CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression.
Cell
; 168(5): 801-816.e13, 2017 02 23.
Article
en En
| MEDLINE
| ID: mdl-28215704
ABSTRACT
DNMT3A mutations occur in â¼25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3AR882H, has dominant negative activity that reduces DNA methylation activity by â¼80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3AR882 mutations. Non-leukemic hematopoietic cells with DNMT3AR882H displayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing and was essentially absent in AMLs with DNMT3AR882 mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3AR882, while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide Aguda
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Islas de CpG
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Metilación de ADN
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ADN (Citosina-5-)-Metiltransferasas
Límite:
Humans
Idioma:
En
Revista:
Cell
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos