{"title":"Incidence, prevalence, and survival outcomes of patients with myeloproliferative neoplasms in the United States: a Surveillance, Epidemiology, and End Results (SEER) database analysis, years 2000-2021.","authors":"Sachi Singhal, Rahul Mishra, Sankalp Arora, Noha Sharafeldin, Ruchi Desai, Tania Jain, Pankit Vachhani","doi":"10.1038/s41375-026-03124-9","DOIUrl":"10.1038/s41375-026-03124-9","url":null,"abstract":"<p><p>Myeloproliferative Neoplasms (MPNs) are rare hematologic neoplasms. The epidemiology and outcomes of these rare neoplasms warrant an update considering new diagnostic tools and advances in treatment options. NCI's Surveillance, Epidemiology and End Results (SEER)-17 registries were interrogated to analyze adult patients diagnosed with MPN [ICD-O-3 codes: polycythemia vera (PV) 9950/3, essential thrombocythemia (ET) 9962/3, primary myelofibrosis (PMF) 9961/3 and chronic myeloid leukemia (CML) 9875/3] during the years 2000 to 2021. Data of 63,242 (ET, n = 24,172; PV, n = 23,456; PMF, n = 6131; CML, n = 9483) patients were analyzed. The overall incidence rate (IR) for ET, PV, PMF and CML was 1.8, 1.7, 0.5 and 0.7 per 100,000 person-years, respectively. The incidence of ET, PV, and MF increased with age, and the majority of cases were seen after the age of 50. 5-year Relative Survival (RS) for PMF was 50.9% in 2009, to 57.4% in 2013 and 60.6% in 2016. The median overall survival (OS) was 152 months for ET, 150 months for PV, 48 months for PMF, and 202 months for CML. Advancing age was associated with adverse survival across MPN subtypes. Survival of patients with PMF continues to improve over recent years. Important racial and gender variations exist, which were noted in our study.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865482","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 : 2026-08-27DOI: 10.1038/s41375-026-03104-z
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
{"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}
LeukemiaPub Date : 2026-08-27DOI: 10.1038/s41375-026-03081-3
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
{"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<sup>low</sup> cells, unlike CD28-based CARs, promotes the expansion of resistant populations. These results suggest that optimizing recognition of CD19<sup>low</sup> 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}
LeukemiaPub Date : 2026-08-25DOI: 10.1038/s41375-026-03100-3
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
{"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}
LeukemiaPub Date : 2026-08-24DOI: 10.1038/s41375-026-03098-8
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
{"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}
LeukemiaPub Date : 2026-08-24DOI: 10.1038/s41375-026-03027-9
RP Gale
{"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}
LeukemiaPub Date : 2026-08-21DOI: 10.1038/s41375-026-03123-w
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
{"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}
LeukemiaPub Date : 2026-08-21DOI: 10.1038/s41375-026-03114-x
Anna Eichinger, Zofia Szmit, Katharina Kleinschmidt, Mouad Abouqateb, Marc Ansari, Peter Bader, Adriana Balduzzi, Friso Calkoen, Arnaud Dalissier, Jean-Hugues Dalle, Cristina Diaz-de-Heredia, Franca Fagioli, Maura Faraci, Jacques-Emmanuel Galimard, Brenda Gibson, Bernd Gruhn, Peter Lang, Oana Mirci-Danicar, Richard Mitchell, Christina Peters, Kanchan Rao, Samppa Ryhänen, Martin Sauer, Petr Sedlacek, Jan Styczynski, Selim Corbacioglu, Krzysztof Kalwak
{"title":"Total body irradiation versus chemotherapy before stem cell transplantation in children aged two to four with acute lymphoblastic leukemia—an EBMT pediatric diseases working party study","authors":"Anna Eichinger, Zofia Szmit, Katharina Kleinschmidt, Mouad Abouqateb, Marc Ansari, Peter Bader, Adriana Balduzzi, Friso Calkoen, Arnaud Dalissier, Jean-Hugues Dalle, Cristina Diaz-de-Heredia, Franca Fagioli, Maura Faraci, Jacques-Emmanuel Galimard, Brenda Gibson, Bernd Gruhn, Peter Lang, Oana Mirci-Danicar, Richard Mitchell, Christina Peters, Kanchan Rao, Samppa Ryhänen, Martin Sauer, Petr Sedlacek, Jan Styczynski, Selim Corbacioglu, Krzysztof Kalwak","doi":"10.1038/s41375-026-03114-x","DOIUrl":"https://doi.org/10.1038/s41375-026-03114-x","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"43 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769355","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 : 2026-08-19DOI: 10.1038/s41375-026-03095-x
Anne Marie Staehle, Florian Perner, Hans Felix Staehle, Katharina Gellrich, Fiona Preiß, Annika Grafemeyer, Jana Schulze, Jean-Luca Funk, Albert Gründer, Julia Berner, Sander Bekeschus, Christoph Koellerer, Heike L. Pahl
{"title":"A novel role for transcription factor NFE2 in redox regulation and chemotherapy resistance in acute myeloid leukemia","authors":"Anne Marie Staehle, Florian Perner, Hans Felix Staehle, Katharina Gellrich, Fiona Preiß, Annika Grafemeyer, Jana Schulze, Jean-Luca Funk, Albert Gründer, Julia Berner, Sander Bekeschus, Christoph Koellerer, Heike L. Pahl","doi":"10.1038/s41375-026-03095-x","DOIUrl":"https://doi.org/10.1038/s41375-026-03095-x","url":null,"abstract":"Elevated activity of transcription factor NFE2 is sufficient to cause leukemic transformation in absence of a classical leukemic driver. However, the molecular mechanism promoting NFE2-driven leukemogenesis is not known. Here we report a previously unrecognized role for NFE2 as a key regulator of the oxidative stress response in leukemic cells. Through a comprehensive analysis of NFE2 genomic occupancy and its effect on chromatin accessibility and transcription, we demonstrate that NFE2 regulates glutathione homeostasis as well as the expression of central detoxifying enzymes. NFE2 constituted one of the highest scoring gene dependencies in MLL-AF9-transformed primary leukemic cells under redox stress, substantially more significant than the universally recognized redox regulator NRF2. Consequently, NFE2 knockdown sensitized leukemic cells to GSH depletion, ferroptosis induction, as well as to cytarabine treatment. Deriving an NFE2 RedOx score, we demonstrate that increased NFE2 activity constitutes an independent predictor of inferior outcome in AML patients at diagnosis.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"2 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769250","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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