Intracellular Mis-Localization of Modified RNA Molecules and Non-Coding RNAs: Facts from Hematologic Malignancies

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Abstract

The intracellular topography of RNA molecules, encompassing ribonucleotides with biochemical modifications, such as N6-methyladenosine(m6A), 5-methylcytosine (m5C) and isomerization of uridine to pseudouridine (Ψ), as well as of the non-coding RNA molecules, are currently studied within the frame of the epigenome. Circulating RNA molecules in the intracellular space, that have incorporated information by carrying specific modifications, depend on the balanced activity and correct subcellular installation of their modifying enzymes, the “writers”, “readers” and “erasers”. Modifications are critical for RNA translocation from nucleus to cytoplasm, stability and translation efficiency and other, still uncovered functions. Moreover, intracellular movement of non-coding RNA molecules depends on membrane transporters, capable of recognizing signal sequences and RNA recognition-binding proteins, that can facilitate their transport to different intracellular locations, guiding the establishment of interconnection possibilities with different macromolecular networks. The potential of long non-coding RNAs to form multilayer molecular connections, as well as the differential topology of micro-RNAs in cell nucleus over cytoplasm have been recognized by several studies. The study of the intracellular compartmentalization of these molecules has recently become feasible thanks to technological progress, however, a wealth of information has not yet been produced that would lead to safe conclusions, regarding non-coding RNA contribution to the early steps of pathogenesis and disease progression of hematological malignancies. Both the bone marrow, as the main hematopoietic tissue, and the lymphoid tissues are composed of cells with high potential of reaction to signals affecting the epigenome and initiating cascade pathways in response. Independently or in combination with the coexistent driver genetic mutations, especially of enzymes involved in epigenomic surveillance, intracellular microenvironmental alterations within the cell nuclear, cytoplasmic and mitochondrial compartments, can lead to disorganization of hematopoietic stem cells’ epigenome, promoting the generation of hematological malignancies. In this review, we discuss the various intracellular processes that, when disrupted, may result in the ectopic placement of RNA molecules, either inducing specific modifications or non-coding molecules, promoting hematological malignant phenotypes. The crosstalk between mitochondrial and nuclear genomes and the complex regulatory effects of mis-localized RNA molecules is highlighted. This research approach may constitute a field for new, more specifically targeted therapies in hematology, based on the RNA technology.

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