PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia
Abstract We compared 24 primary pediatric T‐cell acute lymphoblastic leukemias (T‐ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient‐derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.99). Sim...
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Springer Nature
2018-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201809443 |
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| author | Paulina Richter‐Pechańska Joachim B Kunz Beat Bornhauser Caroline von Knebel Doeberitz Tobias Rausch Büşra Erarslan‐Uysal Yassen Assenov Viktoras Frismantas Blerim Marovca Sebastian M Waszak Martin Zimmermann Julia Seemann Margit Happich Martin Stanulla Martin Schrappe Gunnar Cario Gabriele Escherich Kseniya Bakharevich Renate Kirschner‐Schwabe Cornelia Eckert Martina U Muckenthaler Jan O Korbel Jean‐Pierre Bourquin Andreas E Kulozik |
| author_facet | Paulina Richter‐Pechańska Joachim B Kunz Beat Bornhauser Caroline von Knebel Doeberitz Tobias Rausch Büşra Erarslan‐Uysal Yassen Assenov Viktoras Frismantas Blerim Marovca Sebastian M Waszak Martin Zimmermann Julia Seemann Margit Happich Martin Stanulla Martin Schrappe Gunnar Cario Gabriele Escherich Kseniya Bakharevich Renate Kirschner‐Schwabe Cornelia Eckert Martina U Muckenthaler Jan O Korbel Jean‐Pierre Bourquin Andreas E Kulozik |
| author_sort | Paulina Richter‐Pechańska |
| collection | DOAJ |
| description | Abstract We compared 24 primary pediatric T‐cell acute lymphoblastic leukemias (T‐ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient‐derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.99). Similarly, the genome‐wide chromatin accessibility (ATAC‐Seq) was preserved remarkably well (ρ = 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the regions hypermethylated in PDXs, were associated with immune response, which might reflect the immune deficiency of the mice and potentially the incomplete interaction between murine cytokines and human receptors. The longitudinal approach of this study allowed an observation that samples collected from patients who developed a type 1 relapse (clonal mutations maintained at relapse) preserved their genomic composition; whereas in patients who developed a type 2 relapse (subset of clonal mutations lost at relapse), the preservation of the leukemia's composition was more variable. In sum, this study underlines the remarkable genomic stability, and for the first time documents the preservation of the epigenomic landscape in T‐ALL‐derived PDX models. |
| format | Article |
| id | doaj-art-a41b214baa0c4e7083befa1edbc53289 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2018-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a41b214baa0c4e7083befa1edbc532892025-08-20T04:03:02ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-11-01101211310.15252/emmm.201809443PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemiaPaulina Richter‐Pechańska0Joachim B Kunz1Beat Bornhauser2Caroline von Knebel Doeberitz3Tobias Rausch4Büşra Erarslan‐Uysal5Yassen Assenov6Viktoras Frismantas7Blerim Marovca8Sebastian M Waszak9Martin Zimmermann10Julia Seemann11Margit Happich12Martin Stanulla13Martin Schrappe14Gunnar Cario15Gabriele Escherich16Kseniya Bakharevich17Renate Kirschner‐Schwabe18Cornelia Eckert19Martina U Muckenthaler20Jan O Korbel21Jean‐Pierre Bourquin22Andreas E Kulozik23Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, and Hopp Children's Cancer Center at NCT HeidelbergDepartment of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, and Hopp Children's Cancer Center at NCT HeidelbergDivision of Pediatric Oncology, University Children's HospitalDepartment of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, and Hopp Children's Cancer Center at NCT HeidelbergMolecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL), University of HeidelbergDepartment of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, and Hopp Children's Cancer Center at NCT HeidelbergDivision of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ)Division of Pediatric Oncology, University Children's HospitalDivision of Pediatric Oncology, University Children's HospitalEuropean Molecular Biology Laboratory (EMBL)Department of Pediatric Hematology and Oncology, Hannover Medical SchoolDepartment of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, and Hopp Children's Cancer Center at NCT HeidelbergDepartment of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, and Hopp Children's Cancer Center at NCT HeidelbergDepartment of Pediatric Hematology and Oncology, Hannover Medical SchoolDepartment of Pediatrics, University Hospital Schleswig‐HolsteinDepartment of Pediatrics, University Hospital Schleswig‐HolsteinClinic of Pediatric Hematology and Oncology, University Medical Center Hamburg‐EppendorfClinic of Pediatric Hematology and Oncology, University Medical Center Hamburg‐EppendorfDepartment of Pediatric Oncology/Hematology, Charité Universitätsmedizin BerlinDepartment of Pediatric Oncology/Hematology, Charité Universitätsmedizin BerlinDepartment of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, and Hopp Children's Cancer Center at NCT HeidelbergMolecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL), University of HeidelbergDivision of Pediatric Oncology, University Children's HospitalDepartment of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, and Hopp Children's Cancer Center at NCT HeidelbergAbstract We compared 24 primary pediatric T‐cell acute lymphoblastic leukemias (T‐ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient‐derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.99). Similarly, the genome‐wide chromatin accessibility (ATAC‐Seq) was preserved remarkably well (ρ = 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the regions hypermethylated in PDXs, were associated with immune response, which might reflect the immune deficiency of the mice and potentially the incomplete interaction between murine cytokines and human receptors. The longitudinal approach of this study allowed an observation that samples collected from patients who developed a type 1 relapse (clonal mutations maintained at relapse) preserved their genomic composition; whereas in patients who developed a type 2 relapse (subset of clonal mutations lost at relapse), the preservation of the leukemia's composition was more variable. In sum, this study underlines the remarkable genomic stability, and for the first time documents the preservation of the epigenomic landscape in T‐ALL‐derived PDX models.https://doi.org/10.15252/emmm.201809443ATAC‐SeqPDX stabilityT‐ALLT‐cell leukemia |
| spellingShingle | Paulina Richter‐Pechańska Joachim B Kunz Beat Bornhauser Caroline von Knebel Doeberitz Tobias Rausch Büşra Erarslan‐Uysal Yassen Assenov Viktoras Frismantas Blerim Marovca Sebastian M Waszak Martin Zimmermann Julia Seemann Margit Happich Martin Stanulla Martin Schrappe Gunnar Cario Gabriele Escherich Kseniya Bakharevich Renate Kirschner‐Schwabe Cornelia Eckert Martina U Muckenthaler Jan O Korbel Jean‐Pierre Bourquin Andreas E Kulozik PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia EMBO Molecular Medicine ATAC‐Seq PDX stability T‐ALL T‐cell leukemia |
| title | PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia |
| title_full | PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia |
| title_fullStr | PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia |
| title_full_unstemmed | PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia |
| title_short | PDX models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia |
| title_sort | pdx models recapitulate the genetic and epigenetic landscape of pediatric t cell leukemia |
| topic | ATAC‐Seq PDX stability T‐ALL T‐cell leukemia |
| url | https://doi.org/10.15252/emmm.201809443 |
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