MicroRNA dysregulation in myelodysplastic syndromes: implications for diagnosis, prognosis, and therapeutic response

Abstract

Myelodysplastic syndromes (MDS) are a group of malignant clonal hematological disorders with heterogeneous clinical course and risk of transformation to acute myeloid leukemia. Genetic and epigenetic dysregulation, including alterations in microRNA (miRNA) expression, plays a pivotal role in MDS pathogenesis influencing disease development and progression. MiRNAs, known for their regulatory roles in gene expression, have emerged as promising biomarkers in various malignant diseases. This review aims to explore the diagnostic and prognostic roles of miRNAs in MDS. We discuss research efforts aimed at understanding the clinical utility of miRNAs in MDS management. MiRNA dysregulation is linked to specific chromosomal abnormalities in MDS, providing insights into the molecular landscape of the disease. Circulating miRNAs in plasma offer a less invasive avenue for diagnostic and prognostic assessment, with distinct miRNA profiles identified in MDS patients. Additionally, we discuss investigations concerning the role of miRNAs as markers for treatment response to hypomethylating and immunomodulating agents, which could lead to improved treatment decision-making and monitoring. Despite significant progress, further research in larger patient cohorts is needed to fully elucidate the role of miRNAs in MDS pathogenesis and refine personalized approaches to patient care.

Keywords: circulating microRNA; diagnostic and prognostic biomarkers; microRNA; myelodysplastic syndromes; therapeutic microRNAs.

Figure 1

MiR-22 directly inhibits TET2 expression, resulting in hypermethylation and decreased expression of TET2 target genes such as AIM2 and SP140. AIM2 has a role in the reduction of cell proliferation by inducing cell cycle arrest, and along with SP140, plays a crucial role in MDS development and leukemogenesis. Additionally, miR-22 downregulates PTEN expression, a phosphatase that dephosphorylates phosphatidylinositol-3,4,5-trisphosphate (PIP3), thereby counteracting the activation of the PI3K/AKT pathway, which leads to aberrant hematopoiesis. The concomitant silencing of TET2 and PTEN by miR-22 enhances cell proliferation and survival, ultimately contributing to the development of MDS and leukemogenesis (14).

Figure 2

(A) The figure depicts the signaling cascade initiated by Toll-like receptors (TLRs) upon ligand binding, and the regulatory role of miR-146a in this pathway. Upon binding to their ligands, TLRs undergo a conformational change that recruits the adapter protein MyD88, leading to the activation of IRAK1. Activated IRAK1 then binds to TRAF6, which in turn activates TAK1. TAK1 phosphorylates the IKK complex, resulting in the activation of the transcription factor NF-κB. Activated NF-κB translocates into the nucleus to induce the expression of proinflammatory genes. MiR-146a targets and downregulates IRAK1 and TRAF6, thereby modulating this signaling pathway. In MDS, decreased levels of miR-146a contribute to the activation of NF-κB through IRAK1 and TRAF6, promoting the development of MDS and its progression to AML. (B) The therapeutic potential of a chemically modified miRNA-146a mimic oligonucleotide (C-miR146a) conjugated to a scavenger receptor/Toll-like receptor 9 agonist. This conjugation significantly increases the levels of miR-146a, effectively restoring its function. The restoration of miR-146a levels results in near-complete and durable inhibition of its targets, IRAK1 and TRAF6. This leads to the complete elimination of exacerbated NF-κB activity, thereby preventing exaggerated inflammatory responses and aberrant myeloproliferation (107, 108).