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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

The DNA methylome of pediatric acute lymphoblastic leukemia.

Author

  • Josef Davidsson
  • Henrik Lilljebjörn
  • Anna Andersson
  • Srinivas Veerla
  • Jesper Heldrup
  • Mikael Behrendtz
  • Thoas Fioretos
  • Bertil Johansson

Summary, in English

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.

Department/s

  • Division of Clinical Genetics
  • Paediatrics (Lund)

Publishing year

2009

Language

English

Pages

4054-4065

Publication/Series

Human Molecular Genetics

Volume

Aug 13

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Medical Genetics

Status

Published

ISBN/ISSN/Other

  • ISSN: 0964-6906