Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication
Abstract The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. Motivated by a recent discovery of the significance of DNMT3A-destabilizing mutations (DNMT3A INS) in A...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55691-z |
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| author | Dohoon Lee Bonil Koo Seokhyeon Kim Jamin Byun Junshik Hong Dong-Yeop Shin Choong-Hyun Sun Jaesung Kim Ji-Joon Song Siddhartha Jaiswal Sung-Soo Yoon Sun Kim Youngil Koh |
| author_facet | Dohoon Lee Bonil Koo Seokhyeon Kim Jamin Byun Junshik Hong Dong-Yeop Shin Choong-Hyun Sun Jaesung Kim Ji-Joon Song Siddhartha Jaiswal Sung-Soo Yoon Sun Kim Youngil Koh |
| author_sort | Dohoon Lee |
| collection | DOAJ |
| description | Abstract The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. Motivated by a recent discovery of the significance of DNMT3A-destabilizing mutations (DNMT3A INS) in AML, we here investigate the common characteristics of DNMT3A INS AML methylomes through computational analyses. We present that methylomes of DNMT3A INS AMLs are considerably different from those of DNMT3A R882 AMLs in that they exhibit increased intratumor DNA methylation heterogeneity in bivalent chromatin domains. This epigenetic heterogeneity was associated with the transcriptional variability of developmental and membrane-associated factors shaping stem cell niche, and also was a predictor of the response of AML cells to hypomethylating agents, implying that the survival of AML cells depends on stochastic DNA methylations at bivalent domains. Altogether, our work provides a novel mechanistic model suggesting the genomic origin of the aberrant epigenomic heterogeneity in disease conditions. |
| format | Article |
| id | doaj-art-b4134ccbd5174e88b7f26796ec46553e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b4134ccbd5174e88b7f26796ec46553e2025-01-12T12:30:22ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-024-55691-zIncreased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implicationDohoon Lee0Bonil Koo1Seokhyeon Kim2Jamin Byun3Junshik Hong4Dong-Yeop Shin5Choong-Hyun Sun6Jaesung Kim7Ji-Joon Song8Siddhartha Jaiswal9Sung-Soo Yoon10Sun Kim11Youngil Koh12Bioinformatics Institute, Seoul National UniversityInterdisciplinary Program in Bioinformatics, Seoul National UniversityCancer Research Institute, Seoul National UniversityCancer Research Institute, Seoul National UniversityCancer Research Institute, Seoul National UniversityCancer Research Institute, Seoul National UniversityGenome Opinion IncDepartment of Biological Sciences, KI for BioCentury, Korea Advanced Institute of Science and Technology (KAIST)Department of Biological Sciences, KI for BioCentury, Korea Advanced Institute of Science and Technology (KAIST)Department of Pathology, Stanford UniversityCancer Research Institute, Seoul National UniversityInterdisciplinary Program in Bioinformatics, Seoul National UniversityCancer Research Institute, Seoul National UniversityAbstract The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. Motivated by a recent discovery of the significance of DNMT3A-destabilizing mutations (DNMT3A INS) in AML, we here investigate the common characteristics of DNMT3A INS AML methylomes through computational analyses. We present that methylomes of DNMT3A INS AMLs are considerably different from those of DNMT3A R882 AMLs in that they exhibit increased intratumor DNA methylation heterogeneity in bivalent chromatin domains. This epigenetic heterogeneity was associated with the transcriptional variability of developmental and membrane-associated factors shaping stem cell niche, and also was a predictor of the response of AML cells to hypomethylating agents, implying that the survival of AML cells depends on stochastic DNA methylations at bivalent domains. Altogether, our work provides a novel mechanistic model suggesting the genomic origin of the aberrant epigenomic heterogeneity in disease conditions.https://doi.org/10.1038/s41467-024-55691-z |
| spellingShingle | Dohoon Lee Bonil Koo Seokhyeon Kim Jamin Byun Junshik Hong Dong-Yeop Shin Choong-Hyun Sun Jaesung Kim Ji-Joon Song Siddhartha Jaiswal Sung-Soo Yoon Sun Kim Youngil Koh Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication Nature Communications |
| title | Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication |
| title_full | Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication |
| title_fullStr | Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication |
| title_full_unstemmed | Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication |
| title_short | Increased local DNA methylation disorder in AMLs with DNMT3A-destabilizing variants and its clinical implication |
| title_sort | increased local dna methylation disorder in amls with dnmt3a destabilizing variants and its clinical implication |
| url | https://doi.org/10.1038/s41467-024-55691-z |
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