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}
Pub Date : 2025-11-03DOI: 10.1038/s41375-025-02787-0
Mouhamad Khouja, Elisa Genuardi, Simone Ferrero, Anna Laqua, Beatrice Alessandria, Onno J. H. M. Verhagen, Christa H. E. Homburg, Ramón García Sanz, Alejandro Medina Herrera, Vincent H. J. van der Velden, Maria Gomes da Silva, Paula Gameiro, Jeanette Doorduijn, Eva Giné, Carlo Visco, Monika Brüggemann, Claudia D. Baldus, Marco Ladetto, Christian Schmidt, Martin Dreyling, Linmiao Jiang, Eva Hoster, Nikos Darzentas, Karol Pal, Guranda Chitadze, James Peter Stewart, David Gonzalez, Christiane Pott, on behalf of the European MCL Network
Adding ibrutinib to first-line immunochemotherapy (Ibru-R-chemo) showed superiority in younger mantle cell lymphoma (MCL) patients in the TRIANGLE trial (NCT02858258). To investigate response mechanisms and kinetics across treatment arms, we genotyped 57 patients from cell-free (cf)DNA using targeted-capture sequencing and investigated measurable residual disease (MRD) in cfDNA and peripheral blood by targeted-sequencing and qPCR. Pre-treatment cfDNA and circulating tumor (ct)DNA levels predicted outcomes, and precisely genotyped all patients. Circulating tumor cell (CTC)-clearance was more frequent and rapid than ctDNA-clearance across arms. At interim staging (IS), 55% of patients were ctDNA-positive while 35% and 41% were CTC-positive by qPCR and immunoglobulin gene (IG)-NGS. At end of induction, 43% were ctDNA-positive, while 15% (qPCR) and 25% (IG-NGS) were CTC-positive. MRD by qPCR was most predictive for outcomes. Ibru-R-chemo seemed to overcome TP53mut-mediated risk (hazard ratio 1.9 vs. 10) and induce early MRD response, represented by enhanced CTC (71% vs. 57%) and ctDNA clearance (59% vs. 24%) at IS. Flow-cytometry-based immunomonitoring showed ibrutinib’s influence on inhibitory T-cell phenotypes, showing ≥25% reduction in PD1+ and PD1+ KLRG1+ CD4+-T-cells in four patients. Taken together, besides direct anti-B-cell efficacy, ibrutinib improves chemotherapy efficiency by reconstituting an effective immune system and enhancing immune cell control.
{"title":"Noninvasive genotyping and early disease dynamics demonstrate the efficacy of ibrutinib in combination with immunochemotherapy in patients with mantle cell lymphoma treated in the TRIANGLE trial","authors":"Mouhamad Khouja, Elisa Genuardi, Simone Ferrero, Anna Laqua, Beatrice Alessandria, Onno J. H. M. Verhagen, Christa H. E. Homburg, Ramón García Sanz, Alejandro Medina Herrera, Vincent H. J. van der Velden, Maria Gomes da Silva, Paula Gameiro, Jeanette Doorduijn, Eva Giné, Carlo Visco, Monika Brüggemann, Claudia D. Baldus, Marco Ladetto, Christian Schmidt, Martin Dreyling, Linmiao Jiang, Eva Hoster, Nikos Darzentas, Karol Pal, Guranda Chitadze, James Peter Stewart, David Gonzalez, Christiane Pott, on behalf of the European MCL Network","doi":"10.1038/s41375-025-02787-0","DOIUrl":"10.1038/s41375-025-02787-0","url":null,"abstract":"Adding ibrutinib to first-line immunochemotherapy (Ibru-R-chemo) showed superiority in younger mantle cell lymphoma (MCL) patients in the TRIANGLE trial (NCT02858258). To investigate response mechanisms and kinetics across treatment arms, we genotyped 57 patients from cell-free (cf)DNA using targeted-capture sequencing and investigated measurable residual disease (MRD) in cfDNA and peripheral blood by targeted-sequencing and qPCR. Pre-treatment cfDNA and circulating tumor (ct)DNA levels predicted outcomes, and precisely genotyped all patients. Circulating tumor cell (CTC)-clearance was more frequent and rapid than ctDNA-clearance across arms. At interim staging (IS), 55% of patients were ctDNA-positive while 35% and 41% were CTC-positive by qPCR and immunoglobulin gene (IG)-NGS. At end of induction, 43% were ctDNA-positive, while 15% (qPCR) and 25% (IG-NGS) were CTC-positive. MRD by qPCR was most predictive for outcomes. Ibru-R-chemo seemed to overcome TP53mut-mediated risk (hazard ratio 1.9 vs. 10) and induce early MRD response, represented by enhanced CTC (71% vs. 57%) and ctDNA clearance (59% vs. 24%) at IS. Flow-cytometry-based immunomonitoring showed ibrutinib’s influence on inhibitory T-cell phenotypes, showing ≥25% reduction in PD1+ and PD1+ KLRG1+ CD4+-T-cells in four patients. Taken together, besides direct anti-B-cell efficacy, ibrutinib improves chemotherapy efficiency by reconstituting an effective immune system and enhancing immune cell control.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"95-105"},"PeriodicalIF":13.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02787-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433891","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 : 2025-10-27DOI: 10.1038/s41375-025-02791-4
T. Benz, P. Larghero, C. Meyer, T. Hanewald, D. Brüggmann, A.-E. Hentrich, F. Louwen, R. Marschalek
The chromosomal translocation t(4;11)(q21;q23) is frequently diagnosed in KMT2A-r Acute Leukemia patients. Although we understand much about the function of both wildtype KMT2A and AFF1 multiprotein complexes, little is known about the molecular actions the two fusion proteins KMT2A::AFF1 and AFF1::KMT2A during the very early steps of disease onset and progression. Most published data have been generated in t(4;11) cell lines or transplanted mouse models, where exactly this process remains a black box. Here, we present the results of our efforts to establish a t(4;11) chromosomal translocation in human hematopoietic stem/precursor cells by CRISPR/Cas9. These genetically modified cells can be expanded over 5-6 months in vitro and their potential to differentiate was examined with IL-7 supplementation. The benefit of this model system is that (1) both reciprocal fusion proteins are concomitantly present, and (2) a molecular surveillance is possible at any timepoint through analysis of RNA, DNA or protein. Thus, the CRISPR/Cas9 technique allowed us to create a bona fide model system to study the very early steps of leukemia onset at the molecular level. In conclusion, this approach is the fastest way to investigate and characterize KMT2A-r fusions in primary human cells.
{"title":"CRISPR/Cas9-mediated t(4;11) translocation in human hematopoietic stem/precursor cells demonstrates plasticity to differentiate into either the myeloid or lymphoid lineage","authors":"T. Benz, P. Larghero, C. Meyer, T. Hanewald, D. Brüggmann, A.-E. Hentrich, F. Louwen, R. Marschalek","doi":"10.1038/s41375-025-02791-4","DOIUrl":"10.1038/s41375-025-02791-4","url":null,"abstract":"The chromosomal translocation t(4;11)(q21;q23) is frequently diagnosed in KMT2A-r Acute Leukemia patients. Although we understand much about the function of both wildtype KMT2A and AFF1 multiprotein complexes, little is known about the molecular actions the two fusion proteins KMT2A::AFF1 and AFF1::KMT2A during the very early steps of disease onset and progression. Most published data have been generated in t(4;11) cell lines or transplanted mouse models, where exactly this process remains a black box. Here, we present the results of our efforts to establish a t(4;11) chromosomal translocation in human hematopoietic stem/precursor cells by CRISPR/Cas9. These genetically modified cells can be expanded over 5-6 months in vitro and their potential to differentiate was examined with IL-7 supplementation. The benefit of this model system is that (1) both reciprocal fusion proteins are concomitantly present, and (2) a molecular surveillance is possible at any timepoint through analysis of RNA, DNA or protein. Thus, the CRISPR/Cas9 technique allowed us to create a bona fide model system to study the very early steps of leukemia onset at the molecular level. In conclusion, this approach is the fastest way to investigate and characterize KMT2A-r fusions in primary human cells.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"72-86"},"PeriodicalIF":13.4,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02791-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145373959","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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