MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.
Cancer Cell
; 20(1): 66-78, 2011 Jul 12.
Article
em En
| MEDLINE
| ID: mdl-21741597
ABSTRACT
The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Histonas
/
Rearranjo Gênico
/
Proteína de Leucina Linfoide-Mieloide
/
Lisina
/
Metiltransferases
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article