Pub Date : 2025-12-19DOI: 10.1038/s41375-025-02842-w
Christine E Birdwell,Warren Fiskus,Christopher P Mill,Tapan M Kadia,Naval Daver,Courtney D DiNardo,Koji Sasaki,John A Davis,Kaberi Das,Hanxi Hou,Antrix Jain,Anna Malovannaya,Lauren B Flores,Rasoul Pourebrahim,Selina Yuan,Xiaoping Su,Michele Ceribelli,Kapil N Bhalla
MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry analyses revealed that treatment with mivebresib or dactolisib downregulated MYC-targets and cell-cycle gene-sets whereas CyTOF and Western analyses also demonstrated reduction in the protein levels of EVI1, c-Myb, c-Myc in MECOM-r AML cells. Combination of mivebresib and dactolisib or LCL161 synergistically induced apoptosis. In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.
{"title":"BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML.","authors":"Christine E Birdwell,Warren Fiskus,Christopher P Mill,Tapan M Kadia,Naval Daver,Courtney D DiNardo,Koji Sasaki,John A Davis,Kaberi Das,Hanxi Hou,Antrix Jain,Anna Malovannaya,Lauren B Flores,Rasoul Pourebrahim,Selina Yuan,Xiaoping Su,Michele Ceribelli,Kapil N Bhalla","doi":"10.1038/s41375-025-02842-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02842-w","url":null,"abstract":"MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry analyses revealed that treatment with mivebresib or dactolisib downregulated MYC-targets and cell-cycle gene-sets whereas CyTOF and Western analyses also demonstrated reduction in the protein levels of EVI1, c-Myb, c-Myc in MECOM-r AML cells. Combination of mivebresib and dactolisib or LCL161 synergistically induced apoptosis. In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"173 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786152","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 : 2025-12-19DOI: 10.1038/s41375-025-02819-9
Joshua N Gustine,John A Scaringi,Fabian Bauer,Diana D Cirstea,Andrew R Branagan,Benjamin R Puliafito,Marcela V Maus,Matthew J Frigault,Andrew J Yee,Umar Mahmood,Noopur S Raje
{"title":"Prognostic value of serological and PET/CT response kinetics in patients with multiple myeloma treated with BCMA CAR-T.","authors":"Joshua N Gustine,John A Scaringi,Fabian Bauer,Diana D Cirstea,Andrew R Branagan,Benjamin R Puliafito,Marcela V Maus,Matthew J Frigault,Andrew J Yee,Umar Mahmood,Noopur S Raje","doi":"10.1038/s41375-025-02819-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02819-9","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"114 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786154","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 : 2025-12-19DOI: 10.1038/s41375-025-02835-9
Anna Fedenko,Honorata Czapinska,Alwin Krämer,Friedrich Stölzel,Tilmann Bochtler,Matthias Bochtler
SCHEMATIC VIEW OF THE DEVELOPMENT OF CK-AML DRIVEN BY THE TP53 ABSENCE.: The occurrence of the first, often dominant negative TP53 mutation is quickly followed by the loss of the second TP53 allele and numerous further chromosomal aberrations.
{"title":"Etiology of TP53 mutated complex karyotype acute myeloid leukemia.","authors":"Anna Fedenko,Honorata Czapinska,Alwin Krämer,Friedrich Stölzel,Tilmann Bochtler,Matthias Bochtler","doi":"10.1038/s41375-025-02835-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02835-9","url":null,"abstract":"SCHEMATIC VIEW OF THE DEVELOPMENT OF CK-AML DRIVEN BY THE TP53 ABSENCE.: The occurrence of the first, often dominant negative TP53 mutation is quickly followed by the loss of the second TP53 allele and numerous further chromosomal aberrations.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"22 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786156","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 : 2025-12-19DOI: 10.1038/s41375-025-02816-y
Tzu-Chieh Ho, Mark W LaMere, Hiroki Kawano, Daniel K Byun, Elizabeth A LaMere, Yu-Chiao Chiu, Chunmo Chen, Li-Ju Wang, Jian Wang, Baskar Ramdas, Nikolay V Dokholyan, Laura M Calvi, Jane L Liesveld, Craig T Jordan, Rakesh K Singh, Reuben Kapur, Michael W Becker
Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.
{"title":"Targeting IL-1/IRAK1/4 signaling in acute myeloid leukemia stem cells following treatment and relapse.","authors":"Tzu-Chieh Ho, Mark W LaMere, Hiroki Kawano, Daniel K Byun, Elizabeth A LaMere, Yu-Chiao Chiu, Chunmo Chen, Li-Ju Wang, Jian Wang, Baskar Ramdas, Nikolay V Dokholyan, Laura M Calvi, Jane L Liesveld, Craig T Jordan, Rakesh K Singh, Reuben Kapur, Michael W Becker","doi":"10.1038/s41375-025-02816-y","DOIUrl":"10.1038/s41375-025-02816-y","url":null,"abstract":"<p><p>Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793921","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 : 2025-12-19DOI: 10.1038/s41375-025-02823-z
Catarina M Stein,Raphael Hablesreiter,Friederike Christen,Pelle Löwe,Coral Fustero-Torre,Klara Kopp,Benjamin N Locher,Lena Nitsch,Robert Altwasser,Johanna Franziska Kerschbaum,Lars Bullinger,Leif S Ludwig,Paulina M Strzelecka,Frederik Damm
Autologous stem cell transplantation (ASCT) involves harvesting hematopoietic stem and progenitor cells (HSPCs) prior to chemotherapy and subsequent repopulation of the bone marrow. This process imposes a bottleneck, providing a framework to dissect the unresolved short- and long-term clonal dynamics during hematopoietic reconstitution. By integrating bulk error-corrected targeted sequencing of clonal hematopoiesis (CH)-associated genes with mitochondrial single-cell Assay for Transposase-Accessible Chromatin sequencing (mtscATAC-seq), we characterized mutational trajectories in frequently altered hematological genes and traced clonal evolution through somatic mitochondrial DNA variants, revealing post-transplant cellular heterogeneity and clonal architecture. Among 60 patients (multiple myeloma, n = 51; non-Hodgkin lymphoma, n = 6; Hodgkin lymphoma, n = 3), CH-associated mutations were identified in 53% pre-ASCT, predominantly involving DNMT3A. A transient increase in mutation counts and gene diversity occurred 10-25 days post-ASCT, with a gradual clonal expansion two years post-transplantation. Tandem ASCT amplified clonal complexity, with a twofold increase in mutation count and gene-level diversity, while preserving clonal trajectories across both transplant courses. Mitochondrial single-cell profiling in longitudinal samples of 3 patients showed patient-specific immune reconstitution and clonal dynamics, with balanced multilineage output from graft HSPCs. Collectively, our findings provide a firsthand comprehensive view of ASCT-induced clonal dynamics and immune reconstitution, paving the way for targeted gene-specific post-transplant monitoring.
{"title":"Dynamics of clonal hematopoiesis and cellular responses to stress-induced toxicity in autologous stem cell transplantation.","authors":"Catarina M Stein,Raphael Hablesreiter,Friederike Christen,Pelle Löwe,Coral Fustero-Torre,Klara Kopp,Benjamin N Locher,Lena Nitsch,Robert Altwasser,Johanna Franziska Kerschbaum,Lars Bullinger,Leif S Ludwig,Paulina M Strzelecka,Frederik Damm","doi":"10.1038/s41375-025-02823-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02823-z","url":null,"abstract":"Autologous stem cell transplantation (ASCT) involves harvesting hematopoietic stem and progenitor cells (HSPCs) prior to chemotherapy and subsequent repopulation of the bone marrow. This process imposes a bottleneck, providing a framework to dissect the unresolved short- and long-term clonal dynamics during hematopoietic reconstitution. By integrating bulk error-corrected targeted sequencing of clonal hematopoiesis (CH)-associated genes with mitochondrial single-cell Assay for Transposase-Accessible Chromatin sequencing (mtscATAC-seq), we characterized mutational trajectories in frequently altered hematological genes and traced clonal evolution through somatic mitochondrial DNA variants, revealing post-transplant cellular heterogeneity and clonal architecture. Among 60 patients (multiple myeloma, n = 51; non-Hodgkin lymphoma, n = 6; Hodgkin lymphoma, n = 3), CH-associated mutations were identified in 53% pre-ASCT, predominantly involving DNMT3A. A transient increase in mutation counts and gene diversity occurred 10-25 days post-ASCT, with a gradual clonal expansion two years post-transplantation. Tandem ASCT amplified clonal complexity, with a twofold increase in mutation count and gene-level diversity, while preserving clonal trajectories across both transplant courses. Mitochondrial single-cell profiling in longitudinal samples of 3 patients showed patient-specific immune reconstitution and clonal dynamics, with balanced multilineage output from graft HSPCs. Collectively, our findings provide a firsthand comprehensive view of ASCT-induced clonal dynamics and immune reconstitution, paving the way for targeted gene-specific post-transplant monitoring.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"93 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786155","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 : 2025-12-19DOI: 10.1038/s41375-025-02826-w
Philipp Ernst, Cera Lohse, Michael Lauseker, Jan Geißler, Philipp le Coutre, Tim H. Brümmendorf, Susanne Saußele, Andreas Burchert, Georg-Nikolaus Franke, Paul La Rosée, Annamaria Brioli, Thomas Schenk, Christian Fabisch, Thomas Ernst, Guido Mehlkop, Andreas Hochhaus
Chronic myeloid leukemia (CML) is a chronic condition with excellent long-term survival under tyrosine kinase inhibitor (TKI) therapy. However, patient priorities regarding treatment goals and quality of life remain insufficiently understood. We conducted a nationwide online survey among German CML patients in collaboration with the German CML Alliance and patient organizations to assess treatment goals at diagnosis, during therapy, and in the treatment-free remission phase. The questionnaire included validated measures of treatment satisfaction, fear of progression, and quality-of-life priorities, supplemented by newly developed items. Between November 2024 and February 2025, 582 patients (median age 56 years, 48.8% female) completed the survey. Overall TKI tolerability was rated positively (median 4/5), particularly in first-line therapy and among patients with shorter disease duration, whereas long-term survivors reported more daily-life limitations. Younger patients ( < 45 years) emphasized fertility, sexuality, and work-related concerns, while older patients prioritized tolerability, independence, and mental health. Treatment history shaped expectations: those with discontinuation experience were more willing to accept adverse effects for the prospect of remission. Overall, patient priorities diverged between achieving deep molecular response and maintaining optimal tolerability. Integrating patient-reported preferences into shared decision-making may enhance satisfaction, adherence, and long-term outcomes of patients with CML.
{"title":"Treatment expectations and goals among patients with chronic myeloid leukemia in Germany: a patient-centered perspective","authors":"Philipp Ernst, Cera Lohse, Michael Lauseker, Jan Geißler, Philipp le Coutre, Tim H. Brümmendorf, Susanne Saußele, Andreas Burchert, Georg-Nikolaus Franke, Paul La Rosée, Annamaria Brioli, Thomas Schenk, Christian Fabisch, Thomas Ernst, Guido Mehlkop, Andreas Hochhaus","doi":"10.1038/s41375-025-02826-w","DOIUrl":"10.1038/s41375-025-02826-w","url":null,"abstract":"Chronic myeloid leukemia (CML) is a chronic condition with excellent long-term survival under tyrosine kinase inhibitor (TKI) therapy. However, patient priorities regarding treatment goals and quality of life remain insufficiently understood. We conducted a nationwide online survey among German CML patients in collaboration with the German CML Alliance and patient organizations to assess treatment goals at diagnosis, during therapy, and in the treatment-free remission phase. The questionnaire included validated measures of treatment satisfaction, fear of progression, and quality-of-life priorities, supplemented by newly developed items. Between November 2024 and February 2025, 582 patients (median age 56 years, 48.8% female) completed the survey. Overall TKI tolerability was rated positively (median 4/5), particularly in first-line therapy and among patients with shorter disease duration, whereas long-term survivors reported more daily-life limitations. Younger patients ( < 45 years) emphasized fertility, sexuality, and work-related concerns, while older patients prioritized tolerability, independence, and mental health. Treatment history shaped expectations: those with discontinuation experience were more willing to accept adverse effects for the prospect of remission. Overall, patient priorities diverged between achieving deep molecular response and maintaining optimal tolerability. Integrating patient-reported preferences into shared decision-making may enhance satisfaction, adherence, and long-term outcomes of patients with CML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"29-36"},"PeriodicalIF":13.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02826-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786151","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}
Pub Date : 2025-12-19DOI: 10.1038/s41375-025-02820-2
Marietta Truger, Manja Meggendorfer, Wencke Walter, Stephan Hutter, Winfried Alsdorf, Gero Massenkeil, Uwe M. Martens, Wolfgang Kern, Katharina Hörst, Constanze Kühn, Andreas Reiter, Andreas Hochhaus, Torsten Haferlach
In the rapidly evolving field of hematology, the diagnosis of leukemias and lymphomas poses major challenges, despite significant genetic advancements. Although established diagnostic methods comprise a multidisciplinary approach and are considered gold standard, in some cases they fall short in conclusively identifying hematological neoplasms. In this context, the current SIRIUS study (NCT05046444) delves into the potential of whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) to bridge diagnostic gaps. By analyzing 106 patients with an unclear diagnosis or clinical condition following gold standard diagnostics, our study demonstrates that WGS and WTS can uncover a broader range of somatic alterations, including rare single-nucleotide variants (SNVs), small copy number variations (CNVs), and aberrant gene expression patterns not detected by conventional diagnostics. WGS and WTS provided additional diagnostic insights in 25% of cases, suggesting their value not only in enhancing diagnostic accuracy but also in contributing to more informed prognostic assessments and personalized treatment strategies. Therefore, our study underscores the importance of integrating WGS and WTS into the diagnostic toolbox for hematological neoplasms. This approach promises not only to improve patient outcomes but also to do so in a manner that is both financially sustainable and ethically sound.
{"title":"Solving Riddles Through Sequencing (SIRIUS): unlocking hematologic diagnoses by whole genome and transcriptome sequencing","authors":"Marietta Truger, Manja Meggendorfer, Wencke Walter, Stephan Hutter, Winfried Alsdorf, Gero Massenkeil, Uwe M. Martens, Wolfgang Kern, Katharina Hörst, Constanze Kühn, Andreas Reiter, Andreas Hochhaus, Torsten Haferlach","doi":"10.1038/s41375-025-02820-2","DOIUrl":"10.1038/s41375-025-02820-2","url":null,"abstract":"In the rapidly evolving field of hematology, the diagnosis of leukemias and lymphomas poses major challenges, despite significant genetic advancements. Although established diagnostic methods comprise a multidisciplinary approach and are considered gold standard, in some cases they fall short in conclusively identifying hematological neoplasms. In this context, the current SIRIUS study (NCT05046444) delves into the potential of whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) to bridge diagnostic gaps. By analyzing 106 patients with an unclear diagnosis or clinical condition following gold standard diagnostics, our study demonstrates that WGS and WTS can uncover a broader range of somatic alterations, including rare single-nucleotide variants (SNVs), small copy number variations (CNVs), and aberrant gene expression patterns not detected by conventional diagnostics. WGS and WTS provided additional diagnostic insights in 25% of cases, suggesting their value not only in enhancing diagnostic accuracy but also in contributing to more informed prognostic assessments and personalized treatment strategies. Therefore, our study underscores the importance of integrating WGS and WTS into the diagnostic toolbox for hematological neoplasms. This approach promises not only to improve patient outcomes but also to do so in a manner that is both financially sustainable and ethically sound.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"55-62"},"PeriodicalIF":13.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02820-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786153","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}
Pub Date : 2025-12-17DOI: 10.1038/s41375-025-02839-5
Jonas Fullin, Ebru Topçu, Karolina A. Zielińska, Roman R. Schimmer, Nancy Klemm, Christian Koch, Francisco Caiado, Melissa Lock, Cyril Doerdelmann, Marco M. Bühler, Joelle Tchinda, Kari J. Kurppa, Lubor Borsig, Philip H. Jones, Massimo Lopes, Markus G. Manz, Steffen Boettcher
Therapy-related acute myeloid leukemia and myelodysplastic neoplasms (t-AML/MDS) are devastating complications of chemo- or radiation therapy in patients treated for an unrelated primary malignancy. Cancer patients with TP53-mutant hematopoietic stem and progenitor cells (HSPCs) – a condition termed clonal hematopoiesis (CH) – are at a particularly high risk for t-AML/MDS. However, the pathogenesis of TP53-mutant t-AML/MDS, especially the role of the TP53 allelic state (i.e., mono- vs. biallelic), and its prognostic impact in AML/MDS have remained only poorly understood. We developed novel in vitro and in vivo mouse models to investigate how mono- or biallelic Trp53 mutations influence clonal expansion and leukemic progression from CH to t-AML/MDS. While HSPCs with monoallelic Trp53 mutations gain clonal fitness but retain their genomic integrity under chemo- or radiation therapy, biallelic Trp53 mutations result in genomic instability and are essential for leukemic transformation. Moreover, we provide proof of concept that non-mutational p53 inactivation, such as MDM2 overexpression, can replicate the effects of biallelic TP53 mutations, providing a possible explanation for cases of TP53-mutant AML/MDS that retain one wild-type TP53 allele. Our findings elucidate the pathogenesis of TP53-mutant t-AML/MDS and support the classification of biallelic TP53-mutant AML/MDS as distinct clinical entities.
{"title":"The pathogenesis of therapy-related myeloid neoplasms from TP53-mutant clonal hematopoiesis","authors":"Jonas Fullin, Ebru Topçu, Karolina A. Zielińska, Roman R. Schimmer, Nancy Klemm, Christian Koch, Francisco Caiado, Melissa Lock, Cyril Doerdelmann, Marco M. Bühler, Joelle Tchinda, Kari J. Kurppa, Lubor Borsig, Philip H. Jones, Massimo Lopes, Markus G. Manz, Steffen Boettcher","doi":"10.1038/s41375-025-02839-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02839-5","url":null,"abstract":"Therapy-related acute myeloid leukemia and myelodysplastic neoplasms (t-AML/MDS) are devastating complications of chemo- or radiation therapy in patients treated for an unrelated primary malignancy. Cancer patients with TP53-mutant hematopoietic stem and progenitor cells (HSPCs) – a condition termed clonal hematopoiesis (CH) – are at a particularly high risk for t-AML/MDS. However, the pathogenesis of TP53-mutant t-AML/MDS, especially the role of the TP53 allelic state (i.e., mono- vs. biallelic), and its prognostic impact in AML/MDS have remained only poorly understood. We developed novel in vitro and in vivo mouse models to investigate how mono- or biallelic Trp53 mutations influence clonal expansion and leukemic progression from CH to t-AML/MDS. While HSPCs with monoallelic Trp53 mutations gain clonal fitness but retain their genomic integrity under chemo- or radiation therapy, biallelic Trp53 mutations result in genomic instability and are essential for leukemic transformation. Moreover, we provide proof of concept that non-mutational p53 inactivation, such as MDM2 overexpression, can replicate the effects of biallelic TP53 mutations, providing a possible explanation for cases of TP53-mutant AML/MDS that retain one wild-type TP53 allele. Our findings elucidate the pathogenesis of TP53-mutant t-AML/MDS and support the classification of biallelic TP53-mutant AML/MDS as distinct clinical entities.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"50 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765575","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 : 2025-12-12DOI: 10.1038/s41375-025-02817-x
Nadine E Struckman,Georgia Koutsoumpli,Rob C M de Jong,Dyantha I van der Lee,Dennis F G Remst,Sophie-Anne I Smith,M Willy Honders,Renate S Hagedoorn,Arnoud H de Ru,Masashi Matsuda,Fumihiko Ishikawa,Tamar Tak,Peter J M Valk,Mirjam H M Heemskerk,Peter A van Veelen,J H Frederik Falkenburg,Marieke Griffioen
Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoietic differentiation. RUNX1 mutations in acute myeloid leukemia (AML) are associated with poor prognosis. One-third are frameshift mutations encoding an oncogenic protein with an elongated C-terminus translated in an alternative reading frame. Here, we investigated whether the alternative reading frame of oncogenic RUNX1 can be targeted by immunotherapy. We introduced a construct with a RUNX1 frameshift mutation into B-cell lines with common HLA class I alleles and identified 13 neopeptides by immunopeptidomics. To investigate whether these peptides are neoantigens, peptide-MHC tetramers were used to screen healthy individuals for RUNX1 neoantigen-specific CD8 T cells. T-cell clones were isolated against 5 neoantigens in 4 HLA alleles. Two neoantigens were recognized on an HLA-B*07:02-positive AML cell line with an endogenous RUNX1 frameshift mutation. The T-cell receptors (TCRs) of these clones were sequenced, and analyzed after transfer into CD8 T cells. One TCR induced effective killing of RUNX1-mutated AML cells in vitro and in immunodeficient mice. TCR-engineered T cells also killed patient-derived AML cells, including leukemic stem cells. In conclusion, we showed that RUNX1 frameshift mutations can be effectively targeted, demonstrating the potential relevance of TCR-based immunotherapy to treat patients with RUNX1-mutated AML.
{"title":"A T-cell receptor targeting RUNX1 frameshift mutations in acute myeloid leukemia.","authors":"Nadine E Struckman,Georgia Koutsoumpli,Rob C M de Jong,Dyantha I van der Lee,Dennis F G Remst,Sophie-Anne I Smith,M Willy Honders,Renate S Hagedoorn,Arnoud H de Ru,Masashi Matsuda,Fumihiko Ishikawa,Tamar Tak,Peter J M Valk,Mirjam H M Heemskerk,Peter A van Veelen,J H Frederik Falkenburg,Marieke Griffioen","doi":"10.1038/s41375-025-02817-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02817-x","url":null,"abstract":"Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoietic differentiation. RUNX1 mutations in acute myeloid leukemia (AML) are associated with poor prognosis. One-third are frameshift mutations encoding an oncogenic protein with an elongated C-terminus translated in an alternative reading frame. Here, we investigated whether the alternative reading frame of oncogenic RUNX1 can be targeted by immunotherapy. We introduced a construct with a RUNX1 frameshift mutation into B-cell lines with common HLA class I alleles and identified 13 neopeptides by immunopeptidomics. To investigate whether these peptides are neoantigens, peptide-MHC tetramers were used to screen healthy individuals for RUNX1 neoantigen-specific CD8 T cells. T-cell clones were isolated against 5 neoantigens in 4 HLA alleles. Two neoantigens were recognized on an HLA-B*07:02-positive AML cell line with an endogenous RUNX1 frameshift mutation. The T-cell receptors (TCRs) of these clones were sequenced, and analyzed after transfer into CD8 T cells. One TCR induced effective killing of RUNX1-mutated AML cells in vitro and in immunodeficient mice. TCR-engineered T cells also killed patient-derived AML cells, including leukemic stem cells. In conclusion, we showed that RUNX1 frameshift mutations can be effectively targeted, demonstrating the potential relevance of TCR-based immunotherapy to treat patients with RUNX1-mutated AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"157 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732710","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 : 2025-12-10DOI: 10.1038/s41375-025-02822-0
Ellen Nuttall Musson, Yvette Hoade, Phoebe Dace, Javier Herrero, Spiros Denaxas, Andrew Steptoe, Elspeth Payne
{"title":"Analysis of the association of lipid-lowering therapy on clonal dynamics in clonal haematopoiesis of indeterminate potential: insights from the English Longitudinal Study of Ageing","authors":"Ellen Nuttall Musson, Yvette Hoade, Phoebe Dace, Javier Herrero, Spiros Denaxas, Andrew Steptoe, Elspeth Payne","doi":"10.1038/s41375-025-02822-0","DOIUrl":"https://doi.org/10.1038/s41375-025-02822-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"10 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711559","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：