Pub Date : 2025-11-18DOI: 10.1038/s41375-025-02801-5
Matthew Salmon, Nicole Naumann, Jenny Rinke, Manja Meggendorfer, Deepti Radia, Mark Pomfret, Thomas Ernst, Andreas Hochhaus, Andreas Reiter, William J. Tapper, Helen White, Nicholas C. P. Cross
Diverse haematological neoplasms are driven by tyrosine kinase (TK) fusion genes formed by recurrent or non-recurrent genomic rearrangements. The resulting chimeric proteins often present excellent targets for treatment with kinase inhibitors, and the fusion transcripts or genomic junctions can be used as specific targets for molecular monitoring. Whilst the TK genes involved are generally well characterised (e.g. ABL1, PDGFRA, FGFR1), the fusion partners are very diverse, presenting a challenge for detection and characterisation of these structural variants (SV) using current diagnostic methods. We assessed the ability of targeted nanopore sequencing using adaptive sampling to detect fusion genes in myeloid neoplasms. We sequenced genomic DNA from patients (n = 20) with a known or suspected TK gene fusion and identified rearrangements in 18 cases, including all cases with a known TK fusion, typical and atypical BCR::ABL1 rearrangements, an 843Kb deletion causing a FIP1L1::PDGFRA fusion, novel AGAP2::PDGFRB and NFIA::PDGFRB fusions, and a complex CCDC88C::PDGFRB rearrangement with multiple translocation events. The approach was fast (<72 h/sample from DNA to result), flexible with minimal hands-on laboratory time, and provided accurate, patient-specific characterisation of genomic breakpoints.
{"title":"Long read nanopore DNA sequencing with adaptive sampling to identify tyrosine kinase fusion genes","authors":"Matthew Salmon, Nicole Naumann, Jenny Rinke, Manja Meggendorfer, Deepti Radia, Mark Pomfret, Thomas Ernst, Andreas Hochhaus, Andreas Reiter, William J. Tapper, Helen White, Nicholas C. P. Cross","doi":"10.1038/s41375-025-02801-5","DOIUrl":"10.1038/s41375-025-02801-5","url":null,"abstract":"Diverse haematological neoplasms are driven by tyrosine kinase (TK) fusion genes formed by recurrent or non-recurrent genomic rearrangements. The resulting chimeric proteins often present excellent targets for treatment with kinase inhibitors, and the fusion transcripts or genomic junctions can be used as specific targets for molecular monitoring. Whilst the TK genes involved are generally well characterised (e.g. ABL1, PDGFRA, FGFR1), the fusion partners are very diverse, presenting a challenge for detection and characterisation of these structural variants (SV) using current diagnostic methods. We assessed the ability of targeted nanopore sequencing using adaptive sampling to detect fusion genes in myeloid neoplasms. We sequenced genomic DNA from patients (n = 20) with a known or suspected TK gene fusion and identified rearrangements in 18 cases, including all cases with a known TK fusion, typical and atypical BCR::ABL1 rearrangements, an 843Kb deletion causing a FIP1L1::PDGFRA fusion, novel AGAP2::PDGFRB and NFIA::PDGFRB fusions, and a complex CCDC88C::PDGFRB rearrangement with multiple translocation events. The approach was fast (<72 h/sample from DNA to result), flexible with minimal hands-on laboratory time, and provided accurate, patient-specific characterisation of genomic breakpoints.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"37-46"},"PeriodicalIF":13.4,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02801-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536090","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 : 2025-11-18DOI: 10.1038/s41375-025-02802-4
Maroulio Pertesi, Delphine Demangel, Abhishek Niroula, Emeline Perrial, Maria Laura Mahecha Escobar, Maxime Vallée, Christine Liacos, Mehmet K. Samur, Adam S. Sperling, Nikhil C. Munshi, Efstathios Kastritis, Meletios A. Dimopoulos, James D. McKay, Ulf-Henrik Mellqvist, Markus Hansson, Charles Dumontet, On behalf of the Intergroupe Francophone du Myélome (IFM), Björn Nilsson
Multiple myeloma (MM) is the second most common blood malignancy, with several lines of evidence supporting an inherited genetic component. Here, we sequenced 177 affected individuals from 128 families, and 170 early-onset MM cases diagnosed before 55 years of age. Samples were identified and collected through nationwide efforts in France, Sweden, and Greece. We focused on rare germline protein truncating and likely deleterious missense variants in genes harboring variants in at least two families showing variant-disease segregation, and in additional index (≥2) and/or early-onset (≥2) cases. We identified likely pathogenic variants in ATM (N = 12), ANGPTL6 (N = 5), and FBXW9 (N = 6). Additionally, we detected variants in previously reported MM predisposition genes, including DIS3, EP300, and KDM1A. Our results represent the largest sequencing study on familial and early-onset MM to date, and further illuminate the constitutional genetic basis of MM.
{"title":"Putative multiple myeloma susceptibility genes identified by exome sequencing of 347 familial and early-onset cases","authors":"Maroulio Pertesi, Delphine Demangel, Abhishek Niroula, Emeline Perrial, Maria Laura Mahecha Escobar, Maxime Vallée, Christine Liacos, Mehmet K. Samur, Adam S. Sperling, Nikhil C. Munshi, Efstathios Kastritis, Meletios A. Dimopoulos, James D. McKay, Ulf-Henrik Mellqvist, Markus Hansson, Charles Dumontet, On behalf of the Intergroupe Francophone du Myélome (IFM), Björn Nilsson","doi":"10.1038/s41375-025-02802-4","DOIUrl":"10.1038/s41375-025-02802-4","url":null,"abstract":"Multiple myeloma (MM) is the second most common blood malignancy, with several lines of evidence supporting an inherited genetic component. Here, we sequenced 177 affected individuals from 128 families, and 170 early-onset MM cases diagnosed before 55 years of age. Samples were identified and collected through nationwide efforts in France, Sweden, and Greece. We focused on rare germline protein truncating and likely deleterious missense variants in genes harboring variants in at least two families showing variant-disease segregation, and in additional index (≥2) and/or early-onset (≥2) cases. We identified likely pathogenic variants in ATM (N = 12), ANGPTL6 (N = 5), and FBXW9 (N = 6). Additionally, we detected variants in previously reported MM predisposition genes, including DIS3, EP300, and KDM1A. Our results represent the largest sequencing study on familial and early-onset MM to date, and further illuminate the constitutional genetic basis of MM.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"235-240"},"PeriodicalIF":13.4,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545284","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 : 2025-11-17DOI: 10.1038/s41375-025-02803-3
Pinpin Sui, Ying Li, Juyeong Hong, Caroline R. Delma, Shi Chen, Juan Wang, Peng Zhang, Songmi Han, Asra Noor, Hui Yang, Yakun Pang, Yu Luan, Mingjiang Xu, Jihoon Lee, Feng-Chun Yang
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by high incidence, poor prognosis, and marked genetic and clinical heterogeneity. This heterogeneity poses a significant challenge to effective treatment and underscores the urgent need for tailored therapeutic strategies. Here, we identified the EvC ciliary complex subunits EVC and EVC2 as aberrantly overexpressed in a subset of AMLs, particularly those harboring ASXL1 mutations or the t(8;21) translocation, with elevated expression correlating with poor patient prognosis. Functional studies demonstrated that EVC/EVC2 are essential for maintaining the leukemogenic properties of AML cells, while being dispensable for the function of normal hematopoietic stem/progenitor cells. Loss of EVC/EVC2 impairs leukemia cell proliferation, promotes differentiation, and effectively blocks AML progression in vivo. Mechanistically, we revealed that elevated EVC/EVC2 expression is associated with gained AML1-ETO occupancy or enhanced chromatin interactions at EVC/EVC2 promoter regions in AML cells carrying t(8;21) or ASXL1 mutations, respectively. Notably, we demonstrate that the leukemogenic role of EVC/EVC2 is mediated through MYC pathway activation, independent of their canonical role in Hedgehog signaling. Collectively, our findings demonstrate an oncogenic event of overexpressed EVC/EVC2, identifying novel therapeutic vulnerabilities in AML.
{"title":"Oncogenic activation of EVC/EVC2 defines a therapeutically targetable subset of acute myeloid leukemia","authors":"Pinpin Sui, Ying Li, Juyeong Hong, Caroline R. Delma, Shi Chen, Juan Wang, Peng Zhang, Songmi Han, Asra Noor, Hui Yang, Yakun Pang, Yu Luan, Mingjiang Xu, Jihoon Lee, Feng-Chun Yang","doi":"10.1038/s41375-025-02803-3","DOIUrl":"10.1038/s41375-025-02803-3","url":null,"abstract":"Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by high incidence, poor prognosis, and marked genetic and clinical heterogeneity. This heterogeneity poses a significant challenge to effective treatment and underscores the urgent need for tailored therapeutic strategies. Here, we identified the EvC ciliary complex subunits EVC and EVC2 as aberrantly overexpressed in a subset of AMLs, particularly those harboring ASXL1 mutations or the t(8;21) translocation, with elevated expression correlating with poor patient prognosis. Functional studies demonstrated that EVC/EVC2 are essential for maintaining the leukemogenic properties of AML cells, while being dispensable for the function of normal hematopoietic stem/progenitor cells. Loss of EVC/EVC2 impairs leukemia cell proliferation, promotes differentiation, and effectively blocks AML progression in vivo. Mechanistically, we revealed that elevated EVC/EVC2 expression is associated with gained AML1-ETO occupancy or enhanced chromatin interactions at EVC/EVC2 promoter regions in AML cells carrying t(8;21) or ASXL1 mutations, respectively. Notably, we demonstrate that the leukemogenic role of EVC/EVC2 is mediated through MYC pathway activation, independent of their canonical role in Hedgehog signaling. Collectively, our findings demonstrate an oncogenic event of overexpressed EVC/EVC2, identifying novel therapeutic vulnerabilities in AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"166-177"},"PeriodicalIF":13.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531658","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 : 2025-11-17DOI: 10.1038/s41375-025-02805-1
Florian H. Heidel, Martin Griesshammer, Jean-Jacques Kiladjian, on behalf of the PV-AIM investigators
{"title":"Response to the commentary by Xu et al. on the PV-AIM study","authors":"Florian H. Heidel, Martin Griesshammer, Jean-Jacques Kiladjian, on behalf of the PV-AIM investigators","doi":"10.1038/s41375-025-02805-1","DOIUrl":"10.1038/s41375-025-02805-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"247-249"},"PeriodicalIF":13.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02805-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541183","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 : 2025-11-12DOI: 10.1038/s41375-025-02812-2
Hanxue Zheng, Liansheng Zhang, Lijuan Li
{"title":"Correspondence to “Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis”","authors":"Hanxue Zheng, Liansheng Zhang, Lijuan Li","doi":"10.1038/s41375-025-02812-2","DOIUrl":"10.1038/s41375-025-02812-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"245-246"},"PeriodicalIF":13.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492573","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 : 2025-11-12DOI: 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}
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