Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower‐risk myelodysplastic syndromes
Abstract Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expressio...
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2025-01-01
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| Online Access: | https://doi.org/10.1002/hem3.70073 |
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| author | David Rombaut Sarah Sandmann Tobias Tekath Simon Crouch Aniek O. deGraaf Alexandra Smith Daniel Painter Olivier Kosmider Magnus Tobiasson Andreas Lennartsson Bert A. van derReijden Sophie Park Maud D'Aveni Borhane Slama Emmanuelle Clappier Pierre Fenaux Lionel Adès Arjan van deLoosdrecht Saskia Langemeijer Argiris Symeonidis Jaroslav Čermák Claude Preudhomme Aleksandar Savic Ulrich Germing Reinhard Stauder David Bowen Corine vanMarrewijk Elsa Bernard Theo deWitte Julian Varghese Eva Hellström‐Lindberg Martin Dugas Joost Martens Luca Malcovati Joop H. Jansen Michaela Fontenay MDS‐RIGHT consortium |
| author_facet | David Rombaut Sarah Sandmann Tobias Tekath Simon Crouch Aniek O. deGraaf Alexandra Smith Daniel Painter Olivier Kosmider Magnus Tobiasson Andreas Lennartsson Bert A. van derReijden Sophie Park Maud D'Aveni Borhane Slama Emmanuelle Clappier Pierre Fenaux Lionel Adès Arjan van deLoosdrecht Saskia Langemeijer Argiris Symeonidis Jaroslav Čermák Claude Preudhomme Aleksandar Savic Ulrich Germing Reinhard Stauder David Bowen Corine vanMarrewijk Elsa Bernard Theo deWitte Julian Varghese Eva Hellström‐Lindberg Martin Dugas Joost Martens Luca Malcovati Joop H. Jansen Michaela Fontenay MDS‐RIGHT consortium |
| author_sort | David Rombaut |
| collection | DOAJ |
| description | Abstract Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR‐MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well‐annotated cohort of treatment‐naive patients with LR‐MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome‐wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP‐1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower‐risk IPSS‐M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR‐MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention. |
| format | Article |
| id | doaj-art-0de63b5bc83940d491a74eb6f7347741 |
| institution | OA Journals |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-0de63b5bc83940d491a74eb6f73477412025-08-20T02:12:55ZengWileyHemaSphere2572-92412025-01-0191n/an/a10.1002/hem3.70073Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower‐risk myelodysplastic syndromesDavid Rombaut0Sarah Sandmann1Tobias Tekath2Simon Crouch3Aniek O. deGraaf4Alexandra Smith5Daniel Painter6Olivier Kosmider7Magnus Tobiasson8Andreas Lennartsson9Bert A. van derReijden10Sophie Park11Maud D'Aveni12Borhane Slama13Emmanuelle Clappier14Pierre Fenaux15Lionel Adès16Arjan van deLoosdrecht17Saskia Langemeijer18Argiris Symeonidis19Jaroslav Čermák20Claude Preudhomme21Aleksandar Savic22Ulrich Germing23Reinhard Stauder24David Bowen25Corine vanMarrewijk26Elsa Bernard27Theo deWitte28Julian Varghese29Eva Hellström‐Lindberg30Martin Dugas31Joost Martens32Luca Malcovati33Joop H. Jansen34Michaela Fontenay35MDS‐RIGHT consortiumUniversité Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104 Assistance Publique‐Hôpitaux de Paris.Centre, Laboratory of Hematology, Hôpital Cochin Paris FranceInstitute of Medical Informatics University of Münster Münster GermanyInstitute of Medical Informatics University of Münster Münster GermanyEpidemiology and Cancer Statistics Group, Department of Health Sciences University of York York UKDepartment of Laboratory Medicine, Laboratory of Hematology Radboud University Medical Center Nijmegen The NetherlandsEpidemiology and Cancer Statistics Group, Department of Health Sciences University of York York UKEpidemiology and Cancer Statistics Group, Department of Health Sciences University of York York UKUniversité Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104 Assistance Publique‐Hôpitaux de Paris.Centre, Laboratory of Hematology, Hôpital Cochin Paris FranceCenter for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institute Karolinska University Hospital Stockholm SwedenDepartment of Biosciences and Nutrition Karolinska Institute Stockholm SwedenDepartment of Laboratory Medicine, Laboratory of Hematology Radboud University Medical Center Nijmegen The NetherlandsDepartment of Hematology Université de Grenoble‐Alpes, CHU Grenoble FranceService d'Hématologie Clinique University Hospital of Nancy and University of Lorraine Nancy FranceService d'onco‐hématologie, Centre Hospitalier Général d'Avignon Avignon FranceUniversité Paris Cité, Assistance Publique des Hôpitaux de Paris.Nord, Laboratoire d'Hématologie, Hôpital Saint‐Louis Paris FranceUniversité Paris Cité, Assistance Publique des Hôpitaux de Paris.Nord, Service d'Hématologie Senior, Hôpital Saint‐Louis Paris FranceUniversité Paris Cité, Assistance Publique des Hôpitaux de Paris.Nord, Service d'Hématologie Senior, Hôpital Saint‐Louis Paris FranceDepartment of Hematology Amsterdam UMC, Cancer Center Amsterdam Amsterdam The NetherlandsDepartment of Hematology Radboud University Medical Center Nijmegen The NetherlandsHematology Division, Department of Internal Medicine University of Patras Patras GreeceDepartment of Clinical Hematology Institute of Hematology and Blood Transfusion Prague Czech RepublicLaboratoire d'hématologie Centre Hospitalier Régional Universitaire Lille FranceClinic of Hematology, Clinical Center of Vojvodina Faculty of Medicine, University of Novi Sad Novi Sad SerbiaDepartment of Hematology, Oncology and Clinical Immunology Heinrich‐Heine‐University, Medical Faculty Düsseldorf GermanyDepartment of Internal Medicine V (Haematology and Oncology), Comprehensive Cancer Center Innsbruck Medical University of Innsbruck Innsbruck AustriaSt. James's Institute of Oncology Leeds Teaching Hospitals Leeds UKDepartment of Hematology Radboud University Medical Center Nijmegen The NetherlandsDepartment of Computational Biology Institut Gustave Roussy, INSERM U981 Villejuif FranceDepartment of Tumor Immunology, Radboud Institute of Molecular Life Sciences Radboud University Medical Center Nijmegen The NetherlandsInstitute of Medical Informatics University of Münster Münster GermanyCenter for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institute Karolinska University Hospital Stockholm SwedenInstitute of Medical Informatics University of Heidelberg Heidelberg GermanyDepartment of Molecular Biology Faculty of Science, Radboud University Nijmegen The NetherlandsDepartment of Molecular Medicine and Department of Hematology Oncology University of Pavia and Fondazione IRCCS Policlinico S. Matteo Pavia ItalyDepartment of Laboratory Medicine, Laboratory of Hematology Radboud University Medical Center Nijmegen The NetherlandsUniversité Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR8104 Assistance Publique‐Hôpitaux de Paris.Centre, Laboratory of Hematology, Hôpital Cochin Paris FranceAbstract Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR‐MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well‐annotated cohort of treatment‐naive patients with LR‐MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome‐wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP‐1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower‐risk IPSS‐M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR‐MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.https://doi.org/10.1002/hem3.70073 |
| spellingShingle | David Rombaut Sarah Sandmann Tobias Tekath Simon Crouch Aniek O. deGraaf Alexandra Smith Daniel Painter Olivier Kosmider Magnus Tobiasson Andreas Lennartsson Bert A. van derReijden Sophie Park Maud D'Aveni Borhane Slama Emmanuelle Clappier Pierre Fenaux Lionel Adès Arjan van deLoosdrecht Saskia Langemeijer Argiris Symeonidis Jaroslav Čermák Claude Preudhomme Aleksandar Savic Ulrich Germing Reinhard Stauder David Bowen Corine vanMarrewijk Elsa Bernard Theo deWitte Julian Varghese Eva Hellström‐Lindberg Martin Dugas Joost Martens Luca Malcovati Joop H. Jansen Michaela Fontenay MDS‐RIGHT consortium Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower‐risk myelodysplastic syndromes HemaSphere |
| title | Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower‐risk myelodysplastic syndromes |
| title_full | Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower‐risk myelodysplastic syndromes |
| title_fullStr | Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower‐risk myelodysplastic syndromes |
| title_full_unstemmed | Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower‐risk myelodysplastic syndromes |
| title_short | Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower‐risk myelodysplastic syndromes |
| title_sort | somatic mutations and dna methylation identify a subgroup of poor prognosis within lower risk myelodysplastic syndromes |
| url | https://doi.org/10.1002/hem3.70073 |
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