Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia

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

I: Journal of Clinical Investigation, Vol. 123, Nr. 7, 07.2013, s. 3099-111.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Figueroa, ME, Chen, S-C, 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, nr. 7, s. 3099-111. https://doi.org/10.1172/JCI66203

APA

Figueroa, M. E., 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), 3099-111. https://doi.org/10.1172/JCI66203

CBE

Figueroa ME, Chen S-C, 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. 123(7):3099-111. https://doi.org/10.1172/JCI66203

MLA

Vancouver

Author

Figueroa, Maria E ; 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. I: Journal of Clinical Investigation. 2013 ; Vol. 123, Nr. 7. s. 3099-111.

RIS

TY - JOUR

T1 - Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia

AU - Figueroa, Maria E

AU - Chen, Shann-Ching

AU - Andersson, Anna K

AU - Phillips, Letha A

AU - Li, Yushan

AU - Sotzen, Jason

AU - Kundu, Mondira

AU - Downing, James R

AU - Melnick, Ari

AU - Mullighan, Charles G

PY - 2013/7

Y1 - 2013/7

N2 - 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.

AB - 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.

KW - Cell Transformation, Neoplastic

KW - Child

KW - Cluster Analysis

KW - DNA Copy Number Variations

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Gene Expression Regulation, Leukemic

KW - Genes, Neoplasm

KW - Humans

KW - Oligonucleotide Array Sequence Analysis

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma

KW - Signal Transduction

KW - Transcriptome

U2 - 10.1172/JCI66203

DO - 10.1172/JCI66203

M3 - Article

VL - 123

SP - 3099

EP - 3111

JO - Journal of Clinical Investigation

T2 - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 7

ER -