Pub Date : 2026-02-10DOI: 10.1038/s41375-026-02873-x
Camilla Grud Nielsen, Bodil Als-Nielsen, Birgitte Klug Albertsen, Ólafur Birgir Davídsson, Andreja Dimitrijevic, Henrik Hjalgrim, Marianne Ifversen, Louise Lundgren, Line Stensig Lynggaard, Marianne Olsen, Ulrik Malthe Overgaard, Cecilie Utke Rank, Mathias Rathe, Klaus Rostgaard, Kjeld Schmiegelow, Liv Andrés-Jensen
With increasing survival in acute lymphoblastic leukemia (ALL), long-term toxicities have become a critical aspect. A novel measure, designated Severe Toxicity-free survival (STFS), was developed through international consensus to integrate the most severe, symptomatic organ toxicities in outcome evaluation. This measure has not been applied to real-world data before. We assessed the incidence of 21 predefined Severe Toxicities in a nationwide cohort of 506 ALL patients aged 1–45 years treated according to the NOPHO ALL2008 protocol. At five years, event-free survival was 84.4% (95% CI: 81.3–87.7%) and Severe Toxicity-event-free survival was 78.4% (95% CI: 74.9–82.1%), with significantly lower values in adults (aged 18–45 years) than children (61.6% [52.6–72.2%] vs 82.4% [78.8–86.2%]; log-rank p < 0.001). The most common Severe Toxicities were severe osteonecrosis limiting activities of daily function (N = 20) and disabling paralytic and neuropathic conditions (N = 16). Exploratory analyses showed that 10–17-year-olds had the highest risk of Severe Toxicities similar to that of adults. These findings highlight a burden of severe, long-term toxicities in ALL survivors overlooked by traditional outcome measures, also following frontline therapy only. STFS should be incorporated in future trials for meaningful outcome evaluation and international comparisons across treatment strategies.
{"title":"Severe toxicity-free survival following acute lymphoblastic leukemia in patients aged 1–45 years: a Danish cohort study","authors":"Camilla Grud Nielsen, Bodil Als-Nielsen, Birgitte Klug Albertsen, Ólafur Birgir Davídsson, Andreja Dimitrijevic, Henrik Hjalgrim, Marianne Ifversen, Louise Lundgren, Line Stensig Lynggaard, Marianne Olsen, Ulrik Malthe Overgaard, Cecilie Utke Rank, Mathias Rathe, Klaus Rostgaard, Kjeld Schmiegelow, Liv Andrés-Jensen","doi":"10.1038/s41375-026-02873-x","DOIUrl":"https://doi.org/10.1038/s41375-026-02873-x","url":null,"abstract":"With increasing survival in acute lymphoblastic leukemia (ALL), long-term toxicities have become a critical aspect. A novel measure, designated Severe Toxicity-free survival (STFS), was developed through international consensus to integrate the most severe, symptomatic organ toxicities in outcome evaluation. This measure has not been applied to real-world data before. We assessed the incidence of 21 predefined Severe Toxicities in a nationwide cohort of 506 ALL patients aged 1–45 years treated according to the NOPHO ALL2008 protocol. At five years, event-free survival was 84.4% (95% CI: 81.3–87.7%) and Severe Toxicity-event-free survival was 78.4% (95% CI: 74.9–82.1%), with significantly lower values in adults (aged 18–45 years) than children (61.6% [52.6–72.2%] vs 82.4% [78.8–86.2%]; log-rank p < 0.001). The most common Severe Toxicities were severe osteonecrosis limiting activities of daily function (N = 20) and disabling paralytic and neuropathic conditions (N = 16). Exploratory analyses showed that 10–17-year-olds had the highest risk of Severe Toxicities similar to that of adults. These findings highlight a burden of severe, long-term toxicities in ALL survivors overlooked by traditional outcome measures, also following frontline therapy only. STFS should be incorporated in future trials for meaningful outcome evaluation and international comparisons across treatment strategies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"92 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152276","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}
Pub Date : 2026-02-09DOI: 10.1038/s41375-026-02874-w
Rabea Mecklenbrauck, Angela Villaverde Ramiro, Eric Sträng, Razif Gabdoulline, Javier Martinez Elicegui, Marta Sobas, Lisa Pleyer, Amin Turki, Maria Teresa Voso, Axel Benner, Alberto Hernández-Sánchez, Jesse M Tettero, Laura Tur Gimenez, Klaus H Metzeler, Guadalupe Oñate, Sören Lehmann, Brian Jp Huntly, Ian Thomas, Felicitas R Thol, Florian H Heidel, Peter Jm Valk, Konstanze Döhner, Torsten Haferlach, Kenneth I Mills, Hartmut Döhner, Gastone Castellani, Gert J Ossenkoppele, Jesus María Hernández-Rivas, Lars Bullinger, Michael Heuser
The inclusion of nine myelodysplasia-related gene (MRG) mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse risk factors in the ELN risk classification has reshaped classification in acute myeloid leukemia (AML). AML with FLT3-ITD mutations and co-occurring MRG alterations is now classified to the ELN adverse risk group although supporting evidence remains limited. Among 4,078 patients with AML with available molecular information included in the HARMONY platform, 862 harbored FLT3-ITD mutations and underwent intensive chemotherapy. Of these, 171 (20%) exhibited co-occurring MRG mutations at diagnosis. In this cohort, MRGs were not independently associated with relapse-free survival (RFS) or overall survival (OS). In the FLT3-ITD/NPM1 co-mutated subgroup, MRG mutations were rare (9%) and showed no prognostic impact. Conversely, in FLT3-ITD/NPM1 wildtype AML, MRG mutations were predictive of shorter RFS (HR 1.37, 95%CI 1.01 - 1.88, p = 0.046) and OS (HR 1.34, 95%CI 1.02-1.74, p = 0.032) in multivariable analysis with survival times comparable to the ELN adverse risk category. The allelic ratio of FLT3-ITD did not further stratify OS and RFS in this subgroup. These findings suggest that the prognostic relevance of MRG mutations in FLT3-ITD AML is modulated by NPM1 co-mutational status and mirror findings in AML lacking FLT3-ITD.
将9种骨髓增生异常相关基因（MRG）突变（ASXL1、bor、EZH2、RUNX1、SF3B1、SRSF2、STAG2、U2AF1、ZRSR2）作为不良危险因素纳入ELN风险分类，重塑了急性髓性白血病（AML）的分类。AML伴有FLT3-ITD突变和同时发生的MRG改变现在被归类为ELN不良风险组，尽管支持证据仍然有限。在HARMONY平台中包含可用分子信息的4078例AML患者中，862例携带FLT3-ITD突变并接受了强化化疗。其中，171例（20%）在诊断时表现出共同发生的MRG突变。在这个队列中，mrg与无复发生存期（RFS）或总生存期（OS）没有独立的相关性。在FLT3-ITD/NPM1共突变亚组中，MRG突变很少见（9%），对预后没有影响。相反，在FLT3-ITD/NPM1野生型AML中，在多变量分析中，MRG突变可预测较短的RFS （HR 1.37, 95%CI 1.01 - 1.88, p = 0.046）和OS (HR 1.34, 95%CI 1.02-1.74, p = 0.032)，其生存时间与ELN不良风险类别相当。FLT3-ITD的等位基因比例并不能进一步划分该亚组的OS和RFS。这些发现表明，FLT3-ITD AML中MRG突变的预后相关性是由NPM1共突变状态和缺乏FLT3-ITD AML中的镜像结果调节的。
{"title":"Prognostic impact of myelodysplasia-related gene mutations in FLT3-ITD-mutated acute myeloid leukemia.","authors":"Rabea Mecklenbrauck, Angela Villaverde Ramiro, Eric Sträng, Razif Gabdoulline, Javier Martinez Elicegui, Marta Sobas, Lisa Pleyer, Amin Turki, Maria Teresa Voso, Axel Benner, Alberto Hernández-Sánchez, Jesse M Tettero, Laura Tur Gimenez, Klaus H Metzeler, Guadalupe Oñate, Sören Lehmann, Brian Jp Huntly, Ian Thomas, Felicitas R Thol, Florian H Heidel, Peter Jm Valk, Konstanze Döhner, Torsten Haferlach, Kenneth I Mills, Hartmut Döhner, Gastone Castellani, Gert J Ossenkoppele, Jesus María Hernández-Rivas, Lars Bullinger, Michael Heuser","doi":"10.1038/s41375-026-02874-w","DOIUrl":"https://doi.org/10.1038/s41375-026-02874-w","url":null,"abstract":"<p><p>The inclusion of nine myelodysplasia-related gene (MRG) mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse risk factors in the ELN risk classification has reshaped classification in acute myeloid leukemia (AML). AML with FLT3-ITD mutations and co-occurring MRG alterations is now classified to the ELN adverse risk group although supporting evidence remains limited. Among 4,078 patients with AML with available molecular information included in the HARMONY platform, 862 harbored FLT3-ITD mutations and underwent intensive chemotherapy. Of these, 171 (20%) exhibited co-occurring MRG mutations at diagnosis. In this cohort, MRGs were not independently associated with relapse-free survival (RFS) or overall survival (OS). In the FLT3-ITD/NPM1 co-mutated subgroup, MRG mutations were rare (9%) and showed no prognostic impact. Conversely, in FLT3-ITD/NPM1 wildtype AML, MRG mutations were predictive of shorter RFS (HR 1.37, 95%CI 1.01 - 1.88, p = 0.046) and OS (HR 1.34, 95%CI 1.02-1.74, p = 0.032) in multivariable analysis with survival times comparable to the ELN adverse risk category. The allelic ratio of FLT3-ITD did not further stratify OS and RFS in this subgroup. These findings suggest that the prognostic relevance of MRG mutations in FLT3-ITD AML is modulated by NPM1 co-mutational status and mirror findings in AML lacking FLT3-ITD.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150036","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}
Pub Date : 2026-02-09DOI: 10.1038/s41375-026-02878-6
Rohtesh S Mehta, Shannon R McCurdy, Filippo Milano, Mariam Nawas, Yosra Aljawai, Joseph Cataquiz Rimando, Taha Al-Juhaishi, Annie Im, Jennifer A Kanakry, Aleksandr Lazaryan, Christopher G Kanakry
{"title":"Challenging a clinical dogma with multimodal machine learning: a retrospective analysis of transplant mismatched donor selection.","authors":"Rohtesh S Mehta, Shannon R McCurdy, Filippo Milano, Mariam Nawas, Yosra Aljawai, Joseph Cataquiz Rimando, Taha Al-Juhaishi, Annie Im, Jennifer A Kanakry, Aleksandr Lazaryan, Christopher G Kanakry","doi":"10.1038/s41375-026-02878-6","DOIUrl":"https://doi.org/10.1038/s41375-026-02878-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150082","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}
Pub Date : 2026-02-04DOI: 10.1038/s41375-026-02861-1
Anna Nikkarinen, Jonas Almlöf, Albin Österroos, Claes Ladenvall, Rose-Marie Amini, Peter Hollander, Kristin Ayoola Gustafsson, Panagiotis Baliakas, Ingrid Glimelius
{"title":"Accumulation of high-risk genetic features after chemoimmunotherapy: A longitudinal study in mantle cell lymphoma","authors":"Anna Nikkarinen, Jonas Almlöf, Albin Österroos, Claes Ladenvall, Rose-Marie Amini, Peter Hollander, Kristin Ayoola Gustafsson, Panagiotis Baliakas, Ingrid Glimelius","doi":"10.1038/s41375-026-02861-1","DOIUrl":"https://doi.org/10.1038/s41375-026-02861-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"28 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116163","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}
Pub Date : 2026-02-04DOI: 10.1038/s41375-026-02876-8
Theresa Rohm, Konrad Bochennek, Isabel Taeuber, Jan-Henning Klusmann, Anke Barnbrock, Thomas Lehrnbecher
{"title":"Safety and efficacy of short courses of antibiotic therapy in high-risk febrile neutropenic pediatric patients","authors":"Theresa Rohm, Konrad Bochennek, Isabel Taeuber, Jan-Henning Klusmann, Anke Barnbrock, Thomas Lehrnbecher","doi":"10.1038/s41375-026-02876-8","DOIUrl":"https://doi.org/10.1038/s41375-026-02876-8","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"15 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115769","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}
Pub Date : 2026-02-04DOI: 10.1038/s41375-026-02872-y
Zhi-Zhang Yang, Hyo Jin Kim, Xinyi Tang, Joseph P. Novak, Vaishali Bhardwaj, Prithviraj Mukherjee, Jose C. Villasboas, Anne J. Novak, Patrizia Mondello, Stephen M. Ansell
{"title":"Malignant B cells expressing SIRPα are highly proliferative and are associated with inferior clinical outcomes in B-cell non-Hodgkin lymphoma","authors":"Zhi-Zhang Yang, Hyo Jin Kim, Xinyi Tang, Joseph P. Novak, Vaishali Bhardwaj, Prithviraj Mukherjee, Jose C. Villasboas, Anne J. Novak, Patrizia Mondello, Stephen M. Ansell","doi":"10.1038/s41375-026-02872-y","DOIUrl":"https://doi.org/10.1038/s41375-026-02872-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"9 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115768","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}
Pub Date : 2026-02-03DOI: 10.1038/s41375-026-02877-7
Alberto Guijosa, Nicholas Tsakmaklis, Margaret Kobs, Amanda Kofides, Maria Luisa Guerrera, Gottfried von Keudell, Andrew Branagan, Zachary R. Hunter, Steven P. Treon, Shayna Sarosiek, Jorge J. Castillo
{"title":"Off-trial outcomes of zanubrutinib in Waldenström macroglobulinemia: the prognostic impact of CXCR4 and TP53 alterations","authors":"Alberto Guijosa, Nicholas Tsakmaklis, Margaret Kobs, Amanda Kofides, Maria Luisa Guerrera, Gottfried von Keudell, Andrew Branagan, Zachary R. Hunter, Steven P. Treon, Shayna Sarosiek, Jorge J. Castillo","doi":"10.1038/s41375-026-02877-7","DOIUrl":"https://doi.org/10.1038/s41375-026-02877-7","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"87 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102078","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}
Pub Date : 2026-02-03DOI: 10.1038/s41375-026-02871-z
Xiaoli Wang, Andrew Davis, Cing Siang Hu, Fei Huang, Sophia Jiang, John Mascarenhas, Ronald Hoffman
{"title":"Sequential treatment with ruxolitinib and imetelstat effectively depletes myelofibrosis hematopoietic stem and progenitor cells","authors":"Xiaoli Wang, Andrew Davis, Cing Siang Hu, Fei Huang, Sophia Jiang, John Mascarenhas, Ronald Hoffman","doi":"10.1038/s41375-026-02871-z","DOIUrl":"https://doi.org/10.1038/s41375-026-02871-z","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"290 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102079","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}
Pub Date : 2026-02-03DOI: 10.1038/s41375-026-02879-5
Jennifer Fraszczak, Charles Vadnais, Marissa Rashkovan, Julie Ross, Hugues Beauchemin, Riyan Chen, Damien Grapton, Cyrus Khandanpour, Tarik Möröy
{"title":"Correction: Reduced expression but not deficiency of GFI1 causes a fatal myeloproliferative disease in mice.","authors":"Jennifer Fraszczak, Charles Vadnais, Marissa Rashkovan, Julie Ross, Hugues Beauchemin, Riyan Chen, Damien Grapton, Cyrus Khandanpour, Tarik Möröy","doi":"10.1038/s41375-026-02879-5","DOIUrl":"https://doi.org/10.1038/s41375-026-02879-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113635","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}
Pub Date : 2026-02-02DOI: 10.1038/s41375-025-02843-9
David Kealy, Ruth Ellerington, Suraj Bansal, Jessie J. F. Medeiros, Catherine A. Hawley, Andy G. X. Zeng, Jakub Lukaszonek, Katie A. West, Aparna D. Sinha, Gillian Caalim, Richard T. Gawne, Jacob Pope, Bianca Lima Ferreira, Nicole-Mae Blacknell, Bryce Drylie, Jenny Chatzigerou, Hwei Minn Khoo, Adam C. Wilkinson, Adele K. Fielding, Guanlin Wang, Bethan Psaila, David G. Kent, Ian S. Hitchcock, Andrew N. Holding, Andrew S. Mason, Vikas Gupta, John E. Dick, Katherine S. Bridge
Hypoxia-inducible factors (HIFs) are master transcriptional regulators, central to cellular survival in hypoxia and frequently activated within malignancy. Whilst malignant context directs the role of HIFs within oncogenesis, these mechanisms are not well characterised. Applying the JAK2V617F myeloproliferative neoplasms (MPNs) oncogene-driver model, in which HIF-1α is stabilised in normoxia (20% O2), we sought to determine whether the modality of HIF-1 activation directs its function. Through direct analysis of hypoxia-activated vs. JAK2V617F-activated HIF-1 at the chromatin, we define a JAK2V617F-HIF-1 regulon that diverges from canonical HIF/hypoxia targets. In a cohort of 172 JAK2V617F-MPN patients, we observe significant association of the JAK2V617F-HIF-1 regulon, but not canonical HIF-1 gene signatures, with disease severity, progression, and patient survival. We further define a subset gene signature (HIF1-MPN-BP) significantly associated with spontaneous transformation to blast phase MPNs. Finally, we identify that JAK2V617F-induced HIF-1α stabilisation is mediated via PIM1 kinase. Our findings demonstrate that HIF-1 activation by the JAK2V617F-PIM1 axis significantly alters HIF-1 transcription function, desensitising HIF-1 activity to cellular oxygen levels, and restricting the HIF-1 regulon to a set of disease-associated target genes within JAK2V617F-MPNs. These findings restore the potential for specific therapeutic targeting of HIF-1 by delineating malignant activation from the physiological hypoxic response.
{"title":"JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms","authors":"David Kealy, Ruth Ellerington, Suraj Bansal, Jessie J. F. Medeiros, Catherine A. Hawley, Andy G. X. Zeng, Jakub Lukaszonek, Katie A. West, Aparna D. Sinha, Gillian Caalim, Richard T. Gawne, Jacob Pope, Bianca Lima Ferreira, Nicole-Mae Blacknell, Bryce Drylie, Jenny Chatzigerou, Hwei Minn Khoo, Adam C. Wilkinson, Adele K. Fielding, Guanlin Wang, Bethan Psaila, David G. Kent, Ian S. Hitchcock, Andrew N. Holding, Andrew S. Mason, Vikas Gupta, John E. Dick, Katherine S. Bridge","doi":"10.1038/s41375-025-02843-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02843-9","url":null,"abstract":"Hypoxia-inducible factors (HIFs) are master transcriptional regulators, central to cellular survival in hypoxia and frequently activated within malignancy. Whilst malignant context directs the role of HIFs within oncogenesis, these mechanisms are not well characterised. Applying the JAK2V617F myeloproliferative neoplasms (MPNs) oncogene-driver model, in which HIF-1α is stabilised in normoxia (20% O2), we sought to determine whether the modality of HIF-1 activation directs its function. Through direct analysis of hypoxia-activated vs. JAK2V617F-activated HIF-1 at the chromatin, we define a JAK2V617F-HIF-1 regulon that diverges from canonical HIF/hypoxia targets. In a cohort of 172 JAK2V617F-MPN patients, we observe significant association of the JAK2V617F-HIF-1 regulon, but not canonical HIF-1 gene signatures, with disease severity, progression, and patient survival. We further define a subset gene signature (HIF1-MPN-BP) significantly associated with spontaneous transformation to blast phase MPNs. Finally, we identify that JAK2V617F-induced HIF-1α stabilisation is mediated via PIM1 kinase. Our findings demonstrate that HIF-1 activation by the JAK2V617F-PIM1 axis significantly alters HIF-1 transcription function, desensitising HIF-1 activity to cellular oxygen levels, and restricting the HIF-1 regulon to a set of disease-associated target genes within JAK2V617F-MPNs. These findings restore the potential for specific therapeutic targeting of HIF-1 by delineating malignant activation from the physiological hypoxic response.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"14 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102075","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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