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Characteristics of DNMT3A mutations in acute myeloid leukemia
BACKGROUND: DNMT3A mutations occur in approximately 20% of AML cases and are associated with changes in DNA methylation. CDKN2B plays an important role in the regulation of hematopoietic progenitor cells and DNMT3A mutation is associated with CDKN2B promoter methylation. We analyzed the characterist...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106122/ https://www.ncbi.nlm.nih.gov/pubmed/32269971 http://dx.doi.org/10.5045/br.2020.55.1.17 |
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author | Park, Dong Jin Kwon, Ahlm Cho, Byung-Sik Kim, Hee-Je Hwang, Kyung-Ah Kim, Myungshin Kim, Yonggoo |
author_facet | Park, Dong Jin Kwon, Ahlm Cho, Byung-Sik Kim, Hee-Je Hwang, Kyung-Ah Kim, Myungshin Kim, Yonggoo |
author_sort | Park, Dong Jin |
collection | PubMed |
description | BACKGROUND: DNMT3A mutations occur in approximately 20% of AML cases and are associated with changes in DNA methylation. CDKN2B plays an important role in the regulation of hematopoietic progenitor cells and DNMT3A mutation is associated with CDKN2B promoter methylation. We analyzed the characteristics of DNMT3A mutations including their clinical significance in AML and their influence on promoter methylation and CDKN2B expression. METHODS: A total of 142 adults, recently diagnosed with de novo AML, were enrolled in the study. Mutations in DNMT3A, CEBPA, and NPM1 were analyzed by bidirectional Sanger sequencing. We evaluated CDKN2B promoter methylation and expression using pyrosequencing and RT-qPCR. RESULTS: We identified DNMT3A mutations in 19.7% (N=28) of enrolled patients with AML, which increased to 29.5% when analysis was restricted to cytogenetically normal-AML. Mutations were located on exons from 8–23, and the majority, including R882, were found to be present on exon 23. We also identified a novel frameshift mutation, c.1590delC, in AML with biallelic mutation of CEBPA. There was no significant difference in CDKN2B promoter methylation according to the presence or type of DNMT3A mutations. CDKN2B expression inversely correlated with CDKN2B promoter methylation and was significantly higher in AML with R882H mutation in DNMT3A. We demonstrated that DNMT3A mutation was associated with poor AML outcomes, especially in cytogenetically normal-AML. The DNMT3A mutation remained as the independent unfavorable prognostic factor after multivariate analysis. CONCLUSION: We characterized DNMT3A mutations in AML and revealed the association between the DNMT3A mutation and CDKN2B expression and clinical outcome. |
format | Online Article Text |
id | pubmed-7106122 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis |
record_format | MEDLINE/PubMed |
spelling | pubmed-71061222020-04-08 Characteristics of DNMT3A mutations in acute myeloid leukemia Park, Dong Jin Kwon, Ahlm Cho, Byung-Sik Kim, Hee-Je Hwang, Kyung-Ah Kim, Myungshin Kim, Yonggoo Blood Res Original Article BACKGROUND: DNMT3A mutations occur in approximately 20% of AML cases and are associated with changes in DNA methylation. CDKN2B plays an important role in the regulation of hematopoietic progenitor cells and DNMT3A mutation is associated with CDKN2B promoter methylation. We analyzed the characteristics of DNMT3A mutations including their clinical significance in AML and their influence on promoter methylation and CDKN2B expression. METHODS: A total of 142 adults, recently diagnosed with de novo AML, were enrolled in the study. Mutations in DNMT3A, CEBPA, and NPM1 were analyzed by bidirectional Sanger sequencing. We evaluated CDKN2B promoter methylation and expression using pyrosequencing and RT-qPCR. RESULTS: We identified DNMT3A mutations in 19.7% (N=28) of enrolled patients with AML, which increased to 29.5% when analysis was restricted to cytogenetically normal-AML. Mutations were located on exons from 8–23, and the majority, including R882, were found to be present on exon 23. We also identified a novel frameshift mutation, c.1590delC, in AML with biallelic mutation of CEBPA. There was no significant difference in CDKN2B promoter methylation according to the presence or type of DNMT3A mutations. CDKN2B expression inversely correlated with CDKN2B promoter methylation and was significantly higher in AML with R882H mutation in DNMT3A. We demonstrated that DNMT3A mutation was associated with poor AML outcomes, especially in cytogenetically normal-AML. The DNMT3A mutation remained as the independent unfavorable prognostic factor after multivariate analysis. CONCLUSION: We characterized DNMT3A mutations in AML and revealed the association between the DNMT3A mutation and CDKN2B expression and clinical outcome. Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis 2020-03 2020-03-30 /pmc/articles/PMC7106122/ /pubmed/32269971 http://dx.doi.org/10.5045/br.2020.55.1.17 Text en © 2020 Korean Society of Hematology http://creativecommons.org/licenses/by-nc/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Park, Dong Jin Kwon, Ahlm Cho, Byung-Sik Kim, Hee-Je Hwang, Kyung-Ah Kim, Myungshin Kim, Yonggoo Characteristics of DNMT3A mutations in acute myeloid leukemia |
title | Characteristics of DNMT3A mutations in acute myeloid leukemia |
title_full | Characteristics of DNMT3A mutations in acute myeloid leukemia |
title_fullStr | Characteristics of DNMT3A mutations in acute myeloid leukemia |
title_full_unstemmed | Characteristics of DNMT3A mutations in acute myeloid leukemia |
title_short | Characteristics of DNMT3A mutations in acute myeloid leukemia |
title_sort | characteristics of dnmt3a mutations in acute myeloid leukemia |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106122/ https://www.ncbi.nlm.nih.gov/pubmed/32269971 http://dx.doi.org/10.5045/br.2020.55.1.17 |
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