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The DNA methylome of pediatric acute lymphoblastic leukemia.

Davidsson, Josef LU ; Lilljebjörn, Henrik LU ; Andersson, Anna LU ; Veerla, Srinivas LU ; Heldrup, Jesper LU ; Behrendtz, Mikael; Fioretos, Thoas LU and Johansson, Bertil LU (2009) In Human Molecular Genetics Aug 13. p.4054-4065
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.... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
Aug 13
pages
4054 - 4065
publisher
Oxford University Press
external identifiers
  • wos:000270708300005
  • pmid:19679565
  • scopus:70349988272
ISSN
0964-6906
DOI
10.1093/hmg/ddp354
language
English
LU publication?
yes
id
16fffbc0-d1e8-4ea0-af87-b334ffff22b8 (old id 1469764)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19679565?dopt=Abstract
date added to LUP
2009-09-07 15:29:14
date last changed
2017-09-03 04:49:59
@article{16fffbc0-d1e8-4ea0-af87-b334ffff22b8,
  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.},
  author       = {Davidsson, Josef and Lilljebjörn, Henrik and Andersson, Anna and Veerla, Srinivas and Heldrup, Jesper and Behrendtz, Mikael and Fioretos, Thoas and Johansson, Bertil},
  issn         = {0964-6906},
  language     = {eng},
  pages        = {4054--4065},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {The DNA methylome of pediatric acute lymphoblastic leukemia.},
  url          = {http://dx.doi.org/10.1093/hmg/ddp354},
  volume       = {Aug 13},
  year         = {2009},
}