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}
Pub Date : 2025-12-10DOI: 10.1038/s41375-025-02825-x
Lukas H. Haaksma, Raffaele Palmieri, Tom Reuvekamp, Jesse M. Tettero, Lok Lam Ngai, Costa Bachas, Angèle Kelder, Willemijn J. Scholten, Patrycja Gradowska, Valentina Arena, Anderson João Simione, Luca Maurillo, Adriano Venditti, Bob Löwenberg, Gert J. Ossenkoppele, David C. de Leeuw, Maura R. V. Ikoma-Colturato, Francesco Buccisano, Jacqueline Cloos
{"title":"Prognostic relevance of limit of quantification as low-level cutoff for flow cytometry-based measurable residual disease assessment in acute myeloid leukemia","authors":"Lukas H. Haaksma, Raffaele Palmieri, Tom Reuvekamp, Jesse M. Tettero, Lok Lam Ngai, Costa Bachas, Angèle Kelder, Willemijn J. Scholten, Patrycja Gradowska, Valentina Arena, Anderson João Simione, Luca Maurillo, Adriano Venditti, Bob Löwenberg, Gert J. Ossenkoppele, David C. de Leeuw, Maura R. V. Ikoma-Colturato, Francesco Buccisano, Jacqueline Cloos","doi":"10.1038/s41375-025-02825-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02825-x","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"365 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711544","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/s41375-025-02827-9
Courtney D. DiNardo, Wei-Ying Jen, Koichi Takahashi, Tapan M. Kadia, Sanam Loghavi, Naval G. Daver, Lianchun Xiao, Patrick K. Reville, Ghayas C. Issa, Nicholas J. Short, Koji Sasaki, Sa A. Wang, Jillian K. Mullin, Sherry Pierce, Corey Bradley, Gautam Borthakur, Abhishek Maiti, Yesid Alvarado, Naveen Pemmaraju, Alessandra Ferrajoli, Mahesh Swaminathan, Maro Ohanian, Hussein A. Abbas, Danielle Hammond, Jan Burger, Fadi Haddad, Guillermo Montalban-Bravo, Kelly Chien, Lucia Masarova, Musa Yilmaz, Nitin Jain, Michael Andreeff, Guillermo Garcia-Manero, Steven Kornblau, Farhad Ravandi, Elias Jabbour, Marina Y. Konopleva, Hagop M. Kantarjian
{"title":"Correction: Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia","authors":"Courtney D. DiNardo, Wei-Ying Jen, Koichi Takahashi, Tapan M. Kadia, Sanam Loghavi, Naval G. Daver, Lianchun Xiao, Patrick K. Reville, Ghayas C. Issa, Nicholas J. Short, Koji Sasaki, Sa A. Wang, Jillian K. Mullin, Sherry Pierce, Corey Bradley, Gautam Borthakur, Abhishek Maiti, Yesid Alvarado, Naveen Pemmaraju, Alessandra Ferrajoli, Mahesh Swaminathan, Maro Ohanian, Hussein A. Abbas, Danielle Hammond, Jan Burger, Fadi Haddad, Guillermo Montalban-Bravo, Kelly Chien, Lucia Masarova, Musa Yilmaz, Nitin Jain, Michael Andreeff, Guillermo Garcia-Manero, Steven Kornblau, Farhad Ravandi, Elias Jabbour, Marina Y. Konopleva, Hagop M. Kantarjian","doi":"10.1038/s41375-025-02827-9","DOIUrl":"10.1038/s41375-025-02827-9","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"262-262"},"PeriodicalIF":13.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02827-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724476","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 : 2025-12-10DOI: 10.1038/s41375-025-02838-6
R P Gale,A Hochhaus
{"title":"Things that drive Editors crazy: jargon, unnecessary abbreviations, abusing decimals and a few more.","authors":"R P Gale,A Hochhaus","doi":"10.1038/s41375-025-02838-6","DOIUrl":"https://doi.org/10.1038/s41375-025-02838-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"29 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717998","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 : 2025-12-09DOI: 10.1038/s41375-025-02818-w
Léa Dehgane, Eliane Mallet, Constance Brasseur, Daphné Krzisch, Wail Zeitouni, Casilda Hitier, Marianne Ayoub, Kenza Dubois, Claudia Pérez Carretero, Damien Roos-Weil, Sylvain Choquet, Karim Maloum, Clotilde Bravetti, Marine Armand, Delphine Garnier, Jesús-María Hernández-Rivas, Santos A. Susin, Florence Nguyen-Khac, Elise Chapiro, On behalf of the French Innovative Leukemia Organization (FILO)
The gain of chromosome 2p (2p+) is a recurrent abnormality in chronic lymphocytic leukemia (CLL), frequently observed in advanced or relapsed disease, associated with poor prognosis and reduced response to Bruton’s tyrosine kinase inhibitors (BTKi). To investigate the mechanisms of 2p+-mediated resistance, we performed single-cell RNA sequencing, revealing NF-κB pathway enrichment and REL overexpression in 2p+ B cells. In vitro analyses confirmed increased REL expression and DNA-binding activity in a large cohort of 2p+ primary CLL samples. Functionally, 2p+ CLL cells showed reduced sensitivity to both covalent and non-covalent BTKi. Moreover, upon ibrutinib treatment, REL DNA-binding activity decreased in 2pWT CLL cells but remained sustained in 2p+ CLL cells following BCR stimulation, suggesting that persistent NF-κB activation contributes to resistance. Consistently, CRISPR/Cas9-mediated inactivation of REL in a 2p+ B-lymphoid cell line led to downregulation of canonical NF-κB signaling and restored BTKi sensitivity. Clinically, patients with 2p+ CLL treated with BTKi had a shorter time-to-next-treatment than 2pWT patients. Altogether, our study identifies REL overexpression as a novel 2p+-driven mechanism of BTKi resistance in CLL, complementing the well described BTK and PLCG2 mutations. These findings support the clinical relevance of detecting 2p gain to guide treatment strategies and improve outcomes in CLL.
{"title":"REL overexpression and sustained NF-κB signaling associated with 2p gain induce resistance to BTK inhibitors in Chronic Lymphocytic Leukemia","authors":"Léa Dehgane, Eliane Mallet, Constance Brasseur, Daphné Krzisch, Wail Zeitouni, Casilda Hitier, Marianne Ayoub, Kenza Dubois, Claudia Pérez Carretero, Damien Roos-Weil, Sylvain Choquet, Karim Maloum, Clotilde Bravetti, Marine Armand, Delphine Garnier, Jesús-María Hernández-Rivas, Santos A. Susin, Florence Nguyen-Khac, Elise Chapiro, On behalf of the French Innovative Leukemia Organization (FILO)","doi":"10.1038/s41375-025-02818-w","DOIUrl":"10.1038/s41375-025-02818-w","url":null,"abstract":"The gain of chromosome 2p (2p+) is a recurrent abnormality in chronic lymphocytic leukemia (CLL), frequently observed in advanced or relapsed disease, associated with poor prognosis and reduced response to Bruton’s tyrosine kinase inhibitors (BTKi). To investigate the mechanisms of 2p+-mediated resistance, we performed single-cell RNA sequencing, revealing NF-κB pathway enrichment and REL overexpression in 2p+ B cells. In vitro analyses confirmed increased REL expression and DNA-binding activity in a large cohort of 2p+ primary CLL samples. Functionally, 2p+ CLL cells showed reduced sensitivity to both covalent and non-covalent BTKi. Moreover, upon ibrutinib treatment, REL DNA-binding activity decreased in 2pWT CLL cells but remained sustained in 2p+ CLL cells following BCR stimulation, suggesting that persistent NF-κB activation contributes to resistance. Consistently, CRISPR/Cas9-mediated inactivation of REL in a 2p+ B-lymphoid cell line led to downregulation of canonical NF-κB signaling and restored BTKi sensitivity. Clinically, patients with 2p+ CLL treated with BTKi had a shorter time-to-next-treatment than 2pWT patients. Altogether, our study identifies REL overexpression as a novel 2p+-driven mechanism of BTKi resistance in CLL, complementing the well described BTK and PLCG2 mutations. These findings support the clinical relevance of detecting 2p gain to guide treatment strategies and improve outcomes in CLL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"188-198"},"PeriodicalIF":13.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705082","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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