Pub Date : 2026-01-26DOI: 10.1038/s41375-025-02849-3
Claus-Moritz Gräf, Moritz Reese, Angela Vicente-Luque, Nicolas Mönig, Charlotte Bruzeau, Ferran Nadeu, Maria Latacz, Johanna Bihler, Jörn Meinel, Maria Cartolano, Martin Peifer, Sílvia Beà, Elias Campo, Melanie Thelen, Paul J. Bröckelmann, Ron D. Jachimowicz
{"title":"Establishment and characterization of a CCND1-rearranged non-mantle cell lymphoma cell line and patient-derived xenograft model","authors":"Claus-Moritz Gräf, Moritz Reese, Angela Vicente-Luque, Nicolas Mönig, Charlotte Bruzeau, Ferran Nadeu, Maria Latacz, Johanna Bihler, Jörn Meinel, Maria Cartolano, Martin Peifer, Sílvia Beà, Elias Campo, Melanie Thelen, Paul J. Bröckelmann, Ron D. Jachimowicz","doi":"10.1038/s41375-025-02849-3","DOIUrl":"10.1038/s41375-025-02849-3","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 3","pages":"666-670"},"PeriodicalIF":13.4,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02849-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048366","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 : 2026-01-26DOI: 10.1038/s41375-025-02828-8
Ying Guo, Pinpin Sui, Hui Yang, Ganqian Zhu, Ying Li, Shi Chen, Yuehui Zhao, Guo Ge, Yusra A. Eisa, Caroline R. Delma, Edward A. Medina, Peng Zhang, Jihoon Lee, Mingjiang Xu, Feng-Chun Yang
Somatic mutations in PHF6 (PHD finger protein 6) are common in hematologic malignancies and confer worse overall survival in acute myeloid leukemia patients. These mutations are predominantly frameshift or nonsense variants, resulting in a truncated PHF6 protein. However, the specific role of truncated PHF6 in leukemogenesis remains unclear. Here, we generated a transgenic mouse model, Phf6R274XTg, expressing a patient-derived truncated Phf6 mutation specifically in hematopoietic lineages. Unlike Phf6 knock-out mice, which do not develop spontaneous diseases, Phf6R274XTg mice developed a spectrum of spontaneous hematologic malignancies that recapitulate key features of PHF6-mutated hematologic malignancies in patients. Expression of PHF6aa1-273 led to expansion of the hematopoietic stem cell/progenitor cell (HSC/HPC) pool and promoted myeloid-skewed differentiation. The Phf6R274X mutation also induced substantial transcriptional dysregulation in HSC/HPCs. Single-cell RNA-seq analysis revealed a unique HSC trajectory and enhanced myeloid-biased differentiation in Phf6R274XTg HSC/HPCs. Additionally, truncation of PHF6 altered genome-wide H3K27ac occupancy via enhanced activity of KAT6B acetyltransferase. Treatment with CTx-648, a KAT6A/KAT6B inhibitor, restored HSC function in Phf6R274XTg mice and prolonged the survival of leukemic Phf6R274XTg mice. These findings demonstrate a gain-of-function effect for truncated PHF6aa1-273 in driving leukemogenesis and highlight KAT6B as a promising therapeutic target in PHF6 truncation-associated hematologic malignancies.
{"title":"Phf6 truncating mutation drives leukemogenesis via disrupted epigenetic regulation in mice","authors":"Ying Guo, Pinpin Sui, Hui Yang, Ganqian Zhu, Ying Li, Shi Chen, Yuehui Zhao, Guo Ge, Yusra A. Eisa, Caroline R. Delma, Edward A. Medina, Peng Zhang, Jihoon Lee, Mingjiang Xu, Feng-Chun Yang","doi":"10.1038/s41375-025-02828-8","DOIUrl":"10.1038/s41375-025-02828-8","url":null,"abstract":"Somatic mutations in PHF6 (PHD finger protein 6) are common in hematologic malignancies and confer worse overall survival in acute myeloid leukemia patients. These mutations are predominantly frameshift or nonsense variants, resulting in a truncated PHF6 protein. However, the specific role of truncated PHF6 in leukemogenesis remains unclear. Here, we generated a transgenic mouse model, Phf6R274XTg, expressing a patient-derived truncated Phf6 mutation specifically in hematopoietic lineages. Unlike Phf6 knock-out mice, which do not develop spontaneous diseases, Phf6R274XTg mice developed a spectrum of spontaneous hematologic malignancies that recapitulate key features of PHF6-mutated hematologic malignancies in patients. Expression of PHF6aa1-273 led to expansion of the hematopoietic stem cell/progenitor cell (HSC/HPC) pool and promoted myeloid-skewed differentiation. The Phf6R274X mutation also induced substantial transcriptional dysregulation in HSC/HPCs. Single-cell RNA-seq analysis revealed a unique HSC trajectory and enhanced myeloid-biased differentiation in Phf6R274XTg HSC/HPCs. Additionally, truncation of PHF6 altered genome-wide H3K27ac occupancy via enhanced activity of KAT6B acetyltransferase. Treatment with CTx-648, a KAT6A/KAT6B inhibitor, restored HSC function in Phf6R274XTg mice and prolonged the survival of leukemic Phf6R274XTg mice. These findings demonstrate a gain-of-function effect for truncated PHF6aa1-273 in driving leukemogenesis and highlight KAT6B as a promising therapeutic target in PHF6 truncation-associated hematologic malignancies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 3","pages":"594-608"},"PeriodicalIF":13.4,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048257","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 : 2026-01-23DOI: 10.1038/s41375-025-02852-8
Vivian G. Oehler, Olga Sala-Torra, Neta Gilderman, Lan Beppu, David W. Woolston, Priscilla Namaganda, Jennifer Rynning, Inés García González, Andrea Towlerton, Jenna Voutsinas, Qian Wu, Cecilia C. S. Yeung, Jerald P. Radich
The goal of the “Spot On CML” program is to provide diagnostic and monitoring tests to chronic myeloid leukemia (CML) patients in low- and middle-income countries (LMICs). Previously, we demonstrated reproducible BCR::ABL1 transcript quantification using dried blood spots (DBS). We have now optimized methods of DNA and RNA extraction from DBS, allowing the detection of myeloid gene variants, including ABL1 tyrosine kinase domain mutations. Among 177 CML patients from nine countries, ABL1 mutations were identified in 61 (34%) patients, with multiple mutations present in some cases. The most common ABL1 mutation was T315I (45.9% of patients with ABL1 mutations). Among 69 patients, 89 Tier I–II variants (pathogenic or likely pathogenic) were identified in other genes, including 52 ASXL1 variants in 49 patients. The detection of ASXL1 variants correlated strongly with the presence of ABL1 mutations (P = 3.51E-04). These methodologies are directly applicable to all assays used for the diagnosis, prognosis, and monitoring of CML and have important implications in bringing state-of-the-art genetic analysis to CML patients in LMICs.
{"title":"Next-generation sequencing from chronic myeloid leukemia dried blood spots: insights and implications for global oncology","authors":"Vivian G. Oehler, Olga Sala-Torra, Neta Gilderman, Lan Beppu, David W. Woolston, Priscilla Namaganda, Jennifer Rynning, Inés García González, Andrea Towlerton, Jenna Voutsinas, Qian Wu, Cecilia C. S. Yeung, Jerald P. Radich","doi":"10.1038/s41375-025-02852-8","DOIUrl":"10.1038/s41375-025-02852-8","url":null,"abstract":"The goal of the “Spot On CML” program is to provide diagnostic and monitoring tests to chronic myeloid leukemia (CML) patients in low- and middle-income countries (LMICs). Previously, we demonstrated reproducible BCR::ABL1 transcript quantification using dried blood spots (DBS). We have now optimized methods of DNA and RNA extraction from DBS, allowing the detection of myeloid gene variants, including ABL1 tyrosine kinase domain mutations. Among 177 CML patients from nine countries, ABL1 mutations were identified in 61 (34%) patients, with multiple mutations present in some cases. The most common ABL1 mutation was T315I (45.9% of patients with ABL1 mutations). Among 69 patients, 89 Tier I–II variants (pathogenic or likely pathogenic) were identified in other genes, including 52 ASXL1 variants in 49 patients. The detection of ASXL1 variants correlated strongly with the presence of ABL1 mutations (P = 3.51E-04). These methodologies are directly applicable to all assays used for the diagnosis, prognosis, and monitoring of CML and have important implications in bringing state-of-the-art genetic analysis to CML patients in LMICs.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 3","pages":"587-593"},"PeriodicalIF":13.4,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034048","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 : 2026-01-22DOI: 10.1038/s41375-026-02860-2
Giovanni Barosi, Annalisa De Silvestri, Robert Peter Gale, Vittorio Rosti
{"title":"Prognostic value of anemia plus thrombocytopenia in primary myelofibrosis","authors":"Giovanni Barosi, Annalisa De Silvestri, Robert Peter Gale, Vittorio Rosti","doi":"10.1038/s41375-026-02860-2","DOIUrl":"10.1038/s41375-026-02860-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 3","pages":"698-701"},"PeriodicalIF":13.4,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-026-02860-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021624","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 : 2026-01-22DOI: 10.1038/s41375-025-02855-5
Michela Ansuinelli, Nadia Peragine, Maria Stefania De Propris, Maria Cristina Puzzolo, Mariangela Di Trani, Loredana Elia, Cristina Skert, Roberto Cairoli, Simona Sica, Alessandro Rambaldi, Alessandra Tucci, Marco Cerrano, Daniele Vallisa, Valeria Cardinali, Antonino Mulè, Sabina Chiaretti, Anna Guarini, Robin Foà
In Ph+ acute lymphoblastic leukemia, frontline dasatinib plus blinatumomab (dasa+blina) is associated with long-term survival rates of 75–80%. The phase III GIMEMA ALL2820 trial has explored ponatinib with blinatumomab (pona+blina). In the present study, the immune modulation induced by dasa+blina and pona+blina was investigated. Immune cells were analyzed at the end of induction (T0) and after 2, 4 and 5 blinatumomab cycles (T2, T4, T5). Among 153 patients (43 dasa+blina, 110 pona+blina), the dasa+blina combination induced a significantly greater lymphocyte increase at T4 and T5 compared to pona+blina. The Treg counts decreased only in the dasa+blina treated patients. NK and NK-T cells increased significantly in the dasa+blina group, at all timepoints. Complete molecular responders (CMR) after dasatinib induction had significantly higher lymphocytes, T and NK cells compared to non-CMR patients. Bone marrow analyses showed higher activation (CD25, CD69) and lower exhaustion (PD1, TIM3) markers on NK and NK-T cells in dasa+blina treated patients. Dasa+blina patients exhibited a significantly enhanced NK cell capacity compared to ponatinib treated patients. Patients remaining on dasatinib maintained elevated NK cells with a more mature phenotype, suggesting a durable effect. These results highlight the greater dasa+blina immune activation, supporting a potential synergistic effect of the drug combination.
{"title":"Immunomodulatory effect of dasatinib plus blinatumomab versus ponatinib plus blinatumomab in newly diagnosed Ph+ acute lymphoblastic leukemia","authors":"Michela Ansuinelli, Nadia Peragine, Maria Stefania De Propris, Maria Cristina Puzzolo, Mariangela Di Trani, Loredana Elia, Cristina Skert, Roberto Cairoli, Simona Sica, Alessandro Rambaldi, Alessandra Tucci, Marco Cerrano, Daniele Vallisa, Valeria Cardinali, Antonino Mulè, Sabina Chiaretti, Anna Guarini, Robin Foà","doi":"10.1038/s41375-025-02855-5","DOIUrl":"10.1038/s41375-025-02855-5","url":null,"abstract":"In Ph+ acute lymphoblastic leukemia, frontline dasatinib plus blinatumomab (dasa+blina) is associated with long-term survival rates of 75–80%. The phase III GIMEMA ALL2820 trial has explored ponatinib with blinatumomab (pona+blina). In the present study, the immune modulation induced by dasa+blina and pona+blina was investigated. Immune cells were analyzed at the end of induction (T0) and after 2, 4 and 5 blinatumomab cycles (T2, T4, T5). Among 153 patients (43 dasa+blina, 110 pona+blina), the dasa+blina combination induced a significantly greater lymphocyte increase at T4 and T5 compared to pona+blina. The Treg counts decreased only in the dasa+blina treated patients. NK and NK-T cells increased significantly in the dasa+blina group, at all timepoints. Complete molecular responders (CMR) after dasatinib induction had significantly higher lymphocytes, T and NK cells compared to non-CMR patients. Bone marrow analyses showed higher activation (CD25, CD69) and lower exhaustion (PD1, TIM3) markers on NK and NK-T cells in dasa+blina treated patients. Dasa+blina patients exhibited a significantly enhanced NK cell capacity compared to ponatinib treated patients. Patients remaining on dasatinib maintained elevated NK cells with a more mature phenotype, suggesting a durable effect. These results highlight the greater dasa+blina immune activation, supporting a potential synergistic effect of the drug combination.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 3","pages":"577-586"},"PeriodicalIF":13.4,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030044","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}
MYB is a master transcription factor for the hematopoietic system, and its dysregulation drives the development and therapy resistance of leukemia. However, the mechanisms of MYB regulation and MYB-related therapy resistance are still unclear. Here, we identified two bidirectional enhancer RNAs (eRNAs), MY34UE-AS and MY34UE-S, transcribed from the –34 kb enhancer region of MYB. Both eRNAs promote MYB transcription, proliferation, and migration in human leukemia cells, although through different MYB promoters. MY34UE-AS physically interacts with PURB that binds near MYB TSS2, promoting long-range looping between downstream -34 kb enhancer elements and TSS2, ultimately activating TSS2. While MY34UE-S facilitates DNA looping between upstream –34 kb enhancer elements and TSS1, promoting TSS1 transcription. TSS2, but not TSS1, activity increases in drug resistant leukemia cells, resulting increased expression of N-terminally truncated MYB (ΔN MYB) when total MYB remains unaltered. Compared to full-length MYB, ΔN MYB more potently promotes drug resistance through FTH1 and EZH2 pathway, and targeting MY34UE-AS more efficiently alleviates drug resistance than targeting MY34UE-S. The above relationship of MY34UE-AS/MY34UE-S, TSS2/TSS1, and prognosis was also verified in clinical leukemia samples. For the first time we provide the mechanisms underlying promoter usage of MYB and MYB TSS2 mediated drug resistance in human leukemia.
{"title":"Distal enhancer RNAs regulate alternative promoter usage of MYB and drug resistance in human leukemia cells","authors":"Yucheng Wang, Xiang Wang, Mengjia Li, Hongkuan Song, Chao Liu, Mengjie Shi, Xiaoxiao Tao, Siyu Shen, Xinyu Li, Huiying Fang, Zhenhua Zhou, Junfang Zhang, Bingshe Han","doi":"10.1038/s41375-026-02862-0","DOIUrl":"10.1038/s41375-026-02862-0","url":null,"abstract":"MYB is a master transcription factor for the hematopoietic system, and its dysregulation drives the development and therapy resistance of leukemia. However, the mechanisms of MYB regulation and MYB-related therapy resistance are still unclear. Here, we identified two bidirectional enhancer RNAs (eRNAs), MY34UE-AS and MY34UE-S, transcribed from the –34 kb enhancer region of MYB. Both eRNAs promote MYB transcription, proliferation, and migration in human leukemia cells, although through different MYB promoters. MY34UE-AS physically interacts with PURB that binds near MYB TSS2, promoting long-range looping between downstream -34 kb enhancer elements and TSS2, ultimately activating TSS2. While MY34UE-S facilitates DNA looping between upstream –34 kb enhancer elements and TSS1, promoting TSS1 transcription. TSS2, but not TSS1, activity increases in drug resistant leukemia cells, resulting increased expression of N-terminally truncated MYB (ΔN MYB) when total MYB remains unaltered. Compared to full-length MYB, ΔN MYB more potently promotes drug resistance through FTH1 and EZH2 pathway, and targeting MY34UE-AS more efficiently alleviates drug resistance than targeting MY34UE-S. The above relationship of MY34UE-AS/MY34UE-S, TSS2/TSS1, and prognosis was also verified in clinical leukemia samples. For the first time we provide the mechanisms underlying promoter usage of MYB and MYB TSS2 mediated drug resistance in human leukemia.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 3","pages":"562-576"},"PeriodicalIF":13.4,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021674","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 : 2026-01-19DOI: 10.1038/s41375-025-02847-5
Delphine Rea, Slawomira Kyrcz-Krzemien, Paolo Sportoletti, Jiří Mayer, Arpad Illes, Anna Angona Figueras, Alexander Kiani, Aude Charbonnier, Theodoros Marinakis, Leif Stenke, Juan Luis Steegmann, Giuseppe Saglio, Andrzej Hellmann, Dietger Niederwieser, Peter Schuld, Gianantonio Rosti
The phase 3 ENESTPath study investigated treatment-free remission (TFR) rates in patients with chronic Philadelphia chromosome-positive (Ph+) and/or BCR::ABL1+ chronic myeloid leukemia who had not achieved deep molecular response (DMR) after >2 years of imatinib treatment and were switched to nilotinib 300 mg twice daily (BID). After 24 months of treatment, patients with a stable DMR were randomized to either enter the TFR phase (Arm 1) or continue nilotinib consolidation for an additional 12 months and then enter the TFR phase if in stable DMR (Arm 2). The primary endpoint was the proportion of patients who remained in TFR (≥MR4.0 [BCR::ABL1IS ≤ 0.01%]) without molecular relapse at the end of 12 months. Of the 620 patients enrolled, 239 (38.5%) achieved stable MR4.0 and were randomized to Arm 1 (n = 120) or Arm 2 (n = 119). In the TFR phase, MR4.0 rates at 12 months (Arm 1: 31.9%, Arm 2: 37.5%; p = 0.383) and 24 months (Arm 1: 29.4%, Arm 2: 30.8%) revealed no differences in TFR success between 2 and 3 years of nilotinib. Irrespective of the consolidation duration, switching to nilotinib 300 mg BID provided the opportunity to achieve TFR if patients were unable to reach stable DMR with first-line imatinib.
{"title":"Treatment-free remission after two nilotinib consolidation durations in chronic myeloid leukemia treated with imatinib: Phase 3 ENESTPath results","authors":"Delphine Rea, Slawomira Kyrcz-Krzemien, Paolo Sportoletti, Jiří Mayer, Arpad Illes, Anna Angona Figueras, Alexander Kiani, Aude Charbonnier, Theodoros Marinakis, Leif Stenke, Juan Luis Steegmann, Giuseppe Saglio, Andrzej Hellmann, Dietger Niederwieser, Peter Schuld, Gianantonio Rosti","doi":"10.1038/s41375-025-02847-5","DOIUrl":"10.1038/s41375-025-02847-5","url":null,"abstract":"The phase 3 ENESTPath study investigated treatment-free remission (TFR) rates in patients with chronic Philadelphia chromosome-positive (Ph+) and/or BCR::ABL1+ chronic myeloid leukemia who had not achieved deep molecular response (DMR) after >2 years of imatinib treatment and were switched to nilotinib 300 mg twice daily (BID). After 24 months of treatment, patients with a stable DMR were randomized to either enter the TFR phase (Arm 1) or continue nilotinib consolidation for an additional 12 months and then enter the TFR phase if in stable DMR (Arm 2). The primary endpoint was the proportion of patients who remained in TFR (≥MR4.0 [BCR::ABL1IS ≤ 0.01%]) without molecular relapse at the end of 12 months. Of the 620 patients enrolled, 239 (38.5%) achieved stable MR4.0 and were randomized to Arm 1 (n = 120) or Arm 2 (n = 119). In the TFR phase, MR4.0 rates at 12 months (Arm 1: 31.9%, Arm 2: 37.5%; p = 0.383) and 24 months (Arm 1: 29.4%, Arm 2: 30.8%) revealed no differences in TFR success between 2 and 3 years of nilotinib. Irrespective of the consolidation duration, switching to nilotinib 300 mg BID provided the opportunity to achieve TFR if patients were unable to reach stable DMR with first-line imatinib.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 3","pages":"553-561"},"PeriodicalIF":13.4,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003636","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 : 2026-01-16DOI: 10.1038/s41375-025-02844-8
Valeria Soberón, Lena Osswald, Andrew Moore, Dominika Sosnowska, Gene Swinerd, Jingyu Chen, Seren Baygün, Carina Diehl, Gönül Seyhan, Laura Kraus, Vanessa Gölling, Ricarda Trapp, Thomas J. O’Neill, Sabrina Bortoluzzi, Daniel Kovacs, Tim Ammon, Pankaj Singroul, Yuliia Hubarzhevska, Rupert Öllinger, Sebastian Mueller, Olga Baranov, Piero Giansanti, Felix Gillhuber, Sonja Grath, Oliver Weigert, Andreas Rosenwald, Yoshiteru Sasaki, Klaus Rajewsky, Katja Steiger, Florian Bassermann, Roland Rad, Daniel Krappmann, Ingo Ringshausen, Marc Schmidt-Supprian
Aberrant activation of NF-κB transcription factors is a hallmark of human lymphomas. Most lymphoma-intrinsic as well as microenvironment-induced NF-κB activation occurs upstream of the key kinase IKK2, therefore affecting additional pathways. Here, we show that canonical NF-κB signaling in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant, dose-dependently drives lymphomagenesis. The observed phenotype and stereotypic B cell receptor clonality resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL). Stronger IKK2 signaling drives early B1a cell expansion and uniform SLL/CLL-like lymphomagenesis, while intermediate signals cause more heterogeneous malignancies. Mechanistically, constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and dose-dependently synergize with TCL1 overexpression in driving aggressive CLL. Further, strong constitutive NF-κB activation overcomes critical microenvironmental dependencies of TCL1-driven lymphomas. Our findings establish canonical NF-κB as an oncogenic driver in lymphoma and reveal reduced microenvironment dependency as a key NF-κB-mediated mechanism, thus highlighting its therapeutic relevance.
{"title":"Strong constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironmental dependencies","authors":"Valeria Soberón, Lena Osswald, Andrew Moore, Dominika Sosnowska, Gene Swinerd, Jingyu Chen, Seren Baygün, Carina Diehl, Gönül Seyhan, Laura Kraus, Vanessa Gölling, Ricarda Trapp, Thomas J. O’Neill, Sabrina Bortoluzzi, Daniel Kovacs, Tim Ammon, Pankaj Singroul, Yuliia Hubarzhevska, Rupert Öllinger, Sebastian Mueller, Olga Baranov, Piero Giansanti, Felix Gillhuber, Sonja Grath, Oliver Weigert, Andreas Rosenwald, Yoshiteru Sasaki, Klaus Rajewsky, Katja Steiger, Florian Bassermann, Roland Rad, Daniel Krappmann, Ingo Ringshausen, Marc Schmidt-Supprian","doi":"10.1038/s41375-025-02844-8","DOIUrl":"10.1038/s41375-025-02844-8","url":null,"abstract":"Aberrant activation of NF-κB transcription factors is a hallmark of human lymphomas. Most lymphoma-intrinsic as well as microenvironment-induced NF-κB activation occurs upstream of the key kinase IKK2, therefore affecting additional pathways. Here, we show that canonical NF-κB signaling in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant, dose-dependently drives lymphomagenesis. The observed phenotype and stereotypic B cell receptor clonality resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL). Stronger IKK2 signaling drives early B1a cell expansion and uniform SLL/CLL-like lymphomagenesis, while intermediate signals cause more heterogeneous malignancies. Mechanistically, constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and dose-dependently synergize with TCL1 overexpression in driving aggressive CLL. Further, strong constitutive NF-κB activation overcomes critical microenvironmental dependencies of TCL1-driven lymphomas. Our findings establish canonical NF-κB as an oncogenic driver in lymphoma and reveal reduced microenvironment dependency as a key NF-κB-mediated mechanism, thus highlighting its therapeutic relevance.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 3","pages":"522-539"},"PeriodicalIF":13.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02844-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986500","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 : 2026-01-16DOI: 10.1038/s41375-025-02856-4
Giuseppina Camiolo, Daniel González Silvera, Tom Leah, Jürg Schwaller, Katrin Ottersbach
KMT2A-rearranged infant leukaemia is one of the most severe malignancies in infants and children, and is characterised by a very aggressive phenotype and lineage plasticity. KMT2A::MLLT3 is among the most common translocations initiating leukaemia in infants, where it can manifest with a myeloid or lymphoid leukaemia phenotype. The cell-of-origin and the mechanisms driving lineage choice in KMT2A::MLLT3+ infant leukaemia are poorly understood. In this study, we show that a subset of foetal lymphoid-primed multipotent progenitors (LMPPs) expressing the Colony-Stimulating Factor 1 receptor (CSF1R) gives rise to acute myeloid leukaemia (AML) upon KMT2A::MLLT3 induction in a mouse model, with the myeloid phenotype, at least in part, being dependent on CSF1R signalling. In line with their leukaemia-propagating properties, KMT2A::MLLT3 + CSF1R+ LMPPs possess a stem cell-like and myeloid-biased expression signature and require autophagy to expand and form blast-like colonies in methylcellulose. Interrogation of public datasets confirms the existence of a human foetal-restricted CSF1R+ LMPP population at early stages of embryonic development. Finally, CSF1R inhibition on a KMT2A::MLLT3+ paediatric leukaemia cell line resulted in significant cell death, suggesting that CSF1R could be therapeutically targeted in these patients. Our findings suggest that KMT2A::MLLT3+ infant AML may originate from foetal liver CSF1R+ LMPPs, and that these patients may benefit from anti-CSF1R-CAR-T cell therapy.
kmt2a重排婴儿白血病是婴儿和儿童中最严重的恶性肿瘤之一，其特征是非常具有侵略性的表型和谱系可塑性。KMT2A::MLLT3是引发婴儿白血病最常见的易位之一，它可以表现为骨髓性或淋巴性白血病表型。KMT2A::MLLT3+婴儿白血病的细胞起源和驱动谱系选择的机制尚不清楚。在这项研究中，我们发现在小鼠模型中，表达集落刺激因子1受体（CSF1R）的胎儿淋巴细胞引发的多能祖细胞（lmpp）亚群在KMT2A::MLLT3诱导下引起急性髓系白血病（AML），髓系表型至少部分依赖于CSF1R信号传导。根据其白血病传播特性，KMT2A::MLLT3 + CSF1R+ lmpp具有干细胞样和骨髓偏倚的表达特征，需要自噬才能在甲基纤维素中扩增并形成blast样菌落。对公共数据集的调查证实，在胚胎发育的早期阶段存在人类胎儿限制性CSF1R+ LMPP群体。最后，CSF1R对KMT2A::MLLT3+儿科白血病细胞系的抑制导致了显著的细胞死亡，这表明CSF1R可能是这些患者的治疗靶点。我们的研究结果表明，KMT2A::MLLT3+婴儿AML可能起源于胎儿肝脏CSF1R+ lmpp，这些患者可能受益于抗CSF1R- car - t细胞治疗。
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