دورية أكاديمية
Tissue-Biased Expansion of DNMT3A-Mutant Clones in a Mosaic Individual Is Associated with Conserved Epigenetic Erosion.
| العنوان: | Tissue-Biased Expansion of DNMT3A-Mutant Clones in a Mosaic Individual Is Associated with Conserved Epigenetic Erosion. |
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| المؤلفون: | Tovy A; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Reyes JM; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Gundry MC; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Brunetti L; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA., Lee-Six H; Cancer, Ageing, and Somatic Mutation, Wellcome Sanger Institute, Hinxton, UK., Petljak M; Cancer, Ageing, and Somatic Mutation, Wellcome Sanger Institute, Hinxton, UK., Park HJ; Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA., Guzman AG; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Rosas C; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA., Jeffries AR; RILD Wellcome Wolfson Centre, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK., Baple E; RILD Wellcome Wolfson Centre, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK., Mill J; RILD Wellcome Wolfson Centre, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK., Crosby AH; RILD Wellcome Wolfson Centre, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK., Sency V; DDC Clinic Center for Special Needs Children, Middlefield, OH, USA; Department of Pediatrics, Rainbow Babies & Children's Hospital, Cleveland, OH, USA; Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH, USA., Xin B; DDC Clinic Center for Special Needs Children, Middlefield, OH, USA; Department of Pediatrics, Rainbow Babies & Children's Hospital, Cleveland, OH, USA; Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH, USA., Machado HE; Cancer, Ageing, and Somatic Mutation, Wellcome Sanger Institute, Hinxton, UK., Castillo D; City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Weitzel JN; City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Li W; Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA., Stratton MR; Cancer, Ageing, and Somatic Mutation, Wellcome Sanger Institute, Hinxton, UK., Campbell PJ; Cancer, Ageing, and Somatic Mutation, Wellcome Sanger Institute, Hinxton, UK., Wang H; DDC Clinic Center for Special Needs Children, Middlefield, OH, USA; Department of Pediatrics, Rainbow Babies & Children's Hospital, Cleveland, OH, USA; Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH, USA., Sanders MA; Cancer, Ageing, and Somatic Mutation, Wellcome Sanger Institute, Hinxton, UK; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: ms44@sanger.ac.uk., Goodell MA; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address: goodell@bcm.edu. |
| المصدر: | Cell stem cell [Cell Stem Cell] 2020 Aug 06; Vol. 27 (2), pp. 326-335.e4. Date of Electronic Publication: 2020 Jul 15. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101311472 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1875-9777 (Electronic) Linking ISSN: 18759777 NLM ISO Abbreviation: Cell Stem Cell Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Cambridge, MA : Cell Press |
| مواضيع طبية MeSH: | DNA (Cytosine-5-)-Methyltransferases*/genetics , Hematopoiesis*/genetics, Clone Cells ; DNA Methyltransferase 3A ; Epigenesis, Genetic ; Mutation/genetics |
| مستخلص: | DNA methyltransferase 3A (DNMT3A) is the most commonly mutated gene in clonal hematopoiesis (CH). Somatic DNMT3A mutations arise in hematopoietic stem cells (HSCs) many years before malignancies develop, but difficulties in comparing their impact before malignancy with wild-type cells have limited the understanding of their contributions to transformation. To circumvent this limitation, we derived normal and DNMT3A mutant lymphoblastoid cell lines from a germline mosaic individual in whom these cells co-existed for nearly 6 decades. Mutant cells dominated the blood system, but not other tissues. Deep sequencing revealed similar mutational burdens and signatures in normal and mutant clones, while epigenetic profiling uncovered the focal erosion of DNA methylation at oncogenic regulatory regions in mutant clones. These regions overlapped with those sensitive to DNMT3A loss after DNMT3A ablation in HSCs and in leukemia samples. These results suggest that DNMT3A maintains a conserved DNA methylation pattern, the erosion of which provides a distinct competitive advantage to hematopoietic cells. Competing Interests: Declaration of Interests The authors declare no competing interests. (Copyright © 2020 Elsevier Inc. All rights reserved.) |
| التعليقات: | Comment in: Cell Stem Cell. 2020 Aug 6;27(2):195-197. (PMID: 32763180) |
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| معلومات مُعتمدة: | R56 DK092883 United States DK NIDDK NIH HHS; P01 AG036695 United States AG NIA NIH HHS; R01 CA242218 United States CA NCI NIH HHS; P30 CA125123 United States CA NCI NIH HHS; R01 CA183252 United States CA NCI NIH HHS; R01 DK092883 United States DK NIDDK NIH HHS; United States HHMI Howard Hughes Medical Institute; S10 RR024574 United States RR NCRR NIH HHS; United Kingdom WT_ Wellcome Trust |
| فهرسة مساهمة: | Keywords: DNMT3A; HSC; cell competition; clonal hematopoiesis; hematopoietic stem cells; mutation burden; mutation signature |
| المشرفين على المادة: | 0 (DNMT3A protein, human) EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases) EC 2.1.1.37 (DNA Methyltransferase 3A) |
| تواريخ الأحداث: | Date Created: 20200717 Date Completed: 20210427 Latest Revision: 20220531 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC7494054 |
| DOI: | 10.1016/j.stem.2020.06.018 |
| PMID: | 32673568 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1875-9777 |
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| DOI: | 10.1016/j.stem.2020.06.018 |