Aberrant DNA methylation in acute myeloid leukemia
Author: Qu, Ying
Date: 2017-06-08
Location: R64, Karolinska University Hospital, Huddinge
Time: 09.00
Department: Inst för medicin, Huddinge / Dept of Medicine, Huddinge
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Thesis (560.2Kb)
Abstract
DNA methylation is an important epigenetic mechanism that influences development
and cancer by regulating gene transcription. Aberrant DNA methylation is a feature
of cancer including acute myeloid leukemia (AML). It was first established that
global DNA hypomethylation combined with hypermethylation of specific gene
promoters could often be observed as a DNA methylation signature in cancer. A
common set of tumor suppressor genes are found consistently hypermethylated and
silenced, suggesting that DNA methylation facilitates tumorigenesis. Lately, the more
dynamic DNA methylation at non-CGI regions and CpG sparse regions of the
genome has been observed, and it tightly corresponds to gene expression changes. In
AML, highly distinctive genome-wide DNA methylation profiles have been linked to
different molecular subtypes. It is now suspected that DNA methylation changes play
a crucial role in AML development particularly since the identification of frequent
somatic mutations in the DNA methylation machinery.
This thesis is focused on characterizing aberrant DNA methylation changes in the subgroup of AML patients identified as cytogenetic normal (CN-AML). We described the mutation associated DNA methylation signatures for IDH and NPM1 in a CGI-focused analysis. We also found that PcG target genes were preferentially targeted by methylation changes and methylation of this group of genes predicted the patient clinical outcomes. In the following studies, we analyzed the DNA methylation in more border regions, and we classified the variably methylated CpG sites in correlations with genetic mutations. We found a predominant impact of DNMT3A mutation on determining leukemia-specific methylation patterns and such mutations were associated with a general hypomethylation phenotype, where HOX family was primarily affected. We also observed pronounced DNA methylation changes at nonCGI regions, and these changes reflect the regulation of enhancer activity in leukemia. After integrating chromatin accessibility of DHS sequencing data and histone modification marks of H3K27ac, H3K4me1, H3K4me3 and H2A.Z with identified differentially methylated CpG sites, and our results show that DNA methylation alterations preferentially occur in regulatory regions. AML specific DNA methylation changes associated with altered enhancer activities, and these perturbations correlated with transcriptomic changes in CN-AML involving in oncogenesis and associated with patient prognosis.
Our results provide evidence of aberrant DNA methylation in AML linked to patient molecular and genetic characteristics. Studying DNA methylation changes not only contributes to better characterizing subgroups of AML patients but also reveals potentially pathogenic mechanisms for AML development.
This thesis is focused on characterizing aberrant DNA methylation changes in the subgroup of AML patients identified as cytogenetic normal (CN-AML). We described the mutation associated DNA methylation signatures for IDH and NPM1 in a CGI-focused analysis. We also found that PcG target genes were preferentially targeted by methylation changes and methylation of this group of genes predicted the patient clinical outcomes. In the following studies, we analyzed the DNA methylation in more border regions, and we classified the variably methylated CpG sites in correlations with genetic mutations. We found a predominant impact of DNMT3A mutation on determining leukemia-specific methylation patterns and such mutations were associated with a general hypomethylation phenotype, where HOX family was primarily affected. We also observed pronounced DNA methylation changes at nonCGI regions, and these changes reflect the regulation of enhancer activity in leukemia. After integrating chromatin accessibility of DHS sequencing data and histone modification marks of H3K27ac, H3K4me1, H3K4me3 and H2A.Z with identified differentially methylated CpG sites, and our results show that DNA methylation alterations preferentially occur in regulatory regions. AML specific DNA methylation changes associated with altered enhancer activities, and these perturbations correlated with transcriptomic changes in CN-AML involving in oncogenesis and associated with patient prognosis.
Our results provide evidence of aberrant DNA methylation in AML linked to patient molecular and genetic characteristics. Studying DNA methylation changes not only contributes to better characterizing subgroups of AML patients but also reveals potentially pathogenic mechanisms for AML development.
List of papers:
I. Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks. Deneberg S, Guardiola P, Lennartsson A, Qu Y, Gaidzik V, Blanchet O, Karimi M, Bengtzén S, Nahi H, Uggla B, Tidefelt U, Höglund M, Paul C, Ekwall K, Döhner K, Lehmann S. Blood, 2011 Nov 17;118(20):5573-82.
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II. Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes. Qu Y, Lennartsson A, Gaidzik V, Deneberg S, Karimi M, Bengtzén S, Höglund M, Bullinger L, Döhner K, and Lehmann S. Epigenetics, 2014; (9):8, 1108–1119.
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III. Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia. Qu Y, Siggens L, Cordeddu L, Gaidzik V, Karlsson K, Bullinger L, Döhner K, Ekwall K, Lehmann S, and Lennartsson A. Blood, 2017;129(7):e13-e25.
Fulltext (DOI)
Pubmed
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I. Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks. Deneberg S, Guardiola P, Lennartsson A, Qu Y, Gaidzik V, Blanchet O, Karimi M, Bengtzén S, Nahi H, Uggla B, Tidefelt U, Höglund M, Paul C, Ekwall K, Döhner K, Lehmann S. Blood, 2011 Nov 17;118(20):5573-82.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes. Qu Y, Lennartsson A, Gaidzik V, Deneberg S, Karimi M, Bengtzén S, Höglund M, Bullinger L, Döhner K, and Lehmann S. Epigenetics, 2014; (9):8, 1108–1119.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia. Qu Y, Siggens L, Cordeddu L, Gaidzik V, Karlsson K, Bullinger L, Döhner K, Ekwall K, Lehmann S, and Lennartsson A. Blood, 2017;129(7):e13-e25.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Lehmann, Sören
Co-supervisor: Lennartsson, Andreas
Issue date: 2017-05-18
Rights:
Publication year: 2017
ISBN: 978-91-7676-645-3
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