LeukemiaPub Date : 2024-07-25DOI: 10.1038/s41375-024-02350-3
Lingxu Jiang, Yudi Zhang, Jiejing Qian, Xinping Zhou, Liya Ma, Shuanghong Zhu, Lu Wang, Wei Wang, Wenli Yang, Yingwan Luo, Wei Lang, Gaixiang Xu, Yanling Ren, Chen Mei, Li Ye, Qi Zhang, Xiaozhen Liu, Jie Jin, Jie Sun, Hongyan Tong
{"title":"The m6A methyltransferase METTL14 promotes cell proliferation via SETBP1-mediated activation of PI3K-AKT signaling pathway in myelodysplastic neoplasms","authors":"Lingxu Jiang, Yudi Zhang, Jiejing Qian, Xinping Zhou, Liya Ma, Shuanghong Zhu, Lu Wang, Wei Wang, Wenli Yang, Yingwan Luo, Wei Lang, Gaixiang Xu, Yanling Ren, Chen Mei, Li Ye, Qi Zhang, Xiaozhen Liu, Jie Jin, Jie Sun, Hongyan Tong","doi":"10.1038/s41375-024-02350-3","DOIUrl":"10.1038/s41375-024-02350-3","url":null,"abstract":"N6-methyladenosine (m6A) is the most prevalent epitranscriptomic modification in mammalian mRNA. Recent studies have revealed m6A is involved in the pathogenesis of various malignant tumors including hematologic neoplasms. Nevertheless, the specific roles of m6A modification and m6A regulators in myelodysplastic neoplasms (MDS) remain poorly understood. Herein, we demonstrated that m6A level and the expression of m6A methyltransferase METTL14 were elevated in MDS patients with bone marrow blasts ≥5%. Additionally, m6A level and METTL14 expression were upregulated as the disease risk increased and significantly associated with adverse clinical outcomes. Knockdown of METTL14 inhibited cell proliferation and colony formation ability of MDS cells. Moreover, in vivo experiments showed METTL14 knockdown remarkably reduced tumor burden and prolonged the survival of mice. Mechanistically, METTL14 facilitated the m6A modification of SETBP1 mRNA by formation of METTL3-METTL14 complex, leading to increased stabilization of SETBP1 mRNA and subsequent activation of the PI3K-AKT signaling pathway. Overall, this study elucidated the involvement of the METTL14/m6A/SETBP1/PI3K-AKT signaling axis in MDS, highlighting the therapeutic potential of targeting METTL3-METTL14 complex-mediated m6A modification for MDS therapy.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02350-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759641","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}
LeukemiaPub Date : 2024-07-24DOI: 10.1038/s41375-024-02317-4
Richard L. Wong, Michael Y. Choi, Huan-You Wang, Thomas J. Kipps
{"title":"Mutation in Bruton Tyrosine Kinase (BTK) A428D confers resistance To BTK-degrader therapy in chronic lymphocytic leukemia","authors":"Richard L. Wong, Michael Y. Choi, Huan-You Wang, Thomas J. Kipps","doi":"10.1038/s41375-024-02317-4","DOIUrl":"10.1038/s41375-024-02317-4","url":null,"abstract":"Targeting BTK has profoundly changed the face of CLL treatment over the past decade. Iterative advances in the cat and mouse game of resistance and redesign have moved BTK inhibitors from covalent to non-covalent and now targeted protein degraders. However, contrary to the presumption that protein degraders may be impervious to mutations in BTK, we now present clinical evidence that a mutation in the kinase domain of BTK, namely A428D, can confer disease resistance to a BTK degrader currently in clinical trials, that is BGB-16673. Modeling of a BTK A428D mutation places a negatively charged aspartic acid in place of the hydrophobic side chain of alanine within the binding pocket of another BTK-degrader in clinical development, namely NX-2127, suggesting that CLL cells with BTK A428D also may be resistant to NX-2127, as they already are known to be with either non-covalent or covalent inhibitors of BTK. Consequently, the two BTK degraders furthest advanced in clinical trials potentially may select for CLL cells with BTK A428D that are resistant to all approved BTKi’s.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759639","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}
LeukemiaPub Date : 2024-07-24DOI: 10.1038/s41375-024-02359-8
Simona Piemontese, Myriam Labopin, Goda Choi, Annoek E. C. Broers, Jacopo Peccatori, Ellen Meijer, Gwendolyn Van Gorkom, Montserrat Rovira, Maria Jesús Pascual Cascon, Simona Sica, Jan Vydra, Alexander Kulagin, Alexandros Spyridonidis, Arnon Nagler, Ali Bazarbachi, Bipin Savani, Eolia Brissot, Jaime Sanz, Mohamad Mohty, Fabio Ciceri
{"title":"Older MRD vs. younger MUD in patients older than 50 years with AML in remission using post-transplant cyclophosphamide","authors":"Simona Piemontese, Myriam Labopin, Goda Choi, Annoek E. C. Broers, Jacopo Peccatori, Ellen Meijer, Gwendolyn Van Gorkom, Montserrat Rovira, Maria Jesús Pascual Cascon, Simona Sica, Jan Vydra, Alexander Kulagin, Alexandros Spyridonidis, Arnon Nagler, Ali Bazarbachi, Bipin Savani, Eolia Brissot, Jaime Sanz, Mohamad Mohty, Fabio Ciceri","doi":"10.1038/s41375-024-02359-8","DOIUrl":"10.1038/s41375-024-02359-8","url":null,"abstract":"An increasing number of older patients with acute myeloid leukemia (AML) are offered an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Normally, older patients have older matched related donors (MRD). Matched unrelated donors (MUD) are an important alternative, but it remains unclear whether a younger MUD is associated with better outcomes, especially in the context of post-transplant cyclophosphamide (PTCy). We compared outcomes of patients older than 50 years with AML in first complete remission (CR1) and receiving a first HSCT from a 10/10 MUD aged younger than 40 years to those receiving a graft from a MRD aged older than 50 years, using PTCy and with well-known transplant conditioning intensity (TCI) score. A total of 345 consecutive patients were included and classified according to TCI score as low, intermediate, or high. On multivariable analysis in the TCI-intermediate/high group, MUD was associated with better graft-versus-host disease-free, relapse-free survival, lower non-relapse mortality and lower relapse incidence. For patients receiving a TCI-low regimen, outcomes are independent on the type of donor. In patients with AML in CR1, older than 50 years and receiving a TCI-intermediate/high conditioning regimen using PTCy, a MUD younger than 40 years is preferable over a MRD older than 50 years.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759640","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}
LeukemiaPub Date : 2024-07-23DOI: 10.1038/s41375-024-02357-w
Ngoc Tung Tran, Robin Graf, Ernesto Acevedo-Ochoa, Janine Trombke, Timm Weber, Thomas Sommermann, Claudia Salomon, Ralf Kühn, Klaus Rajewsky, Van Trung Chu
{"title":"In vivo CRISPR/Cas9-mediated screen reveals a critical function of TFDP1 and E2F4 transcription factors in hematopoiesis","authors":"Ngoc Tung Tran, Robin Graf, Ernesto Acevedo-Ochoa, Janine Trombke, Timm Weber, Thomas Sommermann, Claudia Salomon, Ralf Kühn, Klaus Rajewsky, Van Trung Chu","doi":"10.1038/s41375-024-02357-w","DOIUrl":"10.1038/s41375-024-02357-w","url":null,"abstract":"Hematopoiesis is a continuous process of blood cell production driven by hematopoietic stem and progenitor cells (HSPCs) in the bone marrow. Proliferation and differentiation of HSPCs are regulated by complex transcriptional networks. In order to identify transcription factors with key roles in HSPC-mediated hematopoietic reconstitution, we developed an efficient and robust CRISPR/Cas9-based in vivo genetic screen. Using this experimental system, we identified the TFDP1 transcription factor to be essential for HSPC proliferation and post-transplant hematopoiesis. We further discovered that E2F4, an E2F transcription factor, serves as a binding partner of TFDP1 and is required for HSPC proliferation. Deletion of TFDP1 caused downregulation of genes associated with the cell cycle, with around 50% of these genes being identified as direct targets of TFDP1 and E2F4. Thus, our study expands the transcriptional network governing hematopoietic development through an in vivo CRISPR/Cas9-based genetic screen and identifies TFDP1/E2F4 as positive regulators of cell cycle genes in HSPCs.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02357-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752090","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}
LeukemiaPub Date : 2024-07-23DOI: 10.1038/s41375-024-02336-1
Anne Mea Spanjaart, Per Ljungman, Gloria Tridello, Juana Schwartz, Nuria Martinez-Cibrián, Pere Barba, Mi Kwon, Lucia Lopez-Corral, Joaquin Martinez-Lopez, Christelle Ferra, Roberta Di Blasi, Hervé Ghesquieres, Pim Mutsaers, Friso Calkoen, Margot Jak, Jaap van Doesum, Joost S. P. Vermaat, Marjolein van der Poel, Johan Maertens, Massimiliano Gambella, Elisabetta Metafuni, Fabio Ciceri, Riccardo Saccardi, Emma Nicholson, Eleni Tholouli, Collin Matthew, Victoria Potter, Adrian Bloor, Caroline Besley, Claire Roddie, Keith Wilson, Arnon Nagler, Antonio Campos, Soeren Lykke Petersen, Frantisek Folber, Peter Bader, Jurgen Finke, Nicolaus Kroger, Nina Knelange, Rafael de La Camara, Marie José Kersten, Stephan Mielke
{"title":"Improved outcome of COVID-19 over time in patients treated with CAR T-cell therapy: Update of the European COVID-19 multicenter study on behalf of the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party (IDWP) and the European Hematology Association (EHA) Lymphoma Group","authors":"Anne Mea Spanjaart, Per Ljungman, Gloria Tridello, Juana Schwartz, Nuria Martinez-Cibrián, Pere Barba, Mi Kwon, Lucia Lopez-Corral, Joaquin Martinez-Lopez, Christelle Ferra, Roberta Di Blasi, Hervé Ghesquieres, Pim Mutsaers, Friso Calkoen, Margot Jak, Jaap van Doesum, Joost S. P. Vermaat, Marjolein van der Poel, Johan Maertens, Massimiliano Gambella, Elisabetta Metafuni, Fabio Ciceri, Riccardo Saccardi, Emma Nicholson, Eleni Tholouli, Collin Matthew, Victoria Potter, Adrian Bloor, Caroline Besley, Claire Roddie, Keith Wilson, Arnon Nagler, Antonio Campos, Soeren Lykke Petersen, Frantisek Folber, Peter Bader, Jurgen Finke, Nicolaus Kroger, Nina Knelange, Rafael de La Camara, Marie José Kersten, Stephan Mielke","doi":"10.1038/s41375-024-02336-1","DOIUrl":"10.1038/s41375-024-02336-1","url":null,"abstract":"COVID-19 has been associated with high mortality in patients treated with Chimeric Antigen Receptor (CAR) T-cell therapy for hematologic malignancies. Here, we investigated whether the outcome has improved over time with the primary objective of assessing COVID-19-attributable mortality in the Omicron period of 2022 compared to previous years. Data for this multicenter study were collected using the MED-A and COVID-19 report forms developed by the EBMT. One-hundred-eighty patients were included in the analysis, 39 diagnosed in 2020, 35 in 2021 and 106 in 2022. The median age was 58.9 years (min-max: 5.2–78.4). There was a successive decrease in COVID-19-related mortality over time (2020: 43.6%, 2021: 22.9%, 2022: 7.5%) and in multivariate analysis year of infection was the strongest predictor of survival (p = 0.0001). Comparing 2022 with 2020–2021, significantly fewer patients had lower respiratory symptoms (21.7% vs 37.8%, p = 0.01), needed oxygen support (25.5% vs 43.2%, p = 0.01), or were admitted to ICU (5.7% vs 33.8%, p = 0.0001). Although COVID-19-related mortality has decreased over time, CAR T-cell recipients remain at higher risk for complications than the general population. Consequently, vigilant monitoring for COVID-19 in patients undergoing B-cell-targeting CAR T-cell treatment is continuously recommended ensuring optimal prevention of infection and advanced state-of-the art treatment when needed.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02336-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141752089","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}
LeukemiaPub Date : 2024-07-20DOI: 10.1038/s41375-024-02347-y
Johann-Christoph Jann, Christopher B. Hergott, Marisa Winkler, Yiwen Liu, Benjamin Braun, Anne Charles, Kevin M. Copson, Shougat Barua, Manja Meggendorfer, Niroshan Nadarajah, Shai Shimony, Eric S. Winer, Martha Wadleigh, Richard M. Stone, Daniel J. DeAngelo, Jacqueline S. Garcia, Torsten Haferlach, R. Coleman Lindsley, Marlise R. Luskin, Maximilian Stahl, Zuzana Tothova
{"title":"Subunit-specific analysis of cohesin-mutant myeloid malignancies reveals distinct ontogeny and outcomes","authors":"Johann-Christoph Jann, Christopher B. Hergott, Marisa Winkler, Yiwen Liu, Benjamin Braun, Anne Charles, Kevin M. Copson, Shougat Barua, Manja Meggendorfer, Niroshan Nadarajah, Shai Shimony, Eric S. Winer, Martha Wadleigh, Richard M. Stone, Daniel J. DeAngelo, Jacqueline S. Garcia, Torsten Haferlach, R. Coleman Lindsley, Marlise R. Luskin, Maximilian Stahl, Zuzana Tothova","doi":"10.1038/s41375-024-02347-y","DOIUrl":"10.1038/s41375-024-02347-y","url":null,"abstract":"Mutations in the cohesin complex components (STAG2, RAD21, SMC1A, SMC3, and PDS5B) are recurrent genetic drivers in myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Whether the different cohesin subunit mutations share clinical characteristics and prognostic significance is not known. We analyzed 790 cohesin-mutant patients from the Dana-Farber Cancer Institute (DFCI) and the Munich Leukemia Laboratory (MLL), 390 of which had available outcome data, and identified subunit-specific clinical, prognostic, and genetic characteristics suggestive of distinct ontogenies. We found that STAG2 mutations are acquired at MDS stage and are associated with secondary AML, adverse prognosis, and co-occurrence of secondary AML-type mutations. In contrast, mutations in RAD21, SMC1A and SMC3 share features with de novo AML with better prognosis, and co-occurrence with de novo AML-type lesions. The findings show the heterogeneous nature of cohesin complex mutations, and inform clinical and prognostic classification, as well as distinct biology of the cohesin complex.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02347-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732628","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}
LeukemiaPub Date : 2024-07-19DOI: 10.1038/s41375-024-02355-y
Patrizia Mondello
{"title":"Silencing GNAS enhances HDAC3i efficacy in CREBBP wild type B cell lymphoma","authors":"Patrizia Mondello","doi":"10.1038/s41375-024-02355-y","DOIUrl":"10.1038/s41375-024-02355-y","url":null,"abstract":"The genetic era has opened the opportunity of using personalized therapeutic approaches, in part based on targeting genes with somatic mutations. For example, lymphomas harboring the highly recurrent CREBBP mutation show dependency on HDAC3, thus selective inhibition of HDAC3 reversed the epigenetic effects of CREBBP mutation, halted lymphoma growth, and induced MHC class II expression, enabling the T-cells to recognize and kill lymphoma cells. However, CREBBP wild type (WT) cells are less sensitive to this approach. In this issue of Leukemia, He et al. have executed a genome-wide CRISPR screening that identified GNAS as a target to maximize the therapeutic activity of HDAC3 inhibition in CREBBP WT lymphoma.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727390","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}
LeukemiaPub Date : 2024-07-18DOI: 10.1038/s41375-024-02337-0
Tariq Kewan, Waled S. Bahaj, Carmelo Gurnari, Olisaemeka D. Ogbue, Sudipto Mukherjee, Anjali Advani, James R. Cook, Heesun J. Rogers, Hetty E. Carraway, Suresh K. Balasubramanian, Valeria Visconte, Jaroslaw P. Maciejewski
{"title":"Clinical and molecular characteristics of extramedullary acute myeloid leukemias","authors":"Tariq Kewan, Waled S. Bahaj, Carmelo Gurnari, Olisaemeka D. Ogbue, Sudipto Mukherjee, Anjali Advani, James R. Cook, Heesun J. Rogers, Hetty E. Carraway, Suresh K. Balasubramanian, Valeria Visconte, Jaroslaw P. Maciejewski","doi":"10.1038/s41375-024-02337-0","DOIUrl":"10.1038/s41375-024-02337-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02337-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633909","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}
LeukemiaPub Date : 2024-07-18DOI: 10.1038/s41375-024-02339-y
M. Konopleva, M. Milella, P. Ruvolo, J. C. Watts, M. R. Ricciardi, B. Korchin, McQueen Teresa, William Bornmann, T. Tsao, P. Bergamo, D. H. Mak, W. Chen, J. McCubrey, A. Tafuri, M. Andreeff
{"title":"Retraction Note: MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex","authors":"M. Konopleva, M. Milella, P. Ruvolo, J. C. Watts, M. R. Ricciardi, B. Korchin, McQueen Teresa, William Bornmann, T. Tsao, P. Bergamo, D. H. Mak, W. Chen, J. McCubrey, A. Tafuri, M. Andreeff","doi":"10.1038/s41375-024-02339-y","DOIUrl":"10.1038/s41375-024-02339-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02339-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723849","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}