The DNA methylome of pediatric acute lymphoblastic leukemia.
Hum Mol Genet
; 18(21): 4054-65, 2009 Nov 01.
Article
em En
| MEDLINE
| ID: mdl-19679565
ABSTRACT
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with high hyperdiploidy [51-67 chromosomes] and the t(12;21)(p13;q22) [ETV6/RUNX1 fusion] representing the most frequent abnormalities. Although these arise in utero, there is long latency before overt ALL, showing that additional changes are needed. Gene dysregulation through hypermethylation may be such an event; however, this has not previously been investigated in a detailed fashion. We performed genome-wide methylation profiling using bacterial artificial chromosome arrays and promoter-specific analyses of high hyperdiploid and ETV6/RUNX1-positive ALLs. In addition, global gene expression analyses were performed to identify associated expression patterns. Unsupervised cluster and principal component analyses of the chromosome-wide methylome profiles could successfully subgroup the two genetic ALL types. Analysis of all currently known promoter-specific CpG islands demonstrated that several B-cell- and neoplasia-associated genes were hypermethylated and underexpressed, indicating that aberrant methylation plays a significant leukemogenic role. Interestingly, methylation hotspots were associated with chromosome bands predicted to harbor imprinted genes and the tri-/tetrasomic chromosomes in the high hyperdiploid ALLs were less methylated than their disomic counterparts. Decreased methylation of gained chromosomes is a previously unknown phenomenon that may have ramifications not only for the pathogenesis of high hyperdiploid ALL but also for other disorders with acquired or constitutional numerical chromosome anomalies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ilhas de CpG
/
Metilação de DNA
/
Leucemia-Linfoma Linfoblástico de Células Precursoras
Tipo de estudo:
Prognostic_studies
Limite:
Child
/
Humans
Idioma:
En
Revista:
Hum Mol Genet
Assunto da revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Suécia