Experimental Hematology & Oncology最新文献

{"title":"Multimodal AI and single-cell transcriptomics integrate to construct a histopathological prognostic model for bladder cancer, revealing the RTN3-glycolysis axis in chemoresistance.","authors":"Shunli Yu, Yingjian Wang, Dapeng Feng, Xinglai Dai, Yongbo Luo, Jianing Wang, Zihe Wang, Fuxiang Chen, Haoran Wang, Fengyan Tian, Xuejia Zhai, Chaohui Gu","doi":"10.1186/s40164-026-00825-w","DOIUrl":"10.1186/s40164-026-00825-w","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer is a common malignant tumor of the urinary system, and gemcitabine-based chemotherapy often fails because of drug resistance. Tumor heterogeneity, particularly copy number variations (CNVs) heterogeneity at the genomic level, is a core factor that drives disease progression and drug resistance. However, the relationship between CNV heterogeneity at the single-cell level and the histomorphological features that are relied upon in a routine pathological diagnosis remains unclear, limiting its application in clinical prognostic assessments and precision therapy.</p><p><strong>Methods: </strong>This study integrated six public single-cell RNA sequencing (scRNA-seq) datasets as discovery cohorts to systematically analyze the cellular landscape of bladder cancer. The inferCNV algorithm was used to infer CNVs at the single-cell level and identify subpopulations with high CNV (HCNV). A multimodal artificial intelligence (AI) strategy combining deep learning and image analysis was employed to construct a prognostic model based on routine H&E-stained pathological sections, with HCNV activity serving as a biological anchor for pathology feature selection. Hub genes were screened using multiomics data, and in vitro and in vivo functional experiments using bladder cancer cell lines were conducted to validate the functions and mechanisms of these hub genes.</p><p><strong>Results: </strong>The single-cell analysis revealed that HCNV cells constitute a malignant subpopulation with a unique molecular phenotype characterized by widespread activation of oncogenic pathways (such as TGF-β, JAK-STAT and PI3K), active communication with the tumor microenvironment (e.g., cancer-associated fibroblasts and M2 macrophages), and a poor prognosis for patients. The multimodal AI-based pathological imaging model effectively predicted patient survival. The model-derived risk score showed a significant but modest correlation with transcriptomic HCNV activity. Through multi-algorithm feature selection, we identified RTN3 as the core gene driving the HCNV phenotype. Our study confirms that RTN3 not only orchestrates an immunosuppressive microenvironment but also directly mediates resistance to gemcitabine. Mechanistically, RTN3 activates the JAK2/STAT3 signaling pathway, which transcriptionally upregulates key glycolytic enzymes (PKM2, GLUT1, and LDHA), thereby driving glycolytic metabolic reprogramming and ultimately conferring gemcitabine resistance in bladder tumors.</p><p><strong>Conclusions: </strong>This study reveals a malignant cell subtype defined by HCNV in bladder cancer at the single-cell level and elucidates the molecular and microenvironmental basis of the poor prognosis of bladder cancer. A clinically translatable multimodal AI pathological prediction model was successfully developed. Furthermore, our findings establish the RTN3/JAK2/STAT3/glycolysis axis as a critical mechanism of gemcitabine resistance, highlighting R","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976418","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}

{"title":"Tumor-intrinsic NSUN2 orchestrates immunosuppression in lung adenocarcinoma via the m⁵C-HDAC8-CCL5 axis.","authors":"Wangyang Meng, Tong Lu, Mingyuan Du, Xin Dai, Yichao Han, Yingyi Li, Haimin Xu, Biaolong Yang, Zeyu Wang, Hailei Du, Keman Liao, Xinnan Liu, Yidan Sun, Cui Yang, Dong Dong, Yan Yan, Wei Guo, Bin Li, Hecheng Li","doi":"10.1186/s40164-026-00826-9","DOIUrl":"10.1186/s40164-026-00826-9","url":null,"abstract":"<p><strong>Background: </strong>Insufficient T-cell infiltration is a major barrier to the efficacy of immune checkpoint inhibitors (ICIs) in lung adenocarcinoma (LUAD). We aimed to investigate how the tumor-intrinsic m⁵C methyltransferase NSUN2 shapes the immune landscape of LUAD.</p><p><strong>Methods: </strong>Nsun2 conditional knockout mice and syngeneic mice models were employed. Single-cell RNA sequencing (scRNA-seq) and m⁵C sequencing were performed to elucidate the downstream pathway regulated by NSUN2. LUAD specimens from patients receiving neoadjuvant immunotherapy were used to assess the correlation between NSUN2 expression and immune infiltration.</p><p><strong>Results: </strong>Elevated tumoral NSUN2 expression was correlated with a marked lack of CD8⁺ T-cell infiltration and immunotherapy resistance. Mechanistically, NSUN2 enhances the translation of histone deacetylase HDAC8 in an m⁵C-YBX1-dependent manner, which in turn directly represses the transcription of the chemoattractant CCL5, thereby impairing CD8⁺ T-cell recruitment into the tumor. NSUN2 depletion reversed this immunosuppressive axis and converted immunologically \"cold\" tumors into \"hot\". Tumor-targeted liposomes loaded with the NSUN2 inhibitor synergized with anti-PD-1 therapy to induce significant tumor regression.</p><p><strong>Conclusions: </strong>Our findings identify NSUN2 as a critical orchestrator of T-cell exclusion in LUAD. It serves as both a candidate predictive biomarker for ICI failure and a promising druggable target. Targeting NSUN2 offers a potential strategy to overcome immunotherapy resistance and improve clinical outcomes in LUAD patients.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905517","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}

{"title":"CD84 expression stratifies venetoclax response and reveals a targetable vulnerability in resistant acute myeloid leukemia.","authors":"Xuemei Wang, Xiangjie Lin, Tianyi Chen, Yi Chen, Huafeng Wang, Yinghui Zhu","doi":"10.1186/s40164-026-00830-z","DOIUrl":"10.1186/s40164-026-00830-z","url":null,"abstract":"<p><p>Venetoclax-based regimens have become increasingly integrated into the therapeutic landscape of acute myeloid leukemia (AML), yet primary resistance and relapses remain major barriers to durable benefits. Building on our previous discovery of CD84 as a critical survivor and redox regulator in AML, we here demonstrate that CD84 expression contributes to venetoclax sensitivity. Low CD84 expression is associated with favorable clinical response, whereas high CD84 expression correlates with primary resistance and is up-regulated at relapse in two of three paired samples. Functional perturbation of CD84 through genetic knockdown or CD84-targeted CAR-T cells sensitized AML cells to venetoclax in vitro and in vivo cell-derived xenograft models. Mechanistically, CD84 coordinates a pro-survival program with upregulating the antioxidant stress sensor SESN2, which suppresses mitochondrial reactive oxygen species and antagonizes venetoclax-induced apoptosis. SESN2 knockdown phenocopied CD84 depletion, while SESN2 overexpression partially restored venetoclax resistance in CD84-deficient cells. Our findings suggest that CD84-mediated upregulation of SESN2 contributes to venetoclax resistance and may represent a potential therapeutic target to enhance treatment efficacy in AML.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905554","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}

{"title":"Chimeric antigen receptor (CAR)-T cell therapy for solid tumors in pediatric patients: current breakthroughs, dilemmas, and strategies.","authors":"Yumiao Mai, Ziwen Wang, Juan Wang, Mengjia Song, Tong Xiang, Yuelin He, Alex H Chang, Yizhuo Zhang","doi":"10.1186/s40164-026-00822-z","DOIUrl":"10.1186/s40164-026-00822-z","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy has demonstrated substantial clinical efficacy in pediatric hematologic malignancies; however, its application in pediatric solid tumors remains investigational and is constrained by substantial biological and clinical challenges. Key barriers comprise tumor heterogeneity, antigen escape, T-cell exhaustion, physical barriers and immunosuppressive tumor microenvironment, treatment-related toxicities, and pediatric-specific considerations, including optimal dosing and potential long-term developmental sequelae. Ongoing research focuses on identifying novel target antigens, optimizing CAR architectures, genetically engineering CAR-T cells, and improving delivery strategies to address these barriers. In this review, we summarize recent advances, persistent challenges, and emerging strategies for CAR-T cell therapy in pediatric solid tumors. We also discuss rational combination strategies involving CAR-T cell therapy with chemotherapy, radiotherapy, and immune checkpoint inhibitors aimed at improving therapeutic efficacy and safety. As the field continues to evolve, advances in CAR-T cell therapy may expand therapeutic options for pediatric solid tumors, although further clinical investigation is required to establish its long-term efficacy and safety.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896931","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}

{"title":"Clinical outcomes and molecular features of CEBPA-mutated MPAL: a multi-center case series.","authors":"Yirong Wu, Weijie Luo, Na An, Xiaohan Zhang, Jianyun Li, Yixuan Cao, Yunxin Zeng, Peng Ke, Lu Liu, Linlin Yang, Changru Luo, Shiyu Chen, Sitian Yang, Haoyu Peng, Xiaoqing Li, Jingchao Fan, Rujiao Dong, Bingbing Wen, Xin Du, Lixin Wang, Guangyang Weng","doi":"10.1186/s40164-026-00823-y","DOIUrl":"10.1186/s40164-026-00823-y","url":null,"abstract":"<p><p>Mixed phenotype acute leukemia (MPAL) is rare and aggressive, with no standard therapy. CEBPA mutations define favorable-risk AML, but their significance in MPAL is unknown. We reviewed eight CEBPA-mutated MPAL patients from five Chinese centers. Four received allo-HSCT in first complete remission and all remained alive and relapse-free (median follow-up of 24.0 months). Among four non-transplanted patients, three died (one refractory, two relapsed). Molecularly, four had biallelic inactivation and six had bZIP mutations. The high mortality among non-transplanted patients may suggest an aggressive nature of CEBPA-mutated MPAL, even in those with bZIP mutations, unlike its favorable-risk status in AML. Given the small sample and biases, no conclusions regarding optimal post-remission therapy can be drawn, though intensive strategies including transplantation may be considered based on this aggressiveness.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879614","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}

{"title":"Single-cell mapping of thymus-dependent naïve t-cell regeneration reveals CD61-associated states after hematopoietic stem cell transplantation.","authors":"Fangqing Zhang, Xinya Jiang, Shuang Fan, Bixia Wang, Zhigui Wu, Jingrui Zhou, Qi Zhang, Zhiyu Zhang, Jianing Tang, Zheng-Li Xu, Yu Wang, Xiao-Jun Huang, Huidong Guo","doi":"10.1186/s40164-026-00824-x","DOIUrl":"10.1186/s40164-026-00824-x","url":null,"abstract":"<p><p>Thymus-dependent de novo T-cell generation is essential for maintaining T-cell diversity and immune competence. Although thymic involution after puberty reduces thymic output, residual thymic function remains important for immune surveillance and immune reconstitution following hematopoietic stem cell transplantation (HSCT). However, the cellular features that distinguish thymus-derived naïve T cells from those maintained through peripheral homeostatic expansion remain poorly understood. Here, we employed a congenic GFP-labeled mouse transplantation model combined with longitudinal single-cell transcriptomic and T-cell receptor repertoire analyses to define the origin and dynamics of naïve T-cell regeneration after HSCT. By distinguishing thymus-derived de novo generated T cells from peripherally expanded T cells, we found that recent thymic emigrants and both CD4⁺ and CD8⁺ naïve T cells preferentially reconstitute through a thymus-dependent pathway. We further identified distinct naïve T-cell states enriched within the thymus-derived compartment, including CD61-associated and Ly6C-associated naïve T-cell states. These populations displayed dynamic changes during immune reconstitution and were associated with thymic functional status in transplantation and physiological thymic involution mouse models. In human datasets and primary peripheral blood samples, CD61-associated features correlated with age-related thymic activity, sjTREC levels, and preliminary measures of thymic recovery after allogeneic HSCT. Collectively, our study defines cellular features of thymus-dependent naïve T-cell regeneration after HSCT and identifies CD61-associated naïve T-cell states as candidate peripheral features linked to thymic recovery. These findings provide new insights into thymus-dependent immune reconstitution and establish a framework for evaluating peripheral signatures of thymic regeneration after HSCT.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879617","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}

{"title":"Spatial multi omic profiling maps hypoxia-driven pro-fibrotic SPP1⁺ macrophages underpinning immune escape and TACE resistance in hepatocellular carcinoma.","authors":"Fansen Ji, Hao Chen, Boyang Wu, Ying Xiao, Jiawei Zhang, Jianghui Yang, Weihua Yan, Xiaojuan Wang, Bingjun Tang, Huan Li, Siyu Wu, Quan He, Hao Liu, Haoming Xia, Xinquan Liu, Yibo Gao, Pengfei Wang, Shizhong Yang, Jiahong Dong","doi":"10.1186/s40164-026-00820-1","DOIUrl":"10.1186/s40164-026-00820-1","url":null,"abstract":"<p><strong>Background: </strong>To elucidate the cellular and molecular mechanisms underlying therapeutic resistance (refractoriness) following transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) by comprehensively characterizing the post-treatment tumor microenvironment (TME).</p><p><strong>Methods: </strong>We employed an integrative spatial multi-omics strategy, combining bulk and single-cell RNA sequencing, subcellular-resolution spatial transcriptomics, and spatial proteomics on tissues from TACE-treated and treatment-naïve HCC patients. Public datasets were used for prognostic and predictive validation, and key findings were confirmed with multiplex immunofluorescence and in vitro experiments.</p><p><strong>Results: </strong>TACE induced a profoundly hypoxic TME, which drove the selective enrichment of a pro-fibrotic tumor-associated macrophage (TAM) population characterized by high SPP1 expression (SPP1 + TAMs). Spatial mapping demonstrated that these SPP1 + TAMs localize to hypoxic tumor cores, where they remodel the extracellular matrix by producing fibronectin (FN1), establish fibrotic niches, and restrict T-cell activation, thereby orchestrating an immune-excluded microenvironment. The abundance of this macrophage subtype was a robust predictor of TACE resistance.</p><p><strong>Conclusions: </strong>TACE-induced hypoxia promotes a macrophage-driven fibrotic program that is a key determinant of immune evasion and treatment failure in HCC. Targeting this SPP1 + TAM-mediated fibrotic niche presents a potential therapeutic strategy to overcome TACE resistance and improve clinical outcomes.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849849","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}

{"title":"Novel agents and evolving strategies in Waldenström macroglobulinemia: clinical trial updates from ASH 2025.","authors":"Yujing Liang, Xinyi Deng, Ziwen Wang, Chuanmiao Xie, Lie Zheng, He Huang, Shaohan Yin, Huageng Huang","doi":"10.1186/s40164-026-00821-0","DOIUrl":"10.1186/s40164-026-00821-0","url":null,"abstract":"<p><p>Waldenström macroglobulinemia (WM) is a rare, indolent lymphoplasmacytic lymphoma characterized by bone marrow infiltration of IgM-secreting lymphoplasmacytic cells and associated with the MYD88(L265P) mutation in over 90% of cases. This mutation drives constitutive NF-κB signaling through aberrant MYD88 oligomerization, rendering WM dependent on BCR-proximal kinases including BTK for survival. Despite significant therapeutic advances over the past decade, including the established efficacy of BTK inhibitors, proteasome inhibitors, and anti-CD20 monoclonal antibodies in both frontline and relapsed settings, unmet needs persist-particularly regarding treatment durability, acquired resistance to covalent BTK inhibitors via C481S mutations, and the need for chemotherapy-free alternatives. The 2025 American Society of Hematology (ASH) Annual Meeting featured several pivotal clinical trials addressing these challenges, spanning optimized immunochemotherapy combinations in treatment-naive disease, next-generation BTK-targeted agents for relapsed/refractory cases including non-covalent inhibitors that bypass C481S-mediated resistance and protein degraders that eliminate both BTK kinase activity and scaffolding function, and emerging modalities including BCL2 inhibitors that exploit the apoptotic dependence of WM cells on BCL2 family proteins, MALT1 inhibitors that target downstream NF-κB signaling, and CD19-targeted antibody-drug conjugates and cellular therapies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849854","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}

{"title":"Unraveling the role of glutamine metabolism in cancer: from cell death mechanisms to tumor microenvironment modulation.","authors":"Xintong Peng, Shuang Liu, Yongguang Tao","doi":"10.1186/s40164-026-00812-1","DOIUrl":"10.1186/s40164-026-00812-1","url":null,"abstract":"<p><p>Glutamine, the most abundant amino acid in human serum, serves not only as a key nutrient for maintaining normal cellular biological functions but also as an essential metabolic substrate for the proliferation and survival of tumor cells. Tumor cells exhibit a pronounced characteristic of \"glutamine addiction\" through metabolic reprogramming. This trait endows tumor cells with the dual capacity to exhibit both adaptability and vulnerability when confronted with regulated cell death (RCD) under metabolic stress, thereby opening up potential avenues for cancer therapy. This paper systematically reviews the biological functions of glutamine metabolism, delves into its relationships with various types of regulated cell death, elucidates its role in immune microenvironment, and summarizes the current application progress of anti-tumor drugs targeting glutamine metabolism.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817988","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}

{"title":"Subtype-specific outcome after allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis: a registry study of the European competence network on mastocytosis.","authors":"Stefan Haug, Wolfgang R Sperr, Claudia Wehr, Federico Bonofiglio, Saskia K Klein, Hanneke C Kluin-Nelemans, André B Mulder, Olivier Hermine, Julien Rossignol, Felipe Suarez, Ambroise Marcais, William Shomali, Cecelia Perkins, Deborah Christen, Werner Rabitsch, Emir Hadzijusufovic, Jaroslava Voglová, Madlen Jentzsch, Juliana Schwaab, Johannes Lübke, Mattias Mattsson, Hans Hagglund, Ingunn Dybedal, Daniel Baffoe, Patrizia Bonnadonna, Massimiliano Bonifacio, Ilaria Tanasi, Mariarita Sciumè, Marek Niedoszytko, Aleksandar Gorska, Andrzej Mital, Massimo Triggiani, Roberta Parente, Akif Selim Yavuz, Chiara Elena, Luca Malcovati, Jacqueline Ferrari, Friederike Wortmann, Knut Brockow, Tobias Michael Franz, Michael Makris, Sotirios G Papageorgiou, Christine Breynaert, Toon Ieven, Irena Angelova-Fischer, Alex Stefan, Judit Várkonyi, Vito Sabato, Tanja Daniela Schug, Paul L A van Daele, Anna Belloni Fortina, Francesca Caroppo, Theo Gulen, Marc Heizmann, Karin Hartmann, Axel Rüfer, Michael Doubek, Jens Panse, Jason Gotlib, Michel Arock, Hanneke N G Oude Elberink, Andreas Reiter, Peter Valent, Khalid Shoumariyeh","doi":"10.1186/s40164-026-00819-8","DOIUrl":"https://doi.org/10.1186/s40164-026-00819-8","url":null,"abstract":"<p><p>Advanced systemic mastocytosis (AdvSM), comprising aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated hematological neoplasm, is a heterogeneous myeloid neoplasm with poor prognosis. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative treatment, yet its benefit across AdvSM subtypes in the era of KIT-targeted tyrosine kinase inhibitors (TKIs) such as midostaurin and avapritinib remains unclear. To identify patient subgroups benefiting from allo-HCT and to define prognostic factors for post-transplant survival, we analyzed 631 AdvSM patients from the European Competence Network on Mastocytosis registry, including 69 who underwent allo-HCT. Treatment effects were assessed using time-dependent Cox regression in a transplant-eligible complete-case cohort (n = 419). In this cohort, allo-HCT showed no overall survival (OS) benefit (hazard ratio [HR] 1.21, 95% CI 0.80-1.84; p = 0.37), whereas TKI response emerged as a strong independent predictor of survival (HR 0.42; p<0.001). Subtype-stratified analysis revealed an allo-HCT benefit exclusively in patients with systemic mastocytosis associated with acute myeloid leukemia (n = 30; HR 0.20; p = 0.020). Among the 69 transplanted patients, median OS was 49.6 months with 2-year and 5-year survival of 63% and 46%, respectively. The International Prognostic Scoring System for Mastocytosis (IPSM) at transplantation independently predicted both OS (HR per category 1.68; p = 0.026) and progression-free survival (HR 1.99; p = 0.003), whereas the Mutation-Adjusted Risk Score and diagnostic subtype did not reach statistical significance. Competing risk analysis demonstrated that higher IPSM captured both relapse-related and transplant-related mortality. These findings suggest that the survival benefit of allo-HCT in AdvSM is driven primarily by control of the associated myeloid neoplasm. Accordingly, allo-HCT should be prioritized in patients with SM-AML, whereas TKI-directed strategies may be preferred in other subtypes, with IPSM at transplantation potentially guiding transplant selection and timing.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13491673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148790066","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}