Pub Date : 2026-03-23DOI: 10.1038/s41375-026-02912-7
Amelia Fascì, Francesco Edoardo Vallone, Nahal Nabelsi, Elodie Viry, Ilenia Sana, Alessia Morabito, Silvia Seghezzi, Noemi Anna Pesce, Matteo Rovere, Nadia Bertola, Chloé Duculty, Silvia Ravera, Samir Mouhssine, Marta Muzio, Paolo Ghia, Candida Vitale, Marta Coscia, Etienne Moussay, Gianluca Gaidano, John Allan, Richard R. Furman, Jerome Paggetti, Tiziana Vaisitti, Silvia Deaglio
Mutations in NOTCH1, which occur in ~10% of Chronic Lymphocytic Leukemia (CLL) patients at diagnosis, are typically associated with unmutated (UM) B-cell receptor (BCR) subsets and define patients with earlier treatment need. Using primary CLL cells classified as NOTCH1 wild-type (CLL/NWT) or mutated (CLL/NM), both with UM-BCR, we show that BCR stimulation activates the NOTCH1 pathway, upregulating metabolic programs and mitochondrial biogenesis, selectively in CLL/NM. These cells display enhanced basal respiration and glycolysis, driven by higher mitochondrial mass, and further increase metabolic activity upon BCR triggering. To directly implicate NOTCH1 mutations, we engineered an MEC-1 model to generate wild-type (MEC-1/NWT) or mutated (MEC-1/NM) clones in a UM-BCR background. Here, NOTCH1 hyperactivation promoted mitochondrial metabolism through TFAM-dependent transcriptional control. Gene expression profiling, metabolic assays, and stable isotope tracing confirmed that MEC-1/NM cells rely on oxidative metabolism, with increased glutamine dependency and strengthened anabolic pathways, leading to augmented proliferation compared to MEC-1/NWT. Importantly, CLL/NM cells exhibit a marked vulnerability to glutamine deprivation. Combined inhibition of glutamine utilization and BCL2 triggered rapid apoptosis, providing a rationale for tailored therapeutic strategies in NOTCH1-mutated CLL. Representation of the molecular mechanism behind the metabolic reprogramming. BCR and NOTCH1 drive a dual metabolic reprogramming of glucose and glutamine pathways. In NOTCH1-mutated cells, both glucose and glutamine uptake are positively increased and even more upon BCR stimulation. Glucose is preferentially used to fuel the pentose phosphate pathway, and glutamine the TCA cycle. Concurrently, NICD accumulation, driven by BCR signaling, promotes TFAM expression and mitochondrial biogenesis. The resulting increase in mitochondrial mass underpins enhanced ATP production, oxygen consumption, and ROS generation, establishing a glutamine-dependent mitochondrial phenotype. This dependency sensitizes NOTCH1-mutated cells to glutamine blockade, which selectively induces apoptosis, further enhanced by combination with BCL-2 inhibition.
{"title":"Functional cooperation between the B-cell receptor and NOTCH1 in regulating metabolic reprogramming in chronic lymphocytic leukemia","authors":"Amelia Fascì, Francesco Edoardo Vallone, Nahal Nabelsi, Elodie Viry, Ilenia Sana, Alessia Morabito, Silvia Seghezzi, Noemi Anna Pesce, Matteo Rovere, Nadia Bertola, Chloé Duculty, Silvia Ravera, Samir Mouhssine, Marta Muzio, Paolo Ghia, Candida Vitale, Marta Coscia, Etienne Moussay, Gianluca Gaidano, John Allan, Richard R. Furman, Jerome Paggetti, Tiziana Vaisitti, Silvia Deaglio","doi":"10.1038/s41375-026-02912-7","DOIUrl":"https://doi.org/10.1038/s41375-026-02912-7","url":null,"abstract":"Mutations in NOTCH1, which occur in ~10% of Chronic Lymphocytic Leukemia (CLL) patients at diagnosis, are typically associated with unmutated (UM) B-cell receptor (BCR) subsets and define patients with earlier treatment need. Using primary CLL cells classified as NOTCH1 wild-type (CLL/NWT) or mutated (CLL/NM), both with UM-BCR, we show that BCR stimulation activates the NOTCH1 pathway, upregulating metabolic programs and mitochondrial biogenesis, selectively in CLL/NM. These cells display enhanced basal respiration and glycolysis, driven by higher mitochondrial mass, and further increase metabolic activity upon BCR triggering. To directly implicate NOTCH1 mutations, we engineered an MEC-1 model to generate wild-type (MEC-1/NWT) or mutated (MEC-1/NM) clones in a UM-BCR background. Here, NOTCH1 hyperactivation promoted mitochondrial metabolism through TFAM-dependent transcriptional control. Gene expression profiling, metabolic assays, and stable isotope tracing confirmed that MEC-1/NM cells rely on oxidative metabolism, with increased glutamine dependency and strengthened anabolic pathways, leading to augmented proliferation compared to MEC-1/NWT. Importantly, CLL/NM cells exhibit a marked vulnerability to glutamine deprivation. Combined inhibition of glutamine utilization and BCL2 triggered rapid apoptosis, providing a rationale for tailored therapeutic strategies in NOTCH1-mutated CLL.\u0000\u0000Representation of the molecular mechanism behind the metabolic reprogramming. BCR and NOTCH1 drive a dual metabolic reprogramming of glucose and glutamine pathways. In NOTCH1-mutated cells, both glucose and glutamine uptake are positively increased and even more upon BCR stimulation. Glucose is preferentially used to fuel the pentose phosphate pathway, and glutamine the TCA cycle. Concurrently, NICD accumulation, driven by BCR signaling, promotes TFAM expression and mitochondrial biogenesis. The resulting increase in mitochondrial mass underpins enhanced ATP production, oxygen consumption, and ROS generation, establishing a glutamine-dependent mitochondrial phenotype. This dependency sensitizes NOTCH1-mutated cells to glutamine blockade, which selectively induces apoptosis, further enhanced by combination with BCL-2 inhibition.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"15 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496768","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 : 2026-03-23DOI: 10.1038/s41375-026-02934-1
Muhammed Furkan Dasdelen, Ivan Kukuljan, Peter Lienemann, Fatih Ozlugedik, Ario Sadafi, Matthias Hehr, Karsten Spiekermann, Christian Pohlkamp, Carsten Marr
{"title":"AI-based hematological malignancy prediction from peripheral blood smears in a large diagnostic laboratory cohort","authors":"Muhammed Furkan Dasdelen, Ivan Kukuljan, Peter Lienemann, Fatih Ozlugedik, Ario Sadafi, Matthias Hehr, Karsten Spiekermann, Christian Pohlkamp, Carsten Marr","doi":"10.1038/s41375-026-02934-1","DOIUrl":"https://doi.org/10.1038/s41375-026-02934-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"19 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496772","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 : 2026-03-20DOI: 10.1038/s41375-026-02926-1
Mingma G Sherpa,Sutapa Sinha,Weiguo Han,Heather C Darby,Sameer A Parikh,Neil E Kay,Zhiquan Wang
{"title":"Defining the acute BTK-loss transcriptional program in CLL using a BTK degrader.","authors":"Mingma G Sherpa,Sutapa Sinha,Weiguo Han,Heather C Darby,Sameer A Parikh,Neil E Kay,Zhiquan Wang","doi":"10.1038/s41375-026-02926-1","DOIUrl":"https://doi.org/10.1038/s41375-026-02926-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"313 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489917","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}
Despite extensive research and intensive use of chemotherapies in clinics, the 5-year overall survival of acute myeloid leukemia (AML) patients does not exceed 20%. The clonal expansion of leukemic blasts leads to modifications of the bone marrow physical properties, including increased extracellular matrix stiffening, upregulation of intramedullary pressure and reduction of the space available for cells. These biomechanical modifications are speculated to alter therapeutic response and cause treatment resistance. To address this, we herein focused on the role of mechanotransduction pathways in AML. Analysis of primary AML samples or cell lines revealed that BMPR1B and TAZ/TEAD but not YAP levels were higher after patient relapse or in cells resistant to cytarabine or venetoclax. In addition, highly confined resident mesenchymal stem cells expressed higher levels of BMP4, which in turn specifically activated AML-resistant cells. In these cells, TAZ expression was associated with improved adhesion to microenvironmental components and increased intrinsic deformability. Finally, using a 3D human bone marrow-like model, we showed that targeting BMPR1B or TAZ/TEAD in combination with cytarabine impaired persistence of AML primary cells within the AML niche. Future therapeutic approaches could involve BMPR1B and/or TAZ/TEAD targeting in the context of AML patients refractory to chemotherapy or after relapse.
{"title":"Targeting BMP and TAZ/TEAD mechanotransduction pathways impairs acute myeloid leukemia chemoresistance.","authors":"Léa Barral,Nicolas Lespinasse,Camila Martin Cardozo,Sandrine Jeanpierre,Anna Bourgeois,Katharina Rösel,Emmanuel Beillard,Djohana Laurent,Pauline Peyrouze,Amine Belhabri,Yann Guillermin,Frederic Mazurier,Meyling Cheok,Marie-Charlotte Audry-Deschamps,Magalie Faivre,Véronique Maguer-Satta,Sylvain Lefort","doi":"10.1038/s41375-026-02904-7","DOIUrl":"https://doi.org/10.1038/s41375-026-02904-7","url":null,"abstract":"Despite extensive research and intensive use of chemotherapies in clinics, the 5-year overall survival of acute myeloid leukemia (AML) patients does not exceed 20%. The clonal expansion of leukemic blasts leads to modifications of the bone marrow physical properties, including increased extracellular matrix stiffening, upregulation of intramedullary pressure and reduction of the space available for cells. These biomechanical modifications are speculated to alter therapeutic response and cause treatment resistance. To address this, we herein focused on the role of mechanotransduction pathways in AML. Analysis of primary AML samples or cell lines revealed that BMPR1B and TAZ/TEAD but not YAP levels were higher after patient relapse or in cells resistant to cytarabine or venetoclax. In addition, highly confined resident mesenchymal stem cells expressed higher levels of BMP4, which in turn specifically activated AML-resistant cells. In these cells, TAZ expression was associated with improved adhesion to microenvironmental components and increased intrinsic deformability. Finally, using a 3D human bone marrow-like model, we showed that targeting BMPR1B or TAZ/TEAD in combination with cytarabine impaired persistence of AML primary cells within the AML niche. Future therapeutic approaches could involve BMPR1B and/or TAZ/TEAD targeting in the context of AML patients refractory to chemotherapy or after relapse.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"1 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478530","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 : 2026-03-17DOI: 10.1038/s41375-026-02913-6
Mai Fujita,Hiroshi Ureshino
{"title":"Potential impact of NK-cell education on interferon efficacy in the ENDURE trial.","authors":"Mai Fujita,Hiroshi Ureshino","doi":"10.1038/s41375-026-02913-6","DOIUrl":"https://doi.org/10.1038/s41375-026-02913-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"20 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471359","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 : 2026-03-11DOI: 10.1038/s41375-026-02906-5
H Parker,L Carr,K Norris,A Nilsson-Takeuchi,B Stevens,H Amarasinghe,L Kadalayil,M Else,R Clifford,A Pettitt,T Munir,A Schuh,R Walewska,D M Baird,D G Oscier,C Pepper,D Bryant,J Gibson,J C Strefford
High genomic complexity (HGC) is linked to poor prognosis in CLL, but its independent prognostic value remains uncertain amid emerging biomarkers. We analysed copy number alterations (CNA) in 495 untreated patients from (immuno)chemotherapy trials (CLL4, ADMIRE, ARCTIC), incorporating IGHV status, telomere length (TL), targeted sequencing and DNA-methylation subtypes. Patients harboured low (LGC, ≤2 CNAs; n = 334), intermediate (IGC, 3-4 CNAs; n = 97), or high (HGC, ≥5 CNAs; n = 64) genomic complexity. HGC associated with U-CLL (81%, p < 0.001), TP53-aberration (36%, p < 0.001), short TL (TL-S; 61%, p < 0.05), del13q (50%, p < 0.001) and del11q (22%, p < 0.05). IGC was enriched for biallelic ATM disruption and BIRC3 deletions (p < 0.001). Trisomy 12 and NOTCH1 mutations were enriched in LGC (p < 0.001). HGC associated with shorter progression-free and overall survival in univariate models but only remained independent for OS in CLL4 (HR = 1.61, p = 0.02). Independent prognostic factors included TP53 aberration, U-CLL, TL-S and n-CLL. Of 64 HGC patients, 23 had TP53-aberration; 92% of TP53 wild-type cases had other high-risk features (TL-S, U-CLL, or n-CLL). HGC may reflect a convergence of high-risk features rather than represent an independent biomarker. The interplay of telomere attrition, IGHV status and DNA methylation subtype necessitates further validation in targeted therapy cohorts to enhance risk assessment in prognostic models.
高基因组复杂性（HGC）与CLL的不良预后有关，但在新兴生物标志物中，其独立预后价值仍不确定。我们分析了来自（免疫）化疗试验（CLL4，佩服，北极）的495名未经治疗的患者的拷贝数改变（CNA），包括IGHV状态，端粒长度（TL），靶向测序和dna甲基化亚型。患者具有低（LGC，≤2个CNAs， n = 334）、中等（IGC， 3-4个CNAs， n = 97）或高（HGC，≥5个CNAs， n = 64）基因组复杂性。HGC与U-CLL （81%, p < 0.001）、tp53畸变（36%,p < 0.001）、短TL （TL- s; 61%, p < 0.05）、del13q （50%, p < 0.001）和del11q （22%, p < 0.05）相关。IGC在双等位基因ATM破坏和BIRC3缺失中富集（p < 0.001）。12三体和NOTCH1突变在LGC中富集（p < 0.001）。在单变量模型中，HGC与较短的无进展生存期和总生存期相关，但仅与CLL4的OS无关（HR = 1.61, p = 0.02）。独立预后因素包括TP53畸变、U-CLL、TL-S和n-CLL。64例HGC患者中，23例存在tp53畸变；92%的TP53野生型病例具有其他高危特征（TL-S、U-CLL或n-CLL）。HGC可能反映了高风险特征的集合，而不是一个独立的生物标志物。端粒磨损、IGHV状态和DNA甲基化亚型的相互作用需要在靶向治疗队列中进一步验证，以增强预后模型的风险评估。
{"title":"High-risk molecular features may eclipse genomic complexity in predicting chronic lymphocytic leukemia outcomes; UK clinical trial insights.","authors":"H Parker,L Carr,K Norris,A Nilsson-Takeuchi,B Stevens,H Amarasinghe,L Kadalayil,M Else,R Clifford,A Pettitt,T Munir,A Schuh,R Walewska,D M Baird,D G Oscier,C Pepper,D Bryant,J Gibson,J C Strefford","doi":"10.1038/s41375-026-02906-5","DOIUrl":"https://doi.org/10.1038/s41375-026-02906-5","url":null,"abstract":"High genomic complexity (HGC) is linked to poor prognosis in CLL, but its independent prognostic value remains uncertain amid emerging biomarkers. We analysed copy number alterations (CNA) in 495 untreated patients from (immuno)chemotherapy trials (CLL4, ADMIRE, ARCTIC), incorporating IGHV status, telomere length (TL), targeted sequencing and DNA-methylation subtypes. Patients harboured low (LGC, ≤2 CNAs; n = 334), intermediate (IGC, 3-4 CNAs; n = 97), or high (HGC, ≥5 CNAs; n = 64) genomic complexity. HGC associated with U-CLL (81%, p < 0.001), TP53-aberration (36%, p < 0.001), short TL (TL-S; 61%, p < 0.05), del13q (50%, p < 0.001) and del11q (22%, p < 0.05). IGC was enriched for biallelic ATM disruption and BIRC3 deletions (p < 0.001). Trisomy 12 and NOTCH1 mutations were enriched in LGC (p < 0.001). HGC associated with shorter progression-free and overall survival in univariate models but only remained independent for OS in CLL4 (HR = 1.61, p = 0.02). Independent prognostic factors included TP53 aberration, U-CLL, TL-S and n-CLL. Of 64 HGC patients, 23 had TP53-aberration; 92% of TP53 wild-type cases had other high-risk features (TL-S, U-CLL, or n-CLL). HGC may reflect a convergence of high-risk features rather than represent an independent biomarker. The interplay of telomere attrition, IGHV status and DNA methylation subtype necessitates further validation in targeted therapy cohorts to enhance risk assessment in prognostic models.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"113 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393828","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 : 2026-03-11DOI: 10.1038/s41375-026-02911-8
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
{"title":"Correction: 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/s41375-026-02911-8","DOIUrl":"https://doi.org/10.1038/s41375-026-02911-8","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147433991","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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