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Digital gene expression profiling of primary acute lymphoblastic leukemia cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
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2012 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 6, 1218-1227 p.Article in journal (Refereed) Published
Abstract [en]

We determined the genome-wide digital gene expression (DGE) profiles of primary acute lymphoblastic leukemia (ALL) cells from 21 patients taking advantage of 'second-generation' sequencing technology. Patients included in this study represent four cytogenetically distinct subtypes of B-cell precursor (BCP) ALL and T-cell lineage ALL (T-ALL). The robustness of DGE combined with supervised classification by nearest shrunken centroids (NSC) was validated experimentally and by comparison with published expression data for large sets of ALL samples. Genes that were differentially expressed between BCP ALL subtypes were enriched to distinct signaling pathways with dic(9;20) enriched to TP53 signaling, t(9;22) to interferon signaling, as well as high hyperdiploidy and t(12;21) to apoptosis signaling. We also observed antisense tags expressed from the non-coding strand of ∼50% of annotated genes, many of which were expressed in a subtype-specific pattern. Antisense tags from 17 gene regions unambiguously discriminated between the BCP ALL and T-ALL subtypes, and antisense tags from 76 gene regions discriminated between the 4 BCP subtypes. We observed a significant overlap of gene regions with alternative polyadenylation and antisense transcription (P<1 × 10(-15)). Our study using DGE profiling provided new insights into the RNA expression patterns in ALL cells.

Place, publisher, year, edition, pages
2012. Vol. 26, no 6, 1218-1227 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-168670DOI: 10.1038/leu.2011.358ISI: 000305081000009PubMedID: 22173241OAI: oai:DiVA.org:uu-168670DiVA: diva2:502108
Available from: 2012-02-14 Created: 2012-02-14 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Gene Expression and DNA Methylation in Acute Lymphoblastic Leukemia
Open this publication in new window or tab >>Gene Expression and DNA Methylation in Acute Lymphoblastic Leukemia
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pediatric acute lymphoblastic leukemia (ALL) is the most common malignancy in children, which results from the malignant transformation of progenitor cells in the bone marrow into leukemic cells. The precise mechanisms for this transformation are not well defined, however recent studies suggest that aberrant regulation of gene expression or DNA methylation may play an important role. Hence, the aim of this thesis was to use novel methods to investigate genome-wide gene expression and DNA methylation patterns in a large collection of primary ALL cells from pediatric patients. With these studies, we aimed to increase the understanding of factors that regulate gene expression and DNA methylation in ALL.

In the first study of the thesis we found that data obtained from genome-wide digital gene expression analysis enabled excellent cytogenetic subtype-specific classification of ALL cells and revealed new features of gene expression within the disease, such as prevalent antisense transcription and alternative polyadenylation. In the second study we used technology developed for large-scale single nucleotide polymorphism (SNP) genotyping for quantitative analysis of allele-specific gene expression (ASE), revealing widespread ASE in ALL cells. Analysis of DNA methylation in promoter regions of the genes displaying ASE using DNA-microarrays revealed frequent regulation of gene expression by DNA methylation. In the third study, using the same DNA methylation array, we identified differences in the DNA methylation patterns in ALL cells at diagnosis compared to healthy mononuclear cells from the bone marrow of the same children at remission. In the fourth study we measured the DNA methylation of >450,000 CpG sites across the genome in a large collection of ALL samples and non-leukemic control cells. We found that ALL cells displayed highly divergent DNA methylation patterns depending on their cytogenetic subtype and widespread regions of differential methylation were enriched for repressive histone marks. DNA methylation levels at distinct regions in the genome were substantially increased at relapse compared to matched cells from diagnosis.

Collectively, the results presented in this thesis provide new insights into the patterns of gene expression and epigenetic changes in ALL and further increase our understanding of the development and progression of the disease, which will hopefully lead to better treatment options in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 799
Keyword
Digital gene expression, Allele-specific gene expression, DNA methylation, Epigenetics, Acute lymphoblastic leukemia
National Category
Pediatrics Hematology Cancer and Oncology
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-179680 (URN)978-91-554-8442-2 (ISBN)
Public defence
2012-10-05, Rudbecksalen, Rudbeck Laboratoriet, Uppsala, 13:00 (English)
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Available from: 2012-09-13 Created: 2012-08-21 Last updated: 2013-01-22Bibliographically approved

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Nordlund, JessicaKarlberg, OlofBerglund, Eva CGöransson-Kultima, HannaGustafsson, Mats GLönnerholm, GudmarSyvänen, Ann-Christine

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