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Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia

Figueroa, Maria E; Chen, Shann-Ching; Andersson, Anna K LU ; Phillips, Letha A; Li, Yushan; Sotzen, Jason; Kundu, Mondira; Downing, James R; Melnick, Ari and Mullighan, Charles G (2013) In Journal of Clinical Investigation 123(7). p.111-3099
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... (More)

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.

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author
publishing date
type
Contribution to journal
publication status
published
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
in
Journal of Clinical Investigation
volume
123
issue
7
pages
13 pages
publisher
American Society for Clinical Investigation
external identifiers
  • Scopus:84879634027
ISSN
0021-9738
DOI
10.1172/JCI66203
language
English
LU publication?
no
id
c3824203-6138-46a6-9e84-b84787ba9469
date added to LUP
2016-04-11 15:48:49
date last changed
2016-12-04 04:50:21
@misc{c3824203-6138-46a6-9e84-b84787ba9469,
  abstract     = {<p>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.</p>},
  author       = {Figueroa, Maria E and Chen, Shann-Ching and Andersson, Anna K and Phillips, Letha A and Li, Yushan and Sotzen, Jason and Kundu, Mondira and Downing, James R and Melnick, Ari and Mullighan, Charles G},
  issn         = {0021-9738},
  keyword      = {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},
  language     = {eng},
  number       = {7},
  pages        = {111--3099},
  publisher    = {ARRAY(0x8e63570)},
  series       = {Journal of Clinical Investigation},
  title        = {Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia},
  url          = {http://dx.doi.org/10.1172/JCI66203},
  volume       = {123},
  year         = {2013},
}