 interacts with nucleoporin 214 (NUP214) and has been implicated in the pathogenesis of SET::NUP214 acute myeloid leukemia (AML). We evaluated DEK::NUP214 (DN), characterizing a distinct AML entity, for its dependency on XPO1 in human AML models. Deletion of XPO1 in DN-positive FKH-1 cells revealed a strong dependency on XPO1. Pharmacologic inhibition of XPO1 by the second-generation selective inhibitor of nuclear export, eltanexor, in primary human and FKH-1 cells reduced XPO1 expression, disrupted co-localization of XPO1 and DN, and induced apoptosis and cell cycle arrest. Functionally, XPO1 and DN co-localized at chromatin, and this co-localization was strongly reduced by XPO1 inhibition. Loss of chromatin binding resulted in downregulation of DN target genes and pathways related to cell cycle and self-renewal. Eltanexor treatment of a patient-derived DN-AML xenograft model disrupted leukemia development, showing molecular clearance in bone marrow after a median of 377 days in eltanexor-treated mice, while control mice succumbed after a median of 244 days. In summary, XPO1 stabilizes DN at chromatin to allow the activation of its oncogenic gene signature, while targeting XPO1 treats leukemia successfully in vivo. These findings establish XPO1 as a molecular target in DEK::NUP214 AML.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"183 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713040","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":"What is radiation-induced acute myeloid leukaemia/can it be accurately identified?","authors":"Christophe Badie, Robert Peter Gale","doi":"10.1038/s41375-025-02561-2","DOIUrl":"https://doi.org/10.1038/s41375-025-02561-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730569","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":"Malignant JAK-signaling: at the interface of inflammation and malignant transformation","authors":"Florian Perner, Heike L. Pahl, Robert Zeiser, Florian H. Heidel","doi":"10.1038/s41375-025-02569-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02569-8","url":null,"abstract":"<p>The JAK pathway is central to mammalian cell communication, characterized by rapid responses, receptor versatility, and fine-tuned regulation. It involves Janus kinases (JAK1, JAK2, JAK3, TYK2), which are activated when natural ligands bind to receptors, leading to autophosphorylation and activation of STAT transcription factors [1, 2]. JAK-dependent signaling plays a pivotal role in coordinating cell communication networks across a broad spectrum of biological systems including development, immune responses, cell growth, and differentiation. JAKs are frequently mutated in the aging hematopoietic system [3, 4] and in hematopoietic cancers [5]. Thus, dysregulation of the pathway results in various diseases, including cancers and immune disorders. The binding of extracellular ligands to class I and II cytokine receptors initiates a critical signaling cascade through the activation of Janus kinases (JAKs). Upon ligand engagement, JAKs become activated and phosphorylate specific tyrosine residues on the receptor, creating docking sites for signal transducer and activator of transcription (STAT) proteins. Subsequent JAK-mediated phosphorylation of STATs enables their dimerization and nuclear translocation, where they function as transcription factors to modulate gene expression. Under physiological conditions, JAK-signaling is a tightly regulated mechanism that governs cellular responses to external cues, such as cytokines and growth factors, ensuring homeostasis and maintaining the functional integrity of tissues and organs. Highly defined regulation of JAK-signaling is essential for balancing cellular responses to inflammatory stimuli and growth signals, thus safeguarding tissue health. In contrast, dysregulated JAK-signaling results in chronic inflammation and unrestrained cellular proliferation associated with various diseases. Understanding the qualitative and quantitative differences at the interface of physiologic JAK-signaling and its aberrant activation in disease is crucial for the development of targeted therapies that precisely tune this pathway to target pathologic activation patterns while leaving homeostatic processes largely unaffected. Consequently, pharmaceutical research has targeted this pathway for drug development leading to the approval of several substances with different selectivity profiles towards individual JAKs. Yet, the precise impact of inhibitor selectivity and the complex interplay of different functional modules within normal and malignant cells remains incompletely understood. In this review, we summarize the current knowledge on JAK-signaling in health and disease and highlight recent advances and future directions in the field.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"20 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713042","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":"Implementation of standard of care CAR-T-cell treatment for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia in Sweden","authors":"Mats Jerkeman, Karin Mellgren, Kristina Sonnevi, Mikael Lisak, Ingemar Lagerlöf, Balazs Kapas, Hanna Sjölund, Jacek Toporski, Hans Hagberg, Stephan Mielke, Gunilla Enblad","doi":"10.1038/s41375-025-02573-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02573-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"57 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713041","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}