دورية أكاديمية
Focal disruption of DNA methylation dynamics at enhancers in IDH-mutant AML cells.
| العنوان: | Focal disruption of DNA methylation dynamics at enhancers in IDH-mutant AML cells. |
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| المؤلفون: | Wilson ER; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA., Helton NM; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA., Heath SE; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA., Fulton RS; McDonnell Genome Institute, Washington University, St. Louis, MO, USA., Payton JE; Department of Pathology and Immunology, Washington University, St. Louis, MO, USA., Welch JS; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA., Walter MJ; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA., Westervelt P; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA., DiPersio JF; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA., Link DC; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA., Miller CA; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA.; McDonnell Genome Institute, Washington University, St. Louis, MO, USA., Ley TJ; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA., Spencer DH; Department of Medicine, Division of Oncology, Section of Stem Cell Biology, Washington University, St. Louis, MO, USA. dspencer@wustl.edu.; Department of Pathology and Immunology, Washington University, St. Louis, MO, USA. dspencer@wustl.edu.; McDonnell Genome Institute, Washington University, St. Louis, MO, USA. dspencer@wustl.edu. |
| المصدر: | Leukemia [Leukemia] 2022 Apr; Vol. 36 (4), pp. 935-945. Date of Electronic Publication: 2021 Dec 06. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2000- : London : Nature Publishing Group, Specialist Journals Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987- |
| مواضيع طبية MeSH: | DNA Methylation* , Leukemia, Myeloid, Acute*/genetics , Leukemia, Myeloid, Acute*/pathology, Humans ; Isocitrate Dehydrogenase/genetics ; Mutation ; Regulatory Sequences, Nucleic Acid |
| مستخلص: | Recurrent mutations in IDH1 or IDH2 in acute myeloid leukemia (AML) are associated with increased DNA methylation, but the genome-wide patterns of this hypermethylation phenotype have not been comprehensively studied in AML samples. We analyzed whole-genome bisulfite sequencing data from 15 primary AML samples with IDH1 or IDH2 mutations, which identified ~4000 focal regions that were uniquely hypermethylated in IDH mut samples vs. normal CD34+ cells and other AMLs. These regions had modest hypermethylation in AMLs with biallelic TET2 mutations, and levels of 5-hydroxymethylation that were diminished in IDH and TET-mutant samples, indicating that this hypermethylation results from inhibition of TET-mediated demethylation. Focal hypermethylation in IDH mut AMLs occurred at regions with low methylation in CD34+ cells, implying that DNA methylation and demethylation are active at these loci. AML samples containing IDH and DNMT3A R882 mutations were significantly less hypermethylated, suggesting that IDH mut -associated hypermethylation is mediated by DNMT3A. IDH mut -specific hypermethylation was highly enriched for enhancers that form direct interactions with genes involved in normal hematopoiesis and AML, including MYC and ETV6. These results suggest that focal hypermethylation in IDH-mutant AML occurs by altering the balance between DNA methylation and demethylation, and that disruption of these pathways at enhancers may contribute to AML pathogenesis. (© 2021. The Author(s).) |
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| معلومات مُعتمدة: | R50 CA211782 United States CA NCI NIH HHS; P50 CA171963 United States CA NCI NIH HHS; P01 CA101937 United States CA NCI NIH HHS; R35 CA197561 United States CA NCI NIH HHS; K08 CA190815 United States CA NCI NIH HHS |
| المشرفين على المادة: | EC 1.1.1.41 (Isocitrate Dehydrogenase) |
| تواريخ الأحداث: | Date Created: 20211207 Date Completed: 20220406 Latest Revision: 20230223 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8979817 |
| DOI: | 10.1038/s41375-021-01476-y |
| PMID: | 34873300 |
| قاعدة البيانات: | MEDLINE |
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