Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia

Maria Figueroa, Shann Ching Chen, Anna K. Andersson, Letha A. Phillips, Yushan Li, Jason Sotzen, Mondira Kundu, James R. Downing, Ari Melnick, Charles G. Mullighan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3099-3111
Number of pages13
JournalJournal of Clinical Investigation
Volume123
Issue number7
DOIs
StatePublished - Jul 1 2013
Externally publishedYes

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Epigenomics
Methylation
Cytosine
DNA Methylation
Genes
Genome
Gene Expression
DNA
Microarray Analysis
Transcriptome
Ligation
Maintenance
Polymerase Chain Reaction
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Figueroa, M., Chen, S. C., Andersson, A. K., Phillips, L. A., Li, Y., Sotzen, J., ... Mullighan, C. G. (2013). Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia. Journal of Clinical Investigation, 123(7), 3099-3111. https://doi.org/10.1172/JCI66203

Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia. / Figueroa, Maria; Chen, Shann Ching; Andersson, Anna K.; Phillips, Letha A.; Li, Yushan; Sotzen, Jason; Kundu, Mondira; Downing, James R.; Melnick, Ari; Mullighan, Charles G.

In: Journal of Clinical Investigation, Vol. 123, No. 7, 01.07.2013, p. 3099-3111.

Research output: Contribution to journalArticle

Figueroa, M, Chen, SC, Andersson, AK, Phillips, LA, Li, Y, Sotzen, J, Kundu, M, Downing, JR, Melnick, A & Mullighan, CG 2013, 'Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia', Journal of Clinical Investigation, vol. 123, no. 7, pp. 3099-3111. https://doi.org/10.1172/JCI66203
Figueroa, Maria ; Chen, Shann Ching ; Andersson, Anna K. ; Phillips, Letha A. ; Li, Yushan ; Sotzen, Jason ; Kundu, Mondira ; Downing, James R. ; Melnick, Ari ; Mullighan, Charles G. / Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 7. pp. 3099-3111.
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