Journal
EPIGENOMICS
Volume 2, Issue 1, Pages 53-70Publisher
FUTURE MEDICINE LTD
DOI: 10.2217/EPI.09.43
Keywords
chronic lymphocytic leukemia; DNA methylation; epigenetics; histone modification; microRNAs; WNT pathway
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Funding
- NLM NIH HHS [T15 LM007089-18S1, T15 LM007089, T15 LM007089-18] Funding Source: Medline
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Certain WNT and WNT network target genes are expressed at higher or lower levels in chronic lymphocytic leukemia compared with normal B-cells. This includes upregulation of nuclear complex genes, as well as genes for cytoplasmic proteins and WNT ligands and their cognate receptors. In addition, epigenetic silencing of several negative regulators of the WNT pathway have been identified. The balance between epigenetic downregulation of negative effector genes and increased expression of positive effector genes demonstrate that the epigenetic down regulation of WNT antagonists is one mechanism, perhaps the main mechanism, that is permissive to active WNT signaling in chronic lymphocytic leukemia. Moreover, constitutive activation of the WNT network and target genes is likely to impact on additional interacting signaling pathways. Based on published studies, we propose a model of WNT signaling that involves mainly permissive expression, and sometimes overexpression, of positive effectors and downregulation of negative regulators in the network. In this model, DNA methylation, histone modifications and altered expression of microRNA molecules interact to allow continuous WNT signaling.
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