Hypermethylation of the VTRNA1-3 Promoter is Associated with Poor Outcome in Lower Risk Myelodysplastic Syndrome Patients

Abstract

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders. MDS is frequently associated with deletions on chromosome 5q as well as aberrant DNA methylation patterns including hypermethylation of key tumor suppressors. We have previously shown that hypermethylation and silencing of the non-coding RNA VTRNA2-1 are correlated with poor outcomes in acute myeloid leukemia patients. In this study, we find that VTRNA1-2 and VTRNA1-3, both located on chromosome 5q, can be regulated and silenced by promoter DNA methylation, and that the hypomethylating agent 5-aza-2-deoxycytidine causes reactivation these genes. In normal hematopoiesis, we find that vault RNAs (vtRNAs) show differential methylation between various hematopoietic cell populations, indicating that allele-specific methylation events may occur during hematopoiesis. In addition, we show that VTRNA1-3 promoter hypermethylation is frequent in lower risk MDS patients and is associated with a decreased overall survival.

Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in myelodysplastic syndromes

“…Patients show aberrant methylation of cytosine residues in CpG sequences [ 2 , 3 ] and a DNA hypermethylation profile, particularly in promoter regions of tumor suppressor genes [ 4 , 5 ]. These genetic alterations can impact patients’ survival [ 6 – 10 ], yet whether they can also influence their response to azacitidine/decitabine treatment has not been clearly elucidated.…”

Response to treatment with azacitidine in children with advanced myelodysplastic syndrome prior to hematopoietic stem cell transplantation

“…Hypermethylation leads to the silencing of regulatory genes and aberrant cell behavior. Furthermore, hypermethylation of the promoters of various genes, such as p15, 15,16 DLX4, 17 p73, 18 and VTRNA1- 3,19 has been associated with unfavorable prognosis in MDS.…”

‘High vault-age’: non-coding RNA control of autophagy

“…Promoter methylation was shown to inversely correlate with the expression levels of vtRNA1-2, vtRNA1-3 and vtRNA2-1 [41,42]. Interestingly, DNA hypermethylation, especially of the VTRNA2-1 gene, further correlated with poor prognosis of some cancers, suggesting a potential role of this non-coding RNA as a tumour suppressor [41][42][43][44][45][46]. By contrast, the VTRNA1-1 locus does not seem to be subject to methylation in a similar fashion [41].…”