LeukemiaPub Date : 2025-07-16DOI: 10.1038/s41375-025-02707-2
Jennifer H. Cooperrider, Diren Arda Karaoglu, Tadeusz Kubicki, Can Rui Jiang, Ella Postich, Kathryn Shimamoto, Olivia Arnold, Jommel Macaraeg, Aubrianna Ramsland, Anna Pula, Ashwin Kishtagari, Yash Pershad, Taralynn M. Mack, Angela Jones, Alexander G. Bick, Michael Savona, Michael W. Drazer, Dominik Dytfeld, Andrzej Jakubowiak, Benjamin A. Derman, Caner Saygin
{"title":"Evolution of clonal hematopoiesis on and off lenalidomide maintenance for multiple myeloma","authors":"Jennifer H. Cooperrider, Diren Arda Karaoglu, Tadeusz Kubicki, Can Rui Jiang, Ella Postich, Kathryn Shimamoto, Olivia Arnold, Jommel Macaraeg, Aubrianna Ramsland, Anna Pula, Ashwin Kishtagari, Yash Pershad, Taralynn M. Mack, Angela Jones, Alexander G. Bick, Michael Savona, Michael W. Drazer, Dominik Dytfeld, Andrzej Jakubowiak, Benjamin A. Derman, Caner Saygin","doi":"10.1038/s41375-025-02707-2","DOIUrl":"https://doi.org/10.1038/s41375-025-02707-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"23 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640347","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}
LeukemiaPub Date : 2025-07-16DOI: 10.1038/s41375-025-02679-3
Tobias Rausch, Hendrik Schäfer, Julia Bein, Felix Mölder, Lilian Kara Beeck, Bernd Kölsch, Sabrina Borchert, Vladimir Benes, Teresa Halbsguth, Uta Brunnberg, Thomas Oellerich, Thomas Tousseyn, Maurilio Ponzoni, Johannes Köster, Martin-Leo Hansmann, Ralf Küppers, Sylvia Hartmann
{"title":"Genetic lesions in nodular lymphocyte-predominant Hodgkin lymphoma and T cell/histiocyte-rich large B-cell lymphoma identified by whole genome sequencing","authors":"Tobias Rausch, Hendrik Schäfer, Julia Bein, Felix Mölder, Lilian Kara Beeck, Bernd Kölsch, Sabrina Borchert, Vladimir Benes, Teresa Halbsguth, Uta Brunnberg, Thomas Oellerich, Thomas Tousseyn, Maurilio Ponzoni, Johannes Köster, Martin-Leo Hansmann, Ralf Küppers, Sylvia Hartmann","doi":"10.1038/s41375-025-02679-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02679-3","url":null,"abstract":"<p>Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare malignant lymphoma characterised by a few large tumour cells expressing B-cell antigens in an inflammatory background. T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is now considered to be closely related to NLPHL. Little is known about the mutational spectrum of the lymphoma cells in primary NLPHL and THRLBCL due to the rarity of the diseases and the technical challenges of analysing these tumours. Therefore, the aim of the present study was to elucidate mechanisms contributing to the pathogenesis of NLPHL and THRLBCL by whole genome sequencing of laser microdissected tumour cells from seven cases. We observed a heterogeneity of transforming events, with cases showing abundant somatic mutations, others with a predominance of structural variations, and cases with few aberrations. The genes that were most frequently affected by aberrations encode factors influencing JAK-STAT, NF-κB, and/or WNT signaling, and apoptosis regulators. However, the mutated genes, such as <i>SOCS3, JUNB, IRF1</i> and <i>ITPKB</i>, were not the typical targets known from classical Hodgkin lymphoma (cHL). Two cases showed recurrent rearrangements of <i>BCL6</i> and <i>CD74</i>. In conclusion, our data enrich our understanding of NLPHL and THRLBCL and highlight common and distinct features with respect to cHL.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"2 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640350","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}
LeukemiaPub Date : 2025-07-16DOI: 10.1038/s41375-025-02702-7
Kritika Yadav, Meera Mohan, Charlotte Wagner, Rajshekhar Chakraborty, Douglas Sborov, Amandeep Godara, Brian McClune, Carolina Schinke, Binod Dhakal, Anita D’Souza, Aniko Szabo, Ghulam Rehman Mohyuddin
{"title":"Patterns of relapse in patients with multiple myeloma receiving chimeric antigen receptor T cell therapy: a multi-center analysis","authors":"Kritika Yadav, Meera Mohan, Charlotte Wagner, Rajshekhar Chakraborty, Douglas Sborov, Amandeep Godara, Brian McClune, Carolina Schinke, Binod Dhakal, Anita D’Souza, Aniko Szabo, Ghulam Rehman Mohyuddin","doi":"10.1038/s41375-025-02702-7","DOIUrl":"https://doi.org/10.1038/s41375-025-02702-7","url":null,"abstract":"<p><b>To the Editor:</b></p><p>Extramedullary disease (EMD) is a risk factor for poor outcomes in multiple myeloma (MM) [1,2,3], including amongst recipients of chimeric antigen receptor T-cell therapy (CAR-T) [4, 5]. With CD-19 CAR-T, discordant responses have also been observed, with clearance of disease in the marrow and persistence of disease in extramedullary sites, highlighting how CAR-T activity may be limited in extramedullary sites [6]. While patterns of progression at relapse have been studied, no prior work has specifically examined relapse patterns in CAR-T recipients with MM [7, 8]. Most early disease progressions are biochemical, highlighting the importance of routine bloodwork [7, 8]. The percentage of biochemical relapses that precede a clinical relapse in the post-CAR-T setting remains to be determined, as does the frequency of relapses with EMD or end-organ damage despite extensive surveillance.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"10 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640346","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}
LeukemiaPub Date : 2025-07-16DOI: 10.1038/s41375-025-02695-3
Eric J. Vick, Aishlin Hassan, Kwangmin Choi, Joshua Bennett, Tomoya Muto, Courtnee A. Clough, Ashley E. Culver-Cochran, Kathleen Hueneman, Lyndsey C. Bolanos, Mark Wunderlich, Xiaohu Zhang, Crystal McKnight, Michele Ceribelli, David Holland, Carleen Klumpp-Thomas, Kenneth D. Greis, Craig J. Thomas, Daniel T. Starczynowski
{"title":"Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization","authors":"Eric J. Vick, Aishlin Hassan, Kwangmin Choi, Joshua Bennett, Tomoya Muto, Courtnee A. Clough, Ashley E. Culver-Cochran, Kathleen Hueneman, Lyndsey C. Bolanos, Mark Wunderlich, Xiaohu Zhang, Crystal McKnight, Michele Ceribelli, David Holland, Carleen Klumpp-Thomas, Kenneth D. Greis, Craig J. Thomas, Daniel T. Starczynowski","doi":"10.1038/s41375-025-02695-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02695-3","url":null,"abstract":"<p>IRAK4 is a therapeutic target in myeloid malignancies, but current IRAK4 inhibitors show only modest clinical efficacy in acute myeloid leukemia, highlighting the need for combination strategies. To identify drugs with synergistic potential alongside IRAK4 inhibitors, we conducted a high-throughput screen of 2803 investigational and approved drugs in isogenic IRAK4-deficient and wild-type human AML cells. The top hit from this screen was the Cereblon E3 ligase modulator (CELMoD) CC-885. Validation in vitro and in vivo confirmed that CC-885 and related CELMoDs synergize with IRAK4 inhibitors to suppress leukemic cells. Among CC-885 substrates, GSPT1 loss showed the most pronounced effects in IRAK4-inhibited leukemic cells. Transcriptional and proteomic analyses revealed that CC-885 treatment led to c-Myc suppression in IRAK4-deficient leukemic cells. GSPT1 loss reduces translation efficiency, particularly for proteins with short half-lives, such as c-Myc. Accelerated c-Myc protein loss was confirmed following GSPT1 degradation in leukemic cells, with decreased protein stability observed following inhibition of IRAK4. These effects were validated in AML patient cells, supporting the potential of IRAK4 inhibitors to modulate c-Myc activity and enhance combinatorial therapies. This study demonstrates that IRAK4 is a therapeutic target in AML, and that combination therapies, such as with certain GSPT1-targeting CELMoDs, will be necessary to achieve maximal clinical responses.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"666 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640351","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}
LeukemiaPub Date : 2025-07-15DOI: 10.1038/s41375-025-02704-5
Gaurav Goyal, Aldo A. Acosta-Medina, Ronald S. Go, Jithma P. Abeykoon
{"title":"Molecular profiling is critical to guide MEK inhibitor use in Erdheim-Chester disease","authors":"Gaurav Goyal, Aldo A. Acosta-Medina, Ronald S. Go, Jithma P. Abeykoon","doi":"10.1038/s41375-025-02704-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02704-5","url":null,"abstract":"<p>We appreciate the interest of Pegoraro et al. [1] in our study evaluating the impact of MAPK-ERK pathway alterations on the efficacy of MEK inhibitor (MEKi) therapy in Erdheim-Chester Disease (ECD) [2]. Their real-world cohort provides valuable additional data regarding MEKi efficacy in a broader patient population. However, we highlight several key distinctions between their findings and ours.</p><p>Firstly, the “wild-type” (WT) cohort reported by Pegoraro et al. [1] does not appear to include patients harboring pathogenic variants outside of the MAPK-ERK pathway, such as <i>CSF1R</i> mutations or resistant <i>BRAF</i> and <i>MEK</i> mutations, which are known drivers of ECD [2,3,4]. In contrast, in our study all patients who did not respond to MEKi harbored either non-MAPK-ERK mutations or a class II <i>BRAF</i> variant. Importantly, these patients subsequently achieved responses to alteration-specific targeted therapies (e.g., pexidartinib for <i>CSF1R</i> mutations). Thus, the presence of alternative oncogenic drivers—rather than the absence of a MAPK-ERK variant—appeared to underlie resistance to MEKi. The Franco-Italian WT subcohort lacks detailed information regarding the sensitivity and depth of the next-generation sequencing (NGS) panels employed. Moreover, their study reports a 20% rate of MAPK-ERK wild-type cases—considerably higher than that reported in other contemporary ECD cohorts [5, 6]—possibly signaling a failure to detect, rather than a true absence of low burden pathogenic MAPK-ERK pathway mutations or a selection bias toward patients with negative NGS who were treated with a MEKi. Crucially, the authors do not report any cases of patients with known non-MAPK-ERK driver alterations who responded to a MEKi. As such, without detailed molecular profiling, it is challenging to definitively conclude that MEKi efficacy is independent of MAPK-ERK pathway mutations.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"109 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629673","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}
LeukemiaPub Date : 2025-07-14DOI: 10.1038/s41375-025-02680-w
Simge Kelekçi, Katherine Kelly, Ashish Goyal, Nick Wehrwein, Anna Riedel, Dieter Weichenhan, Michael Scherer, Birgitta E. Michels, Cindy Körner, Irene Orzella, Mariam Hakobyan, Marion Bähr, Elena Everatt, James Dunford, Daniel B. Lipka, Pavlo Lutsik, Udo Oppermann, Christoph Plass
{"title":"DNA demethylation-mediated downregulation of MNX1 in acute myeloid leukemia","authors":"Simge Kelekçi, Katherine Kelly, Ashish Goyal, Nick Wehrwein, Anna Riedel, Dieter Weichenhan, Michael Scherer, Birgitta E. Michels, Cindy Körner, Irene Orzella, Mariam Hakobyan, Marion Bähr, Elena Everatt, James Dunford, Daniel B. Lipka, Pavlo Lutsik, Udo Oppermann, Christoph Plass","doi":"10.1038/s41375-025-02680-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02680-w","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"14 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622353","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}
LeukemiaPub Date : 2025-07-14DOI: 10.1038/s41375-025-02701-8
Saurabh Zanwar,S Vincent Rajkumar
{"title":"Solitary but not simple─a call for precision risk stratification and individualized treatment in solitary plasmacytoma.","authors":"Saurabh Zanwar,S Vincent Rajkumar","doi":"10.1038/s41375-025-02701-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02701-8","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"52 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144630350","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}
LeukemiaPub Date : 2025-07-14DOI: 10.1038/s41375-025-02672-w
Yeqian Zhao, Weijie Cao, Jimin Shi, Yang Cao, Ying Lu, Yi Luo, Guifang Ouyang, Lieguang Chen, Jianping Lan, Xiaolu Song, Yi Chen, Li Yu, Jian Yu, Xiaoyu Lai, Lizhen Liu, Huarui Fu, Yishan Ye, Luxin Yang, Xiaodong Mo, Xiaoxia Hu, He Huang, Yanmin Zhao
{"title":"Impact of TP53 variants and germline mutations on allogeneic stem cell transplantation outcomes in acute myeloid leukemia and myelodysplastic neoplasms","authors":"Yeqian Zhao, Weijie Cao, Jimin Shi, Yang Cao, Ying Lu, Yi Luo, Guifang Ouyang, Lieguang Chen, Jianping Lan, Xiaolu Song, Yi Chen, Li Yu, Jian Yu, Xiaoyu Lai, Lizhen Liu, Huarui Fu, Yishan Ye, Luxin Yang, Xiaodong Mo, Xiaoxia Hu, He Huang, Yanmin Zhao","doi":"10.1038/s41375-025-02672-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02672-w","url":null,"abstract":"<p><i>TP53</i>-mutated myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) are typically characterized by complex cytogenetic abnormalities and resistance to intensive chemotherapy [1, 2]. Allogeneic stem cell transplantation (allo-HSCT) remains the only curative option, yet the outcomes of germline versus somatic <i>TP53</i>-mutated AML/MDS under allo-HSCT remain poorly explored. Moreover, the prognostic impact of <i>TP53</i> mutations (<i>TP53mut</i>) across different domains is not well characterized. Additionally, the effects of missense versus truncating mutations [3, 4] and the prognostic significance of multi-hit <i>TP53</i> status in AML/MDS remain controversial [5, 6]. Given the clinical and biological heterogeneity of <i>TP53</i> mutations, this multi-center retrospective study aims to delineate the differences between germline and somatic <i>TP53mut</i> to refine disease trajectories and optimize transplant strategies.</p><p>Somatic mutations were identified by next-generation sequencing, while germline <i>TP53</i> variants were confirmed using oral mucosa testing. Germline <i>TP53mut</i> carriers received allo-HSCT from related donors negative for the corresponding variant. Pre-transplant MRD was assessed by multiparameter flow cytometry (MFC) on bone marrow, with MRD positivity defined as ≥0.01% leukemic-associated immunophenotypes.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"14 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622216","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":"Aberrant splicing of CHEK1 is a driver of megakaryocytic dysplasia in U2AF1S34F mutant myelodysplastic neoplasms","authors":"Wenjun Zhang, Bing Li, Jinqin Liu, Yiru Yan, Lin Yang, Tiejun Qin, Zefeng Xu, Qi Sun, Yujiao Jia, Huijun Wang, Gang Huang, Hongtao Wang, Lihong Shi, Jiaxi Zhou, Zhijian Xiao","doi":"10.1038/s41375-025-02684-6","DOIUrl":"https://doi.org/10.1038/s41375-025-02684-6","url":null,"abstract":"<p><i>U2AF1</i> mutations are common in patients with myelodysplastic neoplasms (MDS), suggesting that aberrant splicing of pre-mRNAs driven by mutant U2AF1 could play a critical role in MDS pathogenesis. Previous studies have demonstrated that <i>U2AF1</i><sup><i>S34F</i></sup> mutation impairs the differentiation of erythrocytes and granulocytes, but the impact on megakaryocytes (MKs) remains unclear. Here, by integrating data from MDS patients and cell lines with <i>U2AF1</i> mutations, we determined that <i>U2AF1</i> mutations are associated with dysmegakaryopoiesis, induce the generation of abnormal MKs, especially micro-MKs, and induce significant thrombocytopenia. We determined that mutant U2AF1-mediated aberrant splicing of DNA biosynthesis-related genes, such as <i>CHEK1</i>, is required for normal MK polyploidization. The mis-splicing of <i>CHEK1</i>, in turn, accounts for the increased number of abnormal MKs in U2AF1-mutant MDS patients. Moreover, <i>U2AF1</i><sup><i>S34</i></sup> mutations induce the deficiency of CHK1 and the activation of its phosphorylation, thereby further driving the impairment of MK polyploidization and maturation. Accordingly, treatment with selective CHK1 inhibitor significantly reduces abnormal MK production in vitro. Taken together, these findings demonstrate that <i>U2AF1</i> mutations induce the generation of abnormal MKs by driving aberrant splicing of the <i>CHEK1</i> cell cycle-related gene, revealing the molecular basis for dysmegakaryopoiesis in MDS and identifying a new potential target for MDS treatment.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"26 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611114","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}
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