Leukemia最新文献

{"title":"Cheminformatic identification of small molecules targeting acute myeloid leukemia.","authors":"Megan R Daneman, Bernadetta Meika, Lois Armendariz, Elissa Tjahjono, Alexey V Revtovich, Leonid A Stolbov, Natthakan Thongon, Natalia Baran, Scott R Gilbertson, Vladimir V Poroikov, Natalia V Kirienko","doi":"10.1038/s41375-026-03104-z","DOIUrl":"10.1038/s41375-026-03104-z","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis and high relapse rates when treated with cytotoxic chemotherapeutics. Previously, we identified a family of small molecules that modulate mitochondrial function, referred to as PS127-family compounds. These drugs were selectively toxic to AML and were characterized by two predicted functions: apoptotic agonism and thioredoxin/glutathione reductase inhibition. Here, we uncovered a third critical predicted function, autophagic induction. Using a cheminformatic screen of ~4.2 million compounds for molecules with high predicted probability for all three functions, we found and validated hits that selectively killed AML cells, activated apoptosis, were dependent upon autophagic activation, and compromised glutathione metabolism by interfering with glutathione reductase, all of which are consistent with predictions. Compound treatment increased pools of cytosolic and mitochondrial ROS, decreased oxygen consumption, and reduced ATP synthesis. Structurally unrelated compounds caused the same phenotypes, validating our approach of screening for predicted function. Finally, we also observed strong synergy between these compounds and midostaurin and venetoclax, underscoring their therapeutic potential. Key phenotypes, including the compounds' impact on glutathione metabolism and synergy with doxorubicin and midostaurin, were confirmed in AML-patient-derived primary cells, validating the potential of these compounds for the development of future AML treatments.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840724","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":"Tisa-cel and axi-cel CAR structure influences the development of resistance to CD19-CAR-T therapy.","authors":"Marta Krawczyk, Klaudyna Fidyt, Narcis Fernandez-Fuentes, Tomasz Winiarski, Monika Pepek, Pablo Bousquets-Muñoz, Xose S Puente, Ana Gutiérrez-Fernández, Jacinta Davis, Daria Owczarek, Agnieszka Graczyk-Jarzynka, Pablo Sanz-Galarreta, Pablo Menendez, Anna Szumera-Ciećkiewicz, Emmanuelle Benard, Sébastien Wälchli, Andrei Thomas-Tikhonenko, Víctor M Pérez-García, Víctor Galán-Gómez, Adela Escudero López, Elisa Izquierdo Delgado, Jordi Minguillón, Antonio Pérez-Martínez, Magdalena Winiarska","doi":"10.1038/s41375-026-03081-3","DOIUrl":"https://doi.org/10.1038/s41375-026-03081-3","url":null,"abstract":"<p><p>CD19-CAR-T cells are a major therapy for relapsed/refractory B-cell malignancies, yet ~50% of patients relapse after infusion. Clinical data suggest that tisa-cel treatment is associated with higher rates of CD19 mutation than axi-cel, though direct comparisons have been lacking. Although both products target the FMC63 epitope, they employ different structures of hinge/transmembrane/costimulatory domains (CD8α/CD8α/4-1BB in tisa-cel, CD28/CD28/CD28 in axi-cel). Here, we show that CAR structure is a critical determinant of CD19 loss in tumor B cells. Specifically, repeated exposure to CD19-4-1BB-based CAR-T cells, but not CD19-CD28-based counterparts, drives FMC63-epitope and total CD19 protein loss. Consistent with clinical observations, resistance to CD19-4-1BB-based treatment is associated with aberrant splicing, loss of heterozygosity, and frameshift/missense mutations in CD19 in exons encoding the FMC63 epitope. Mathematical modeling indicates that the failure of CD19-4-1BB-based CAR-T cells to eliminate CD19^low cells, unlike CD28-based CARs, promotes the expansion of resistant populations. These results suggest that optimizing recognition of CD19^low cells could prevent the emergence of resistant clones and reduce relapse rates. We also show that commonly used diagnostic anti-CD19 monoclonal antibodies detect epitopes distinct from FMC63 and may therefore give misleading CD19-positive results, underscoring the need for FMC63-specific assessment to guide diagnostic and therapeutic decisions.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840758","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":"Ivosidenib monotherapy in IDH1 mutated myelodysplastic neoplasm/syndrome.","authors":"Marie Sébert, Emmanuelle Clappier, Sylvie Chevret, Hugo Bergugnat, Odile Rauzy, Aspasia Stamatoullas, Sophie Dimicoli-Salazar, Lamya Ait Si Selmi, Cendrine Chaffaut, Fatiha Chermat, Lise Larcher, Lauriane Goldwirt, Sylvain Thepot, Pierre Peterlin, Sophie Park, Marie-Pierre Gourin, Norbert Vey, Cécile Bally, Sébastien Maury, Gaelle Fossard, Maud D'Aveni, Anne-Laure Taksin, Thomas Cluzeau, Pierre Fenaux, Lionel Adès","doi":"10.1038/s41375-026-03100-3","DOIUrl":"https://doi.org/10.1038/s41375-026-03100-3","url":null,"abstract":"<p><p>Ivosidenib (IVO) is an oral inhibitor of mutant IDH1 (IDH1m) approved for treatment of IDH1m acute myeloid leukemia (AML) in association with Azacitidine (AZA). We investigated safety and efficacy of IVO monotherapy in patients with IDH1m myelodysplastic neoplasm/syndrome (MDS). This multicenter phase 2 trial enrolled three cohorts: high-risk (HR-) relapse or refractory (R/R) patients after AZA (cohort A), treatment-naïve HR-patients (cohort B) and low-risk patients refractory to erythropoiesis-stimulating agents (cohort C). All patients received 28-day cycles of IVO at 500 mg once daily. Between 2019 and 2023, 48 patients were included (median age 76.5 years). The ORR after 3 cycles was 63.6% (95%CI, 40.7-82.8) in cohort A, and 78.3% (95%CI, 56.3-92.5) in cohort B; the 12-month OS rate in cohorts A and B was 18.2% (95%CI, 7.5-44.1) and 91.3% (95%CI, 80.5-100), respectively. In cohort C, no significant toxicities were reported. Higher baseline IDH1 mutant clone size predicted response, whereas TP53 or IDH2 co-mutations were associated with resistance. Molecular clearance was not required for clinical benefit. IVO monotherapy was well tolerated and demonstrated sustained clinical activity across all IDH1m cohorts representing a potential therapeutic breakthrough in this frail population, particularly as a first-line therapeutic option in treatment naïve IDH1m HR-MDS patients (IDIOME, NCT03503409).</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818957","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":"Multimodal spatial profiling reveals distinct myeloid-defined ENKTL subgroups and tumor-myeloid cooperativity within prognostic inflammatory niche.","authors":"Lichang Deng, Min Liu, Reagan Entigu Anak Linton, Kaijie Hu, Shruti Sridhar, Giorgio Bertolazzi, Sai Mun Leong, Ling-Wen Ding, Nicholas Syn, Shuangyi Fan, Cho Mar Myint Wai, Yi-Qi Li, Jin-Xin Bei, Jie Xiong, Wei-Li Zhao, Susan Swee-Shan Hue, Joe Poh Sheng Yeong, Li Yen Chong, Li-Mei Poon, Choon Kiat Ong, Jing Quan Lim, Soon Thye Lim, Jinmiao Chen, Hang Xu, Anand Devaprasath Jeyasekharan, Claudio Tripodo, Siok-Bian Ng","doi":"10.1038/s41375-026-03118-7","DOIUrl":"https://doi.org/10.1038/s41375-026-03118-7","url":null,"abstract":"<p><p>Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive Epstein-Barr virus (EBV)-associated malignancy with a heterogeneous tumor microenvironment, yet macrophage heterogeneity and tumor-macrophage crosstalk remain poorly defined. Here, we integrate spatial transcriptomic and proteomic profiling with single-cell spatial molecular imaging of ENKTL samples and identify two subgroups defined by distinct macrophage programs. Subgroup 1 is enriched for inflammatory macrophages exhibiting IFN-α/γ responses and immune-regulatory molecules including IDO1 and CD274, whereas Subgroup 2 is immune-quiescent and macrophage-sparse, with its macrophage compartment skewed towards STAB1 macrophages with scavenging features. Notably, an NF-κB-activated and EBV-associated tumor subset is specifically enriched in Subgroup 1, displaying concurrent immunostimulatory and immunoregulatory features that parallel the co-enriched myeloid states and showing reproducible sample-level associations with these myeloid states across datasets. Spatial neighborhood analysis further delineates an inflammation niche where NF-κB tumor cells physically co-localize with these inflammatory macrophages, accompanied by enhanced tumor-myeloid and myeloid-myeloid signaling, implicating a process of tumor-associated myeloid recruitment followed by CCL- and IL1-mediated myeloid self-reinforcement. Critically, higher abundance of this niche correlates with improved survival across independent cohorts, revealing contrasting spatial tumor-immune architectures with prognostic relevance. Together, our study provides a spatially resolved framework for understanding ENKTL biology and guiding immunotherapeutic strategies.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813364","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":"PTBP1 controls oncogenic transcript processing and maintenance of acute myeloid leukemia.","authors":"Zhendong Cao, Kurtis N McCannell, Sixiang Yu, Krista A Budinich, Won Jun Kim, Yuqing Jing, Michelle Y Wang, Steven Tittley, Zhuoyu Wen, Kathy Fange Liu, Junwei Shi, Omar Abdel-Wahab","doi":"10.1038/s41375-026-03098-8","DOIUrl":"10.1038/s41375-026-03098-8","url":null,"abstract":"<p><p>RNA-binding proteins are critical regulators of gene expression in both normal physiology and cancer. Here we set out to systematically annotate the functions of RNA-associated proteins across multiple cancer types via domain-focused CRISPR screens targeting RNA-modifying enzymes and RNA-binding proteins. We utilized 3182 sgRNAs targeting 527 RNA-enzymatic and binding domains in 341 RNA-associated proteins and identified multiple RNA-binding proteins as dependencies in acute myeloid leukemia (AML), including the RNA splicing factor PTBP1 and the N6-methyladenosine reader RBM15, with a bias toward the aggressive KMT2A-rearranged (KMT2A-r) subtype of AML. Genetic and cellular validation confirmed all four RNA-binding domains of PTBP1 as required for KMT2A-r AML proliferation. In contrast to the lack of requirement for PTBP1 in myelopoiesis, PTBP1 suppression in AML caused cell cycle arrest, apoptosis, and induction of myeloid differentiation programs. Transcriptomic analysis revealed that PTBP1 loss disrupted the KMT2A-r-essential transcriptional program and caused widespread dysregulation of splicing. CLIP-seq analysis further identified that PTBP1 preferentially binds to a subset of transcripts critical for KMT2A-r AML proliferation, including IKZF1, MEF2C, EZH2, SIK3, and PBX3. Collectively, these findings demonstrate that PTBP1 supports AML proliferation by fine-tuning the expression and splicing of AML-essential genes, providing a workflow for systematically annotating RNA-associated protein dependencies in cancer.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813422","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":"Daratumumab, lenalidomide, and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: MAIA final survival analysis.","authors":"Thierry Facon, Shaji K Kumar, Robert Z Orlowski, Nizar Bahlis, Philippe Moreau, Hartmut Goldschmidt, Supratik Basu, Cyrille Hulin, Sonja Zweegman, Katja Weisel, Aurore Perrot, Caroline Jacquet, Noopur Raje, Salomon Manier, Ajai Chari, Markus Hansson, Mohamad Mohty, Michel Delforge, Torben Plesner, Gordon Cook, Xavier Leleu, Hang Quach, Christopher P Venner, Mourad Tiab, Margaret Macro, Laurent Frenzel, George Wang, Huiling Pei, Kasey Bolyard, Robin Carson, Fredrik Borgsten, Saad Z Usmani","doi":"10.1038/s41375-026-03097-9","DOIUrl":"https://doi.org/10.1038/s41375-026-03097-9","url":null,"abstract":"<p><p>In previous analyses of MAIA, daratumumab plus lenalidomide/dexamethasone (D-Rd) significantly improved progression-free survival and overall survival (OS) versus lenalidomide/dexamethasone (Rd) in transplant-ineligible newly diagnosed multiple myeloma (NDMM). We report results on long-term OS and subsequent antimyeloma therapies from the MAIA final analysis. A protocol amendment (July 20, 2021) led to a long-term extension of MAIA, during which patients were followed for OS. A total of 737 patients were randomized to D-Rd (n = 368) or Rd (n = 369). At a median follow-up of 89.3 months (range, 0.0-102.2; interquartile range, 85.3-93.0), median OS was 90.3 months (95% confidence interval [CI], 80.8-not estimable [NE]) with D-Rd versus 64.1 months (56.0-70.8) with Rd (hazard ratio [HR], 0.67; 95% CI, 0.55-0.82); estimated 7-year OS rates were 53.1% (95% CI, 47.8-58.2) and 39.3% (34.1-44.5), respectively. Median time to subsequent antimyeloma treatment was not reached (95% CI, 84.1-NE) for D-Rd versus 42.4 months (33.5-50.6) for Rd (HR, 0.51; 95% CI, 0.41-0.63; P < 0.0001). Death due to adverse events occurred in 84 patients (D-Rd, n = 44/364 [12%]; Rd, n = 40/365 [11%]). With >7 years of follow-up, D-Rd demonstrated a new benchmark for median OS (7.5 years) in transplant-ineligible NDMM, further supporting frontline D-Rd use to maximize survival.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813445","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":"Chernobyl at 40 years: leukaemias, cancers and implications for nuclear safety","authors":"RP Gale","doi":"10.1038/s41375-026-03027-9","DOIUrl":"10.1038/s41375-026-03027-9","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 10","pages":"2127-2128"},"PeriodicalIF":8.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-026-03027-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813462","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":"TP53-mutant CHIP defines a pro-inflammatory phenotype and predicts adverse outcomes after CAR T-cell therapy.","authors":"Giulia Rappa, Frank Ziemann, Kieron White, Linus Kruk, Samar Shamas, Amelie Muth, Kayleen Shi, Cristina Zucchinetti, Savanna Süß, Maja Rothenberg-Thurley, Alessandra Holzem, Tobias Tix, Agnese Petrera, Bianka Ksienzyk, Charlotte Bentenrieder, Katharina S Götze, Fabian Müller, Veit Bücklein, Kai Rejeski, Marion Subklewe","doi":"10.1038/s41375-026-03083-1","DOIUrl":"https://doi.org/10.1038/s41375-026-03083-1","url":null,"abstract":"<p><p>Clonal hematopoiesis of indeterminate potential (CHIP) has been well-characterized in patients receiving chemotherapy and hematopoietic cell transplantation. However, its immunologic relevance and potential role in modulating chimeric antigen receptor T-cell (CAR-T) therapy-related toxicities, inflammation, and clinical outcomes remains incompletely defined. In this exploratory study of 104 CAR-T recipients, we investigated the prognostic impact of pre-existing CHIP clones on toxicity and survival, and examined CHIP-associated inflammatory proteomic signatures leveraging longitudinal serum samples. Overall CHIP status was not associated with inflammatory toxicities, outcomes, or systemic inflammatory profiles. Analysis of clonal dynamics revealed TP53- and ASXL1-mutated clones to be the dominant expanding CHIP clones post-infusion, whereas DNMT3A- and PPM1D-mutated clones showed reduced clonal abundance over time. Notably, TP53-mutated CHIP was linked to lower platelet and hemoglobin levels, a higher baseline CAR-HEMATOTOX score, inferior clinical outcomes, and a distinct inflammatory signature. These findings identify TP53-mutated CHIP in CAR-T-treated patients as a high-risk CHIP genotype compared with other CHIP mutations. Importantly, patients who developed treatment-emergent myeloid neoplasms after CAR T-cell therapy exhibited distinct patterns of clonal expansion and inflammatory profiles. Together, these findings support a risk-adapted approach prioritizing longitudinal monitoring of TP53-mutated CHIP, especially in patients with high CAR-HEMATOTOX scores who develop cytopenias.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813399","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":"Health status impairments in tyrosine kinase inhibitor-treated chronic myeloid leukemia patients versus blood or marrow transplant survivors and non-cancer controls","authors":"Smita Bhatia, Qingrui Meng, Lindsey Hageman, Sarah B. Palmer, Eunice E. Choe, Nora Balas, Wendy Landier, Omer Jamy, Pankit Vachhani, Alysia Bosworth, F. Lennie Wong, Jorge Cortes, Stephen J. Forman, Daniel J. Weisdorf, Saro H. Armenian, Ravi Bhatia","doi":"10.1038/s41375-026-03123-w","DOIUrl":"https://doi.org/10.1038/s41375-026-03123-w","url":null,"abstract":"Tyrosine kinase inhibitor (TKI) therapy has resulted in a significant reduction in chronic myeloid leukemia (CML)-related mortality. However, the impact of TKIs on the health status of long-term CML survivors remains unstudied. We examined the health status of 62 TKI-treated CML patients who did not receive blood or marrow transplantation (BMT) (CML_TKI; median follow-up: 12.5 y) compared with an unaffected population (303 non-CML controls), and CML patients treated with BMT but without TKI exposure (220 CML_BMT; median follow-up 19.4 y). Participants self-reported general health, functional status, activity limitations, and pre-frailty/frailty. Overall, 71.0% of CML_TKI participants had ≥1 adversely-affected domain vs. 42.6% of non-CML and 65.9% of CML_BMT participants. When compared with the non-CML controls, the CML_TKI cohort was more like to have poor general health (aOR = 4.43, 95%CI = 1.8–10.7), functional impairment (aOR=2.84, 95%CI = 1.4–6.0), and activity limitation (aOR=3.37, 95%CI = 1.7–6.7) and more likely to be frail/pre-frail (aOR=3.71, 95%CI = 1.7–8.1). The CML_TKI and CML_BMT cohorts were comparable with respect to poor general health (aOR = 0.95, 95%CI = 0.5–2.0), functional impairment (aOR = 1.59, 95%CI = 0.8–3.0), and pre-frailty/frailty (aOR = 1.92, 95%CI = 0.92–4.0), but the CML_TKI cohort was more likely to report activity limitation (aOR = 2.2, 95%CI = 1.1–4.5). These findings inform a need for long-term monitoring and development of risk mitigation strategies to improve the health status as a treatment goal in CML care.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"42 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769249","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":"Oncogenic DHX15 mutation enhances mitochondrial metabolism and sustains leukemia stemness","authors":"Qilong Li, Peiqi Xing, Jin Xu, Jifei Li, Liangjie Chen, Xinlu Li, Yinpeng Bai, Gang Li, Ting Xie, Luzhen Wang, Yuan Wang, Guoliang Qing, Huafeng Wang, Liang Shao, Wei Wu, Zhaoqi Liu, Hudan Liu","doi":"10.1038/s41375-026-03102-1","DOIUrl":"https://doi.org/10.1038/s41375-026-03102-1","url":null,"abstract":"The RUNX1::RUNX1T1 translocation, also termed AML1-ETO, is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML) and is associated with variable clinical outcomes. The R222G hotspot mutation, located in the RNA helicase gene DHX15, is enriched and predominantly found in AML with this translocation, but its diagnostic significance and underlying mechanism remain largely unclear. In this study, we show that pediatric AML patients carrying DHX15 mutations exhibit an inferior prognosis. Functional analysis demonstrates that DHX15R222G cooperates with AML1-ETO fusion protein to enhance AML leukemia stem cell (LSC) activity and promote resistance to standard chemotherapy. Mechanistically, AML1-ETO transcriptionally upregulates mitochondrial transcription factor A (TFAM), while DHX15R222G promotes TFAM protein stabilization and nuclear translocation, resulting in robust activation of oxidative phosphorylation (OXPHOS) gene expression and mitochondrial respiration. Inhibition of oxidative phosphorylation by the Complex V inhibitor S-Gboxin exerts strong anti-leukemic effects and efficiently circumvents chemotherapy resistance in AML1-ETO+ DHX15R222G leukemia. These findings underscore the pivotal role of oncogenic DHX15 mutations in regulating AML LSC activity and identify DHX15R222G as a potential genetic biomarker for AML risk stratification. Moreover, this mutation may predict therapeutic vulnerability to OXPHOS inhibition.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"17 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769252","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}