Leukemia最新文献

{"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}

{"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}

{"title":"A novel approach for highly sensitive and rapid identification of HMGA2 submicroscopic deletions in myeloproliferative neoplasms","authors":"Bartalucci Niccolò, Danilo Tarantino, Alessio Enderti, Daniele Colazzo, Paola Guglielmelli, Alessandro M. Vannucchi","doi":"10.1038/s41375-025-02678-4","DOIUrl":"https://doi.org/10.1038/s41375-025-02678-4","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"32 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622217","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":"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}

{"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>^<i>S34F</i> 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>^<i>S34</i> 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}

{"title":"Rituximab, high-dose methotrexate plus orelabrutinib as induction therapy in newly diagnosed primary central nervous system lymphoma","authors":"Shi-Hua Zhao, Zun-Min Zhu, Tao Yang, Da Gao, Li-Hong Liu, Wei Yang, Xiao-Bo Wang, Yu-Xia Zhao, Meng Li, Yi-Nan Gao, Rong-Jun Ma, Ying Yang, Hui-Ping Li, Li Li, Xiao-Lei Ao, Xiu-Bin Xiao, Chong-Ling Hu, Shun-Zong Yuan, Yao Ding, Xi-Lin Chen, Jian-Xia He, Yao Liu, Wen-Rong Huang","doi":"10.1038/s41375-025-02658-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02658-8","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"6 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144612900","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":"Ontogeny-specific induction of the KMT2A::AFF1-fusion drives development of a distinct CD24 positive pre-leukemic state","authors":"Ariana S. Calderón, Roshanak Ghazanfari, Zahra Masoumi, Shabnam Kharazi, Sara Palo, Stefan Lang, Kristijonas Žemaitis, Mohamed Eldeeb, Agatheeswaran Subramaniam, Shamit Soneji, Ronald W. Stam, David Bryder, Charlotta Böiers","doi":"10.1038/s41375-025-02665-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02665-9","url":null,"abstract":"<p>Infant Acute Lymphoblastic Leukemia (ALL) driven by the <i>KMT2A::AFF1</i> onco-fusion is an aggressive, poor prognosis disease with few co-operative mutations. The fusion originates <i>in utero</i>, yet the embryonic initiating steps of disease development remain poorly understood. Here, we present a novel murine <i>KMT2A::AFF1</i> model, that provides key insights into <i>KMT2A::AFF1</i> pre-leukemia, relevant to human disease. The model enables precise oncogene induction, and upon targeting hematopoietic stem and progenitor cells (HSPCs) a selective negative impact on proliferation of hematopoietic stem cells (HSCs) was observed, regardless of developmental state during induction. However, a unique CD24⁺PreProB subset expanded exclusively within the <i>KMT2A::AFF1</i> embryonic context. This population was absent when targeting lymphoid progenitors, highlighting the importance of the cell of origin for leukemic development. The CD24⁺PreProB subset displayed key features of pre-leukemic stem cells, including lineage plasticity and aberrant engraftment ability. In line with their pre-malignant phenotype, single-cell transcriptomics revealed a signature consistent with stemness, and notable, up-regulation of <i>Hmga2</i>, a regulator of self-renewal. The signature was critically transferable to human KMT2A::AFF1 patients. Furthermore, given that CD24 is a potential therapeutic target, our findings uncover a distinct embryonic pre-leukemic state with direct relevance to human disease.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"1 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602887","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":"Interleukin-6 is a highly prognostic biomarker for POEMS syndrome","authors":"Joselle Cook, Rahma Warsame, Maryam Omar, Francis K. Buadi, Nadine Abdallah, David Dingli, Suzanne R. Hayman, Prashant Kapoor, Taxiarchis Kourelis, Moritz Binder, Eli Muchtar, Amie Fonder, Yi L. Hwa, Miriam A. Hobbs, Yi Lin, Wilson I. Gonsalves, Morie A. Gertz, Shaji K. Kumar, S. Vincent Rajkumar, Angela Dispenzieri","doi":"10.1038/s41375-025-02659-7","DOIUrl":"https://doi.org/10.1038/s41375-025-02659-7","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"22 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602886","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 genome-wide association study identifies an African-specific locus on chromosome 21q22.12 associated with Burkitt lymphoma risk and survival","authors":"Diptavo Dutta, Mateus H. Gouveia, Bryan R. Gorman, Atuahene Adu-Gyamfi, Chia-Han Lee, Martin D. Ogwang, Patrick Kerchan, Steven J. Reynolds, Constance N. Tenge, Pamela A. Were, Walter N. Wekesa, Robert K. Tenge, Nestory Masalu, Esther L. Kawira, Tobias Kinyera, Isaac Otim, Hadijah Nabalende, Herry Dhudha, Bosco Candia, Janet Abaru, Wusheng Yan, Oscar Florez-Vargas, Yi Xie, Michelle Ho, Leona W. Ayers, Kishor Bhatia, James J. Goedert, Ruth M. Pfeiffer, Michelle Manning, Amy Hutchinson, Nathan Cole, Wen Luo, Belynda Hicks, George Chagaluka, W. Thomas Johnston, Nora Mutalima, Eric Borgstein, George N. Liomba, Steven Kamiza, Nyengo Mkandawire, Elizabeth M. Molyneux, Collins Mitambo, Robert Newton, Reiner Siebert, Michael Dean, Meredith Yeager, Stephen J. Chanock, Ludmila Prokunina-Olsson, Sam M. Mbulaiteye","doi":"10.1038/s41375-025-02690-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02690-8","url":null,"abstract":"<p>Burkitt lymphoma (BL) is a B-cell malignancy that disproportionately affects children in sub-Saharan Africa. We performed a genome-wide association study (GWAS) in a combined set of 800 childhood cases and 3865 controls in East Africa, controlling for age, sex, country, population-specific principal components, and a genetic relationship matrix. This analysis identified a BL-protective region within chromosome 21q22.12 tagged by the rs111457485-T allele (odds ratio [OR] = 0.57; <i>p</i> = 5.7 × 10⁻⁹). The results were robust in standard meta-analysis (OR = 0.57, <i>p</i> &lt; 1.6 × 10⁻⁸), sensitivity analyses (removing genomic outliers and related individuals), and after adjustment for Epstein-Barr virus (EBV) status. Genomic analyses revealed long-range (over ~700 kb) chromatin interactions between the chr21q22.12 locus and the <i>RUNX1</i>-P1 promoter region. The African-specific rs2242780-C allele (<i>r</i>^<i>2</i> = 0.69 with the rs111457485-T allele in the study controls) showed increased enhancer activity in in-vitro Luciferase reporter assays (<i>p</i> = 4.5 × 10⁻¹⁰), nominating it as the likely functional variant for the BL-associated loci. In addition to the association with reduced BL risk in GWAS (OR = 0.62, <i>p</i> = 2.24 × 10⁻⁸), the rs2242780-C allele was also associated with better survival in patients with abdominal-only BL in exploratory analyses (hazard ratio = 0.39, <i>p</i> = 0.038, 106 patients, 59 deaths). Our GWAS uncovered novel BL-protective loci near <i>RUNX1</i>, offering insights into the genetic etiology of BL in African children.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"1 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602889","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}