Pub Date : 2025-11-12DOI: 10.1038/s41375-025-02809-x
Wei Wei, Zhihui Song, Yajun Wang, Shen Li, Lingli Tan, John Lee, Kathy Q. Cai, Reza Nejati, Marshall E. Kadin, Kerry S. Campbell, Masao Nakagawa, Yibin Yang
Anaplastic large cell lymphoma (ALCL), an aggressive T-cell malignancy, is marked by elevated expression of CD30 and the immune checkpoint molecule PD-L1. While CD30-directed chimeric antigen receptor (CAR) therapies have demonstrated clinical promise, therapeutic resistance remains a major hurdle. Here, we conducted integrated genome-wide CRISPR-Cas9 loss-of-function screens using CD30-specific CAR-engineered natural killer (CAR-NK) cells, alongside a complementary PD-L1 regulator screen, and uncovered a critical role for interleukin-1 receptor (IL-1R) signaling in modulating CAR therapy efficacy in both ALK⁺ and ALK⁻ ALCL. Mechanistically, IL-1R signaling drives an NFKBIZ – IL-17F – MAPK axis that sustains PD-L1 expression via an autocrine loop, while simultaneously inducing proinflammatory cytokines and chemokines that reinforce immune evasion and shape an immunosuppressive tumor microenvironment. Notably, NFKBIZ (IκBζ) emerges as a central transcriptional regulator orchestrating this immune suppression program upstream of IL-17F. Importantly, pharmacologic inhibition of IL-1R signaling significantly enhances the antitumor activity of CD30-specific CAR therapies both in vitro and in ALCL xenograft models. Collectively, our findings uncover a novel mechanism of immune resistance and nominate IL-1R blockade as a promising combinatorial strategy to improve CAR-based immunotherapy in ALCL.
{"title":"The IL-1R and NFKBIZ pathway mediates immunoregulatory responses and immunotherapy efficacy in anaplastic large cell lymphoma","authors":"Wei Wei, Zhihui Song, Yajun Wang, Shen Li, Lingli Tan, John Lee, Kathy Q. Cai, Reza Nejati, Marshall E. Kadin, Kerry S. Campbell, Masao Nakagawa, Yibin Yang","doi":"10.1038/s41375-025-02809-x","DOIUrl":"10.1038/s41375-025-02809-x","url":null,"abstract":"Anaplastic large cell lymphoma (ALCL), an aggressive T-cell malignancy, is marked by elevated expression of CD30 and the immune checkpoint molecule PD-L1. While CD30-directed chimeric antigen receptor (CAR) therapies have demonstrated clinical promise, therapeutic resistance remains a major hurdle. Here, we conducted integrated genome-wide CRISPR-Cas9 loss-of-function screens using CD30-specific CAR-engineered natural killer (CAR-NK) cells, alongside a complementary PD-L1 regulator screen, and uncovered a critical role for interleukin-1 receptor (IL-1R) signaling in modulating CAR therapy efficacy in both ALK⁺ and ALK⁻ ALCL. Mechanistically, IL-1R signaling drives an NFKBIZ – IL-17F – MAPK axis that sustains PD-L1 expression via an autocrine loop, while simultaneously inducing proinflammatory cytokines and chemokines that reinforce immune evasion and shape an immunosuppressive tumor microenvironment. Notably, NFKBIZ (IκBζ) emerges as a central transcriptional regulator orchestrating this immune suppression program upstream of IL-17F. Importantly, pharmacologic inhibition of IL-1R signaling significantly enhances the antitumor activity of CD30-specific CAR therapies both in vitro and in ALCL xenograft models. Collectively, our findings uncover a novel mechanism of immune resistance and nominate IL-1R blockade as a promising combinatorial strategy to improve CAR-based immunotherapy in ALCL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"152-165"},"PeriodicalIF":13.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492524","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 : 2025-11-10DOI: 10.1038/s41375-025-02807-z
Fangshi Xu, Zongyu Li, Hangyu Fu, Jiancang Ma
{"title":"Challenges in predicting hydroxyurea resistance and reducing thrombotic risk in polycythemia vera patients: unmasking the limits of its machine learning study","authors":"Fangshi Xu, Zongyu Li, Hangyu Fu, Jiancang Ma","doi":"10.1038/s41375-025-02807-z","DOIUrl":"10.1038/s41375-025-02807-z","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"3052-3053"},"PeriodicalIF":13.4,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477832","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 : 2025-11-10DOI: 10.1038/s41375-025-02799-w
Arjun Dhir, Alexander Ethell, Riley Watkins, Calvin Lam, Kevin Tur-Rodriguez, Jimmie Persinger, Kasidy K. Dobish, Sipra Panda, Shannon M. Buckley, Samantha A. Swenson, Sandipan Brahma, M. Jordan Rowley, R. Katherine Hyde
Runt-related Transcription Factor 1 (RUNX1) is essential for definitive hematopoiesis and is among the most frequently mutated genes in leukemia. Previous work from our lab demonstrated that Histone Deacetylase 1 (HDAC1), a known RUNX1 partner, is unexpectedly required for active transcription suggesting a non-histone role for HDAC1 in regulating components of the RUNX1 complex. Here, we use proteomics, genomics, and long-read transcriptomics to identify novel RUNX1 interacting partners and decipher their role in gene regulation and RNA splicing in leukemia cells. We demonstrate that Polypyrimidine Tract Binding Protein 1 (PTBP1) interacts with RUNX1 in an HDAC1-dependent manner. Chromatin profiling revealed extensive genome-wide overlap in sites occupied by RUNX1 and PTBP1, with significant enrichment at promoters of actively transcribed genes. Loss of PTBP1 in AML cells led to widespread alterations in RNA splicing and decreased expression of genes whose promoters are bound by both factors, including metabolic genes. In agreement with these findings, we found that loss of PTBP1 reduced glycolysis and glucose uptake and ultimately caused cell death. Based on our data, we propose that the interaction between RUNX1 and PTBP1 facilitates expression of metabolic proteins essential for leukemia cell growth and survival.
{"title":"The splicing factor PTBP1 interacts with RUNX1 and is required for leukemia cell survival","authors":"Arjun Dhir, Alexander Ethell, Riley Watkins, Calvin Lam, Kevin Tur-Rodriguez, Jimmie Persinger, Kasidy K. Dobish, Sipra Panda, Shannon M. Buckley, Samantha A. Swenson, Sandipan Brahma, M. Jordan Rowley, R. Katherine Hyde","doi":"10.1038/s41375-025-02799-w","DOIUrl":"10.1038/s41375-025-02799-w","url":null,"abstract":"Runt-related Transcription Factor 1 (RUNX1) is essential for definitive hematopoiesis and is among the most frequently mutated genes in leukemia. Previous work from our lab demonstrated that Histone Deacetylase 1 (HDAC1), a known RUNX1 partner, is unexpectedly required for active transcription suggesting a non-histone role for HDAC1 in regulating components of the RUNX1 complex. Here, we use proteomics, genomics, and long-read transcriptomics to identify novel RUNX1 interacting partners and decipher their role in gene regulation and RNA splicing in leukemia cells. We demonstrate that Polypyrimidine Tract Binding Protein 1 (PTBP1) interacts with RUNX1 in an HDAC1-dependent manner. Chromatin profiling revealed extensive genome-wide overlap in sites occupied by RUNX1 and PTBP1, with significant enrichment at promoters of actively transcribed genes. Loss of PTBP1 in AML cells led to widespread alterations in RNA splicing and decreased expression of genes whose promoters are bound by both factors, including metabolic genes. In agreement with these findings, we found that loss of PTBP1 reduced glycolysis and glucose uptake and ultimately caused cell death. Based on our data, we propose that the interaction between RUNX1 and PTBP1 facilitates expression of metabolic proteins essential for leukemia cell growth and survival.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"138-151"},"PeriodicalIF":13.4,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02799-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477836","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 : 2025-11-07DOI: 10.1038/s41375-025-02794-1
K. S. Kurz, A. Zamo, C. Drewes, E. Madej, C. Laurent, B. Burroni, M. Donzel, L. Xerri, L. Mescam, L. Plank, L. M. R. Gjerdrum, J. Geyer, J. Richter, I. Oschlies, W. Klapper, S. Gramlich, J. Doll, S. Roth, K. Maurus, A. M. Staiger, R. Siebert, M-Q. Du, A. Rosenwald, G. Ott, H. Horn
Rearrangement of Cyclin D1 (CCND1-R) is the hallmark genetic lesion of mantle cell lymphoma (MCL). However, recently diffuse large B-cell lymphomas (DLBCL) have been described carrying a CCND1-R, often with additional rearrangements of BCL2, BCL6 and/or MYC raising the question if these are bona fide DLBCL or pleomorphic MCL. Protein expression and fluorescence in situ hybridisation (FISH) screening of 708 aggressive B-cell lymphomas failed to disclose CCND1-R, demonstrating the rarity of such cases. Fifteen large B-cell tumours, with CCND1-R were collected from different institutions and characterized by immunohistochemistry and for their molecular features. Three of 15 cases were CD5 positive, and all cases were negative for SOX11 but exhibited cyclin D1 staining and CCND1-R by FISH. In 10/15 cases IG could be determined as rearrangement partner by FISH or WGS with occurrence of both aberrant VDJ rearrangement and IGH class-switch recombination (CSR). Eight of 15 tumours had additional translocations involving MYC, BCL2, or BCL6. 8/12 evaluable cases showed significantly mutated IGHV genes and evidence of intraclonal variations in their rearranged IGHV genes. WES disclosed a mutational spectrum typical of DLBCL in 14/14 evaluable cases. We conclude that DLBCL CCND1-R do exist and that CCND1-R in DLBCL can occur without additional translocations.
{"title":"Cyclin D1 rearranged diffuse large B-cell lymphoma—an evolving concept","authors":"K. S. Kurz, A. Zamo, C. Drewes, E. Madej, C. Laurent, B. Burroni, M. Donzel, L. Xerri, L. Mescam, L. Plank, L. M. R. Gjerdrum, J. Geyer, J. Richter, I. Oschlies, W. Klapper, S. Gramlich, J. Doll, S. Roth, K. Maurus, A. M. Staiger, R. Siebert, M-Q. Du, A. Rosenwald, G. Ott, H. Horn","doi":"10.1038/s41375-025-02794-1","DOIUrl":"10.1038/s41375-025-02794-1","url":null,"abstract":"Rearrangement of Cyclin D1 (CCND1-R) is the hallmark genetic lesion of mantle cell lymphoma (MCL). However, recently diffuse large B-cell lymphomas (DLBCL) have been described carrying a CCND1-R, often with additional rearrangements of BCL2, BCL6 and/or MYC raising the question if these are bona fide DLBCL or pleomorphic MCL. Protein expression and fluorescence in situ hybridisation (FISH) screening of 708 aggressive B-cell lymphomas failed to disclose CCND1-R, demonstrating the rarity of such cases. Fifteen large B-cell tumours, with CCND1-R were collected from different institutions and characterized by immunohistochemistry and for their molecular features. Three of 15 cases were CD5 positive, and all cases were negative for SOX11 but exhibited cyclin D1 staining and CCND1-R by FISH. In 10/15 cases IG could be determined as rearrangement partner by FISH or WGS with occurrence of both aberrant VDJ rearrangement and IGH class-switch recombination (CSR). Eight of 15 tumours had additional translocations involving MYC, BCL2, or BCL6. 8/12 evaluable cases showed significantly mutated IGHV genes and evidence of intraclonal variations in their rearranged IGHV genes. WES disclosed a mutational spectrum typical of DLBCL in 14/14 evaluable cases. We conclude that DLBCL CCND1-R do exist and that CCND1-R in DLBCL can occur without additional translocations.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"2988-2996"},"PeriodicalIF":13.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02794-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455513","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 : 2025-11-07DOI: 10.1038/s41375-025-02795-0
Riccardo Moia, Simone Ragaini, Luciano Cascione, Andrea Rinaldi, Elisa Genuardi, Donatella Talotta, Mohammad Almasri, Alessio Bruscaggin, Gian Maria Zaccaria, Andrea Evangelista, Aurora Maria Civita, Alice Di Rocco, Luigi Petrucci, Federica Cavallo, Melania Celli, Mario Luppi, Caterina Stelitano, Piero Maria Stefani, Carlo Visco, Atto Billio, Ivana Casaroli, Claudia Castellino, Enzo Pavone, Sara Galimberti, Caterina Plenteda, Francesco Merli, Abdurraouf Mokhtar Mahmoud, Davide Rossi, Gianluca Gaidano, Marco Ladetto, Francesco Bertoni, Simone Ferrero
{"title":"The integration of gene mutations and copy number variations refines the prognosis of mantle cell lymphoma: long-term results of the Fondazione Italiana Linfomi MCL0208 clinical trial","authors":"Riccardo Moia, Simone Ragaini, Luciano Cascione, Andrea Rinaldi, Elisa Genuardi, Donatella Talotta, Mohammad Almasri, Alessio Bruscaggin, Gian Maria Zaccaria, Andrea Evangelista, Aurora Maria Civita, Alice Di Rocco, Luigi Petrucci, Federica Cavallo, Melania Celli, Mario Luppi, Caterina Stelitano, Piero Maria Stefani, Carlo Visco, Atto Billio, Ivana Casaroli, Claudia Castellino, Enzo Pavone, Sara Galimberti, Caterina Plenteda, Francesco Merli, Abdurraouf Mokhtar Mahmoud, Davide Rossi, Gianluca Gaidano, Marco Ladetto, Francesco Bertoni, Simone Ferrero","doi":"10.1038/s41375-025-02795-0","DOIUrl":"10.1038/s41375-025-02795-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"219-223"},"PeriodicalIF":13.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02795-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455413","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 : 2025-11-03DOI: 10.1038/s41375-025-02790-5
Lingge Tu, Fangfang He, Jun Mun Liew, Chun-Fung Sin, Lichuan Zheng, Sze-Pui Tsui, Xinyu Miao, Hoi-yi Chan, Alvin Chun Hang Ma, Wenqing Zhang, Yiyue Zhang, Anskar Y. H. Leung, Xuan Sun
{"title":"asxl1 C-terminal truncation and SRSF2 mutation drive leukemogenesis via immune reprogramming","authors":"Lingge Tu, Fangfang He, Jun Mun Liew, Chun-Fung Sin, Lichuan Zheng, Sze-Pui Tsui, Xinyu Miao, Hoi-yi Chan, Alvin Chun Hang Ma, Wenqing Zhang, Yiyue Zhang, Anskar Y. H. Leung, Xuan Sun","doi":"10.1038/s41375-025-02790-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02790-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"28 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427425","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 : 2025-11-03DOI: 10.1038/s41375-025-02793-2
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/s41375-025-02793-2","DOIUrl":"10.1038/s41375-025-02793-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"3060-3060"},"PeriodicalIF":13.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02793-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427427","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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