Leukemia最新文献

{"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":"https://doi.org/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}

{"title":"Overt and covert genetic causes of pediatric acute lymphoblastic leukemia","authors":"Ulrik Stoltze, Stefanie V. Junk, Anna Byrjalsen, Hélène Cavé, Giovanni Cazzaniga, Sarah Elitzur, Eva Fronkova, Lisa Lyngsie Hjalgrim, Roland P. Kuiper, Louise Lundgren, Melina Mescher, Theis Mikkelsen, Agata Pastorczak, Marion Strullu, Jan Trka, Karin Wadt, Shai Izraeli, Arndt Borkhardt, Kjeld Schmiegelow","doi":"10.1038/s41375-025-02535-4","DOIUrl":"https://doi.org/10.1038/s41375-025-02535-4","url":null,"abstract":"<p>Pediatric acute lymphoblastic leukemia (pALL) is the most common childhood malignancy, yet its etiology remains incompletely understood. However, over the course of three waves of germline genetic research, several non-environmental causes have been identified. Beginning with trisomy 21, seven overt cancer predisposition syndromes (CPSs)—characterized by broad clinical phenotypes that include an elevated risk of pALL—were first described. More recently, newly described CPSs conferring high risk of pALL are increasingly covert, with six exhibiting only minimal or no non-cancer features. These 13 CPSs now represent the principal known hereditary causes of pALL, and human pangenomic data indicates a strong negative selection against mutations in the genes associated with these conditions. Collectively they affect approximately 1 in 450 newborns, of which just a minority will develop the disease. As evidenced by tailored leukemia care protocols for children with trisomy 21, there is growing recognition that CPSs warrant specialized diagnostic, therapeutic, and long-term management strategies. In this review, we investigate the evidence that the 12 other CPSs associated with high risk of pALL may also see benefits from specialized care — even if these needs are often incompletely mapped or addressed in the clinic. Given the rarity of each syndrome, collaborative international research and shared data initiatives will be crucial for advancing knowledge and improving outcomes for these patients.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"183 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677913","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":"Real-time genomic characterization of pediatric acute leukemia using adaptive sampling","authors":"Julie Geyer, Kofi B. Opoku, John Lin, Lori Ramkissoon, Charles Mullighan, Nickhill Bhakta, Thomas B. Alexander, Jeremy R. Wang","doi":"10.1038/s41375-025-02565-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02565-y","url":null,"abstract":"<p>Effective treatment of pediatric acute leukemia is dependent on accurate genomic classification, typically derived from a combination of multiple time-consuming and costly techniques such as flow cytometry, fluorescence in situ hybridization (FISH), karyotype analysis, targeted PCR, and microarrays [1,2,3]. We investigated the feasibility of a comprehensive single-assay classification approach using long-read sequencing, with real-time genome target enrichment, to classify chromosomal abnormalities and structural variants characteristic of acute leukemia. We performed whole genome sequencing on DNA from diagnostic peripheral blood or bone marrow for 57 pediatric acute leukemia cases with diverse genomic subtypes. We demonstrated the characterization of known, clinically relevant karyotype abnormalities and structural variants concordant with standard-of-care clinical testing. Subtype-defining genomic alterations were identified in all cases following a maximum of 48 h of sequencing. In 18 cases, we performed real-time analysis— concurrent with sequencing—and identified the driving alteration in as little as 15 min (for karyotype) or up to 6 h (for complex structural variants). Whole genome nanopore sequencing with adaptive sampling has the potential to provide genomic classification of acute leukemia specimens with reduced cost and turnaround time compared to the current standard of care.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"20 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677911","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":"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/s41375-025-02567-w","DOIUrl":"10.1038/s41375-025-02567-w","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700889","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":"Preclinical characterization of the anti-leukemia activity of the CD123 antibody-drug conjugate, pivekimab sunirine (IMGN632)","authors":"Frances M. Cole, George S. Laszlo, Margaret C. Lunn-Halbert, Allie R. Kehret, Patrick A. Zweidler-McKay, Eduardo Rodríguez-Arbolí, David Wu, Kyle Nyberg, Junyang Li, Sheryl Y. T. Lim, Camryn M. Pettenger-Willey, Sribalaji Lakshmikanthan, Roland B. Walter","doi":"10.1038/s41375-025-02571-0","DOIUrl":"https://doi.org/10.1038/s41375-025-02571-0","url":null,"abstract":"<p>Acute myeloid leukemia (AML) remains difficult to cure [1, 2]. Antibody-based drugs have long been pursued to improve these outcomes. While early efforts focused on CD33, there is increasing interest in CD123 as a drug target [3]. Expressed on only a relatively small subset of normal hematopoietic cells, CD123 is displayed on blast cells of 45–95% of AML patients. What makes CD123 particularly attractive is its overexpression on leukemic stem/progenitor cells relative to normal hematopoietic stem/progenitor cells [3].</p><p>One CD123-targeted drug under development is pivekimab sunirine (PVEK; formerly IMGN632), an antibody-drug conjugate consisting of a humanized CD123 antibody with engineered cysteines in the CH3 domain to enable site-specific attachment of an alkylating monoamine indolinobenzodiazepine pseudodimer (IGN) via protease cleavable peptide linker [4]. After demonstration of potent preclinical anti-leukemia activity, PVEK entered early phase testing as monotherapy and in combination with azacitidine and venetoclax, with emerging data indicating significant activity in adults with AML [5,6,7]. So far, critical characteristics for PVEK’s anti-leukemia activity have not been explored in detail. Herein, we therefore examined potential variables that might modulate the in vitro cytotoxic effects of PVEK and sFGN849, the catabolite of PVEK’s payload (both provided by ImmunoGen; Waltham, MA, USA), against human AML cells, using genetically and functionally well-defined cell line models (see Supplementary Data for detailed Materials and Methods).</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"46 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143666004","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}