Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia

Research output: Contribution to journalArticle

Abstract

Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy and is characterized by recurring structural genetic alterations. Previous studies of DNA methylation suggest epigenetic alterations may also be important, but an integrated genome-wide analysis of genetic and epigenetic alterations in ALL has not been performed. We analyzed 137 B-lineage and 30 T-lineage childhood ALL cases using microarray analysis of DNA copy number alterations and gene expression, and genome-wide cytosine methylation profiling using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. We found that the different genetic subtypes of ALL are characterized by distinct DNA methylation signatures that exhibit significant correlation with gene expression profiles. We also identified an epigenetic signature common to all cases, with correlation to gene expression in 65% of these genes, suggesting that a core set of epigenetically deregulated genes is central to the initiation or maintenance of lymphoid transformation. Finally, we identified aberrant methylation in multiple genes also targeted by recurring DNA copy number alterations in ALL, suggesting that these genes are inactivated far more frequently than suggested by structural genomic analyses alone. Together, these results demonstrate subtype- and disease-specific alterations in cytosine methylation in ALL that influence transcriptional activity, and are likely to exert a key role in leukemogenesis.

Details

Authors
  • Maria E Figueroa
  • Shann-Ching Chen
  • Anna K Andersson
  • Letha A Phillips
  • Yushan Li
  • Jason Sotzen
  • Mondira Kundu
  • James R Downing
  • Ari Melnick
  • Charles G Mullighan
External organisations
  • St Jude Children´s Research Hospital, Memphis
  • Cornell University
  • University of Michigan
Research areas and keywords

Keywords

  • Cell Transformation, Neoplastic, Child, Cluster Analysis, DNA Copy Number Variations, DNA Methylation, Epigenesis, Genetic, Gene Expression Regulation, Leukemic, Genes, Neoplasm, Humans, Oligonucleotide Array Sequence Analysis, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Signal Transduction, Transcriptome
Original languageEnglish
Pages (from-to)3099-111
Number of pages13
JournalJournal of Clinical Investigation
Volume123
Issue number7
Publication statusPublished - 2013 Jul
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes