ANGPT2 promoter methylation is strongly associated with gene expression and prognosis in chronic lymphocytic leukemia
2013 (English)In: Epigenetics, ISSN 1559-2294, Vol. 8, no 7, 720-729 p.Article in journal (Refereed) Published
Increasing evidence suggests a key role for angiopoietin-2 (ANGPT2) in influencing the aggressiveness of chronic lymphocytic leukemia (CLL). In the presence of vascular endothelial growth factor (VEGF), ANGPT2 causes vessel destabilization leading to neoangiogenesis. Accordingly, high expression levels of ANGPT2 and high degree of angiogenesis have consistently been associated with poor prognosis in CLL; however, the molecular mechanisms behind the variability in ANGPT2 expression are still to be discovered. Here, for the first time, we investigated the DNA methylation status of the ANGPT2 promoter in a large CLL cohort (n = 88) using pyrosequencing and correlated methylation data with ANGPT2 expression levels, prognostic factors and outcome. Importantly, methylation levels of the ANGPT2 gene correlated inversely with its mRNA expression levels (p < 0.001). Moreover, low ANGPT2 methylation status was highly associated with adverse prognostic markers, shorter time to first treatment and overall survival. Finally, treatment with methyl inhibitors induced re-expression of ANGPT2 in two B-cell lymphoma cell lines, underscoring the importance of DNA methylation in regulating transcriptional silencing of this gene. In conclusion, we believe that the known variability in ANGPT2 expression among CLL patients could be explained by differential promoter DNA methylation and that low methylation levels of the ANGPT2 promoter have an adverse prognostic impact in CLL.
Place, publisher, year, edition, pages
2013. Vol. 8, no 7, 720-729 p.
chronic lymphocytic leukemia, prognosis, ANGPT2, gene methylation, pyrosequencing
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-209879DOI: 10.4161/epi.24947ISI: 000324741500007OAI: oai:DiVA.org:uu-209879DiVA: diva2:659851
De två (2) första författarna delar förstaförfattarskapet.
De två (2) sista författarna delar sistaförfattarskapet.2013-10-282013-10-282013-10-28Bibliographically approved