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.
Highlights
Low risk myelodysplastic syndrome (MDS) is a heterogeneous group of clonal diseases characterized by ineffective hematopoiesis due to increased apoptosis and differentiation block of early progenitors, resulting in cytopenia in the myeloid lineages [1]
HL60 cells were treated for 24 h with 5-aza-CdR and harvested on day 2 (D2) or day 8 (D8) after treatment. (A) Expression of VTRNA1-1 in HL60 and normal CD34+ hematopoietic stem cell (HSC); (B) Expression of VTRNA1-2 in HL60 and normal CD34+ HSCs; (C) Expression of
As the region on 5q is of particular interest in Myelodysplastic syndrome (MDS), we examined the role of VTRNA1-3 promoter methylation in Bone marrow mononuclear cells (BM-MNCs) from the time of diagnosis to survival outcome in a pilot cohort of MDS
Summary
Low risk myelodysplastic syndrome (MDS) is a heterogeneous group of clonal diseases characterized by ineffective hematopoiesis due to increased apoptosis and differentiation block of early progenitors, resulting in cytopenia in the myeloid lineages [1]. It has recently been proven that lower risk MDS is derived from the hematopoietic stem cell (HSC) compartment and that the disease is propagated in successive progenitor cells [2,3]. The IPSS allows differentiation of lower risk (low and intermediate-1 (INT-1) IPSS scores) from higher risk (intermediate-2 (INT-2) and high risk IPSS scores) MDS patients in terms of survival and risk of leukemic transformation. MDS blasts have high rates of mutations in epigenetic modifiers and exhibit altered DNA methylation patterns [7,8,9,10]. There is a strong need for prognostic and predictive biomarkers as responses take several months to occur and not all patients respond [16]
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