Contingent Synergistic Interactions between Non-Coding RNAs and DNA-Modifying Enzymes in Myelodysplastic Syndromes

Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders with maturation and differentiation defects exhibiting morphological dysplasia in one or more hematopoietic cell lineages. They are associated with peripheral blood cytopenias and by increased risk for progression into acute myelogenous leukemia. Among their multifactorial pathogenesis, age-related epigenetic instability and the error-rate DNA methylation maintenance have been recognized as critical factors for both the initial steps of their pathogenesis and for disease progression. Although lower-risk MDS is associated with an inflammatory bone marrow microenvironment, higher-risk disease is delineated by immunosuppression and clonal expansion. "Epigenetics" is a multidimensional level of gene regulation that determines the specific gene networks expressed in tissues under physiological conditions and guides appropriate chromatin rearrangements upon influence of environmental stimulation. Regulation of this level consists of biochemical modifications in amino acid residues of the histone proteins' N-terminal tails and their concomitant effects on chromatin structure, DNA methylation patterns in CpG dinucleotides and the tissue-specific non-coding RNAs repertoire, which are directed against various gene targets. The role of epigenetic modifications is widely recognized as pivotal both in gene expression control and differential molecular response to drug therapies in humans. Insights to the potential of synergistic cooperations of epigenetic mechanisms provide new avenues for treatment development to comfort human diseases with a known epigenetic shift, such as MDS. Hypomethylating agents (HMAs), such as epigenetic modulating drugs, have been widely used in the past years as first line treatment for elderly higher-risk MDS patients; however, just half of them respond to therapy and are benefited. Rational outcome predictors following epigenetic therapy in MDS and biomarkers associated with disease relapse are of high importance to improve our efforts in developing patient-tailored clinical approaches.

Keywords: aberrant DNA methylation; acute myeloid leukemia; altered ncRNA expression; epigenetic landscape; myelodysplastic syndromes.

Figure 1

Overview of cells’ aberrations in epigenome of higher-risk MDS patients within the hematopoietic stem cell (HSC) compartment of bone marrow. Impaired gene expression implicated in maturation and differentiation of pluripotent stem cells give rise to myeloid lineage-committed cells showing further phenotypical as well as functional changes. MDS patients of the higher-risk group present significantly expanded granulocytic-monocytic progenitor cells and HSC compartments, while the megakaryocytic–erythroid progenitor cell population is severely reduced. Cellular and molecular changes are in line with the observed cytopenias and emergence of aberrant blast cells in the bone marrow and peripheral blood of higher-risk MDS patients. Aberrant cells characterized by the generation of multiple copies per cell, are indicated by a solid red star. Obstructed pathways of myelopoiesis and erythropoiesis are indicated within a transparent rectangle.

Figure 2

RNAs capable of adopting stem-loop structures exhibit the potential to associate with DNA modifying enzymes depending on RNA secondary structure. The basis of this preferential interaction and targeting of specific CpGs lengthwise genome is the complementarity of DNA-RNA sequences. (A). Immature pre-miRNA clusters may bind and provide a scaffold for either DNMTs or TET enzymes to DNA sites for de novo DNA methylation or demethylation events, respectively. DNA hypermethylation prevents transcription, while even partial demethylation promotes transcription albeit at minimal levels (lower). (B). DNA sequences occupied by lncRNAs may prevent enzymatic modifications to DNA by obstructing enzymes from binding, which results in an ongoing transcriptional activity.