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Epigenetic regulation of non-coding RNAs in haematological malignancies

Traditionally, cancer has been regarded as a genetic disease. Emerging evidence indicates that epigenetic alterations are also associated with neoplastic transformation.
Epigenetic regulation of non-coding RNAs in haematological malignancies
Epigenetic mechanisms refer to heritable changes in gene expression that occur in a cell without producing changes in the genomic sequence. Recent years have witnessed researchers focussing more on the role of epigenetics in various diseases including cancer.

The EU-funded LINCMHEM (Role of DNA methylation in the regulation of lincRNAs in haematological malignancies) project investigated how epigenetic mechanisms affect the expression, and hence, the biological function of non-coding RNAs (ncRNAs), especially long ncRNAs (lncRNAs). Thus far, the knowledge on the mechanisms leading to deregulated lncRNA expression in haematological malignancies remains limited.

Experimental work focused on B cell haematological malignancies including multiple myeloma, lymphoma and acute leukaemia. Researchers studied expression alteration in all types of lncRNAs and re-annotated lncRNA expression in different normal B cell subsets. More than 15 000 lncRNAs were found to be expressed in normal B cells and their expression correlated with that of protein coding genes directly related to cell type identity and differentiation state. This unequivocally proved the functional role of some of these lncRNAs.

With respect to multiple myeloma, scientists observed a highly heterogeneous DNA methylation pattern, with regions of DNA hypermethylation embedded in an overall hypomethylated genome. Hypomethylated DNA lay within intergenic regions associated with lncRNA genes. Experiments showed that inhibition of expression of specific lncRNAs decreased the proliferation and increased the apoptosis of multiple myeloma cells, indicating the role of lncRNAs in disease pathogenesis. It also showed that some of these molecules could serve as therapeutic targets for the treatment of multiple myeloma.

Further lncRNA analysis in samples of patients with acute leukaemia indicated that the altered expression of histone methyltransferase (MT) and DNA MTs (DNMTs) could be responsible for the observed changes in coding gene and lncRNA expression. A dual inhibitor of histone MT and DNMT activity demonstrated therapeutic potency in animal models of haematological malignancies.

Taken together, the findings of the LINCMHEM project underscored the functional involvement of lncRNAs in haematological malignancies and the potential of modulating their expression to find cures.

Related information

Subjects

Life Sciences

Keywords

Epigenetic, haematological malignancies, LINCMHEM, lncRNA, methyltransferase
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