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":"10.1038/s41375-025-02838-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"263-264"},"PeriodicalIF":13.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02838-6.pdf","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":"OA","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}
Pub Date : 2025-12-09DOI: 10.1038/s41375-025-02815-z
Xuxiang Liu, Yunfei Shi, Jibin Zhang, Kunal Shetty, Krystie Chew, Can Küçük, Qiang Gong, Esra Esmeray, Haiqing Li, Ru Chen, Sheng Pan, Katarzyna Dąbrowska, Roger E. Moore, Krystine Garcia-Mansfield, Patrick Pirrotte, Jinhui Wang, Yuping Li, Gehong Dong, Logan Lee, Timothy W. McKeithan, Javeed Iqbal, Wing C. Chan
PRDM1, encoding a transcription factor (TF), regulates plasma cell and CD8+ T-cell terminal differentiation and Th2 lineage specification, while its role in human NK-cell differentiation and homeostasis is largely unknown. Here, we employed a multi-omics approach to dissect the transcriptional control of PRDM1 on human NK-cells. PRDM1 is important in NK-cell terminal differentiation based on gene expression profiling and its targeting of key regulators in the process. PRDM1-deleted NK-cells displayed a less mature phenotype simulating the CD56bright NK-cell population accompanied by upregulation of stem-like gene signatures. PRDM1-bound genes were enriched in T/NK-cell receptor signaling, activation, and NK-cell effector functions. PRDM1 could function as a transcriptional repressor as well as an activator as its activities may be modified by association with different TFs and co-factors. The kinetics of its action also varies among its target genes. As a homeostatic factor, PRDM1 is induced upon IL-2 and feeder cell stimulation, but its ability to restrict NK-cell growth upon feeder stimulation may be counteracted by the AP-1-induced transcriptional network. The loss of PRDM1 activity is frequent in NK-cell malignancies which may lead to decreased homeostatic control, impaired terminal differentiation, enhanced cellular fitness, and the acquisition of more stem-like features, thereby promoting lymphomagenesis.
{"title":"Key regulatory roles of PRDM1 in human NK-cell differentiation and activation","authors":"Xuxiang Liu, Yunfei Shi, Jibin Zhang, Kunal Shetty, Krystie Chew, Can Küçük, Qiang Gong, Esra Esmeray, Haiqing Li, Ru Chen, Sheng Pan, Katarzyna Dąbrowska, Roger E. Moore, Krystine Garcia-Mansfield, Patrick Pirrotte, Jinhui Wang, Yuping Li, Gehong Dong, Logan Lee, Timothy W. McKeithan, Javeed Iqbal, Wing C. Chan","doi":"10.1038/s41375-025-02815-z","DOIUrl":"10.1038/s41375-025-02815-z","url":null,"abstract":"PRDM1, encoding a transcription factor (TF), regulates plasma cell and CD8+ T-cell terminal differentiation and Th2 lineage specification, while its role in human NK-cell differentiation and homeostasis is largely unknown. Here, we employed a multi-omics approach to dissect the transcriptional control of PRDM1 on human NK-cells. PRDM1 is important in NK-cell terminal differentiation based on gene expression profiling and its targeting of key regulators in the process. PRDM1-deleted NK-cells displayed a less mature phenotype simulating the CD56bright NK-cell population accompanied by upregulation of stem-like gene signatures. PRDM1-bound genes were enriched in T/NK-cell receptor signaling, activation, and NK-cell effector functions. PRDM1 could function as a transcriptional repressor as well as an activator as its activities may be modified by association with different TFs and co-factors. The kinetics of its action also varies among its target genes. As a homeostatic factor, PRDM1 is induced upon IL-2 and feeder cell stimulation, but its ability to restrict NK-cell growth upon feeder stimulation may be counteracted by the AP-1-induced transcriptional network. The loss of PRDM1 activity is frequent in NK-cell malignancies which may lead to decreased homeostatic control, impaired terminal differentiation, enhanced cellular fitness, and the acquisition of more stem-like features, thereby promoting lymphomagenesis.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"199-210"},"PeriodicalIF":13.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02815-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705080","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 : 2025-12-08DOI: 10.1038/s41375-025-02804-2
Theis Mikkelsen, Marianne Helenius, Mirella Ampatzidou, Andishe Attarbaschi, Liv Andres-Jensen, Arndt Borkhardt, Nuria Conde Cuevas, Gabriele Escherich, Melanie M. Hagleitner, Christina Halsey, Jonathan Josephs-Spaulding, Louise Lundgren, Simone Pehn, Sophia Polychronopoulou, Ulrik Stoltze, Linea Natalie Toksvang, Ayo Wahlberg, Stefanie Verena Junk, Kjeld Schmiegelow
Childhood acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease, and while somatic alterations inform diagnosis and treatment stratification, germline variants - particularly common host genome variants - rarely influence clinical care. Over the past decade, various host genome variant studies have uncovered numerous common variants associated with ALL susceptibility, treatment efficacy, and toxicity risk. Yet, less than a handful have reached clinical implementation, with TPMT and NUDT15 variants being the only ones widely used clinically. Whether a variant can be readily translated into the clinical setting primarily depends on four features: (1) Phenotype severity, (2) phenotype rarity and the proportion of cases (overall or in subsets of patients) accounted for by genetic variants, (3) the application of the variant as an add-on clinical decision support tool, and (4) the availability, cost, and potential side effects of interventions and/or prophylaxis. Key barriers for such clinical translation include insufficient effect sizes, lack of replication across diverse populations, and lack of well-established treatment modification strategies. However, large-scale international collaborations can generate the necessary statistical power, including enabling more complex bioinformatic approaches, such as polygenic risk scores and more advanced machine learning strategies. In this review, we outline the necessary steps toward bridging the gap between genetic discovery and clinical practice.
{"title":"Role of common host genome variants in Childhood Acute Lymphoblastic Leukemia","authors":"Theis Mikkelsen, Marianne Helenius, Mirella Ampatzidou, Andishe Attarbaschi, Liv Andres-Jensen, Arndt Borkhardt, Nuria Conde Cuevas, Gabriele Escherich, Melanie M. Hagleitner, Christina Halsey, Jonathan Josephs-Spaulding, Louise Lundgren, Simone Pehn, Sophia Polychronopoulou, Ulrik Stoltze, Linea Natalie Toksvang, Ayo Wahlberg, Stefanie Verena Junk, Kjeld Schmiegelow","doi":"10.1038/s41375-025-02804-2","DOIUrl":"10.1038/s41375-025-02804-2","url":null,"abstract":"Childhood acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease, and while somatic alterations inform diagnosis and treatment stratification, germline variants - particularly common host genome variants - rarely influence clinical care. Over the past decade, various host genome variant studies have uncovered numerous common variants associated with ALL susceptibility, treatment efficacy, and toxicity risk. Yet, less than a handful have reached clinical implementation, with TPMT and NUDT15 variants being the only ones widely used clinically. Whether a variant can be readily translated into the clinical setting primarily depends on four features: (1) Phenotype severity, (2) phenotype rarity and the proportion of cases (overall or in subsets of patients) accounted for by genetic variants, (3) the application of the variant as an add-on clinical decision support tool, and (4) the availability, cost, and potential side effects of interventions and/or prophylaxis. Key barriers for such clinical translation include insufficient effect sizes, lack of replication across diverse populations, and lack of well-established treatment modification strategies. However, large-scale international collaborations can generate the necessary statistical power, including enabling more complex bioinformatic approaches, such as polygenic risk scores and more advanced machine learning strategies. In this review, we outline the necessary steps toward bridging the gap between genetic discovery and clinical practice.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"3-24"},"PeriodicalIF":13.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02804-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704303","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 : 2025-12-08DOI: 10.1038/s41375-025-02840-y
Andreas Hochhaus, Robert Peter Gale
{"title":"40 years of LEUKEMIA","authors":"Andreas Hochhaus, Robert Peter Gale","doi":"10.1038/s41375-025-02840-y","DOIUrl":"10.1038/s41375-025-02840-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"1-2"},"PeriodicalIF":13.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02840-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708477","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 : 2025-12-03DOI: 10.1038/s41375-025-02814-0
Carmelo Gurnari, Hideki Makishima, Arda Durmaz, Enrico Attardi, Ryunosuke Saiki, Alex Bataller, Guilherme Sapinho, Lukasz Gondek, Yasuhito Nannya, Steve Best, Pramila Krishnamurthy, Kar Lok Kong, Yoshiko Atsuta, Senji Kasahara, Kazuma Ohyashiki, Yasushi Miyazaki, Nobuhiro Kanemura, Nobuhiro Hiramoto, Francesco Versino, Maria Julia Montoro, Sara Torres-Esquius, Andres Jerez Cayuela, Miguel López-Esteban, Carolina Martínez-Laperche, Hussein Awada, Valeria Visconte, Courtney D. DiNardo, Maria Teresa Voso, Amy E. DeZern, Guillermo Garcia-Manero, Austin G. Kulasekararaj, Jaroslaw P. Maciejewski, Seishi Ogawa
DDX41-mutant myeloid neoplasia (MN) is characterized by unique clinical-molecular characteristics and prognosis. However, it is poorly understood how DDX41 mutational constellations drive MN outcomes. We leveraged collaborative resources to test the new 2022 MN diagnostic and prognostic schemes and account for the diverse mutational configurations of DDX41-mutant MN. Diagnostic re-classification from 2016 to 2022 schemes showed an overall shift of 14.9% and 29.7% for DDX41-mutant MDS and AML, respectively. Current prognostic systems (IPSS-R/M and ELN 2017/22) showed poor applicability to DDX41-mutant MN when compared to wild-type counterparts. Dissecting all possible DDX41 configurations, we assigned the greatest prognostic impact to R525H somatic and germline truncating hits. The former impacted most survival outcomes, while the latter were enriched in AML, independently predicting leukemic evolution. Such features had synergistic effects, albeit with different treatment interactions, and were included in DDX41-specific multivariable outcome models, which alleviated the shortcomings of the current prognostic MN algorithms. We here show that current prognostic tools are not able to adequately assess leukemic evolution and survival outcomes in DDX41-mutant MN. Additional risk factors inherent to this MN subentity hold a prognostic significance beyond the consideration of traditional disease-specific variables, substantiating the need for a dedicated risk scoring system.
{"title":"DDX41-mutant myeloid neoplasms defy current prognostic schemes and require a dedicated risk scoring system: a multicenter, retrospective study","authors":"Carmelo Gurnari, Hideki Makishima, Arda Durmaz, Enrico Attardi, Ryunosuke Saiki, Alex Bataller, Guilherme Sapinho, Lukasz Gondek, Yasuhito Nannya, Steve Best, Pramila Krishnamurthy, Kar Lok Kong, Yoshiko Atsuta, Senji Kasahara, Kazuma Ohyashiki, Yasushi Miyazaki, Nobuhiro Kanemura, Nobuhiro Hiramoto, Francesco Versino, Maria Julia Montoro, Sara Torres-Esquius, Andres Jerez Cayuela, Miguel López-Esteban, Carolina Martínez-Laperche, Hussein Awada, Valeria Visconte, Courtney D. DiNardo, Maria Teresa Voso, Amy E. DeZern, Guillermo Garcia-Manero, Austin G. Kulasekararaj, Jaroslaw P. Maciejewski, Seishi Ogawa","doi":"10.1038/s41375-025-02814-0","DOIUrl":"10.1038/s41375-025-02814-0","url":null,"abstract":"DDX41-mutant myeloid neoplasia (MN) is characterized by unique clinical-molecular characteristics and prognosis. However, it is poorly understood how DDX41 mutational constellations drive MN outcomes. We leveraged collaborative resources to test the new 2022 MN diagnostic and prognostic schemes and account for the diverse mutational configurations of DDX41-mutant MN. Diagnostic re-classification from 2016 to 2022 schemes showed an overall shift of 14.9% and 29.7% for DDX41-mutant MDS and AML, respectively. Current prognostic systems (IPSS-R/M and ELN 2017/22) showed poor applicability to DDX41-mutant MN when compared to wild-type counterparts. Dissecting all possible DDX41 configurations, we assigned the greatest prognostic impact to R525H somatic and germline truncating hits. The former impacted most survival outcomes, while the latter were enriched in AML, independently predicting leukemic evolution. Such features had synergistic effects, albeit with different treatment interactions, and were included in DDX41-specific multivariable outcome models, which alleviated the shortcomings of the current prognostic MN algorithms. We here show that current prognostic tools are not able to adequately assess leukemic evolution and survival outcomes in DDX41-mutant MN. Additional risk factors inherent to this MN subentity hold a prognostic significance beyond the consideration of traditional disease-specific variables, substantiating the need for a dedicated risk scoring system.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"178-187"},"PeriodicalIF":13.4,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664236","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 : 2025-12-02DOI: 10.1038/s41375-025-02824-y
Alessandra Tedeschi, Anna Maria Frustaci, Pierantonio Menna, Giorgio Minotti
{"title":"Correction: Fixed-duration therapy of chronic lymphocytic leukemia with venetoclax and Bruton tyrosine kinase inhibitors: an insight into differences between ibrutinib and acalabrutinib","authors":"Alessandra Tedeschi, Anna Maria Frustaci, Pierantonio Menna, Giorgio Minotti","doi":"10.1038/s41375-025-02824-y","DOIUrl":"10.1038/s41375-025-02824-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"261-261"},"PeriodicalIF":13.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02824-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661526","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}
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