Circulating exosomal microRNAs in acquired aplastic anemia and myelodysplastic syndromes

Abstract

Exosomal microRNAs modulate cancer cell metabolism and the immune response. Specific exosomal microRNAs have been reported to be reliable biomarkers of several solid and hematologic malignancies. We examined the possible diagnostic and prognostic values of exosomal microRNAs in two human bone marrow failure diseases: aplastic anemia and myelodysplastic syndromes. After screening 372 microRNAs in a discovery set (n=42) of plasma exosome samples, we constructed a customized PCR plate, including 42 microRNAs, for validation in a larger cohort (n=99). We identified 25 differentially expressed exosomal microRNAs uniquely or frequently present in aplastic anemia and/or myelodysplastic syndromes. These microRNAs could be related to intracellular functions, such as metabolism, cell survival, and proliferation. Clinical parameters and progression-free survival were correlated to microRNA expression levels in aplastic anemia and myelodysplastic syndrome patients before and after six months of immunosuppressive therapy. One microRNA, mir-126-5p, was negatively correlated with a response to therapy in aplastic anemia: patients with higher relative expression of miR-126-5p at diagnosis had the shortest progression-free survival compared to those with lower or normal levels. Our findings suggest utility of exosomal microRNAs in the differential diagnosis of bone marrow failure syndromes. (Registered at clinicaltrials.gov identifiers: 00260689, 00604201, 00378534, 01623167, 00001620, 00001397, 00217594).

Differential expression of miRNAs and their target genes: Exploring a new perspective of acquired aplastic anemia pathogenesis

“…As aAA is also a prototype of “de‐regulated” immune disorder, it may be prudent to believe that miRNAs may be contributing to the aberrant T cell responses observed in aAA. There are, however, only a handful of studies that have explored the role of miRNAs in aAA, and the preliminary results are compelling 11‐17 . Microarray‐based screening investigations in aAA have shown the dysregulation of certain miRNAs, viz; miR‐126‐3p, miR‐145‐5p, miR‐150‐5p, miR‐34a, miR‐155, and miR‐146‐5p, implicated in T cell regulation.…”

Aplastic anemia: Etiology, molecular pathogenesis, and emerging concepts

“…40,41 miR-126-5p is also found to be decreased in patients with AA responding to IST, suggesting miRNA interference of cytokine and growth factor-related proinflammatory and immune signaling. 41…”

“…Hypersecreting genotypes of the multifunctional and regulatory transforming growth factor beta 1 (TGFβ1) have also been demonstrated and taken together this may suggest a quicker and more robust immune response to antigenic exposure and myelosuppression . MicroRNAs (miRNAs) including miR‐532‐5p, MiR‐4651, and miR‐126‐5p, which modulate downstream proinflammatory pathway components such as Toll‐like receptors and TNF‐α, are uniquely and commonly identified in AA . miR‐126‐5p is also found to be decreased in patients with AA responding to IST, suggesting miRNA interference of cytokine and growth factor‐related proinflammatory and immune signaling …”

Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells

“…Recently, a study was performed by Guidice et al into the utility of 25 differentially expressed exosomal microRNAs, related to intracellular functions, such as metabolism, cell survival, and proliferation in differential diagnosis between patients with AA and MDS. Moreover, one microRNA, mir-126-5p, was negatively correlated with a response to therapy for aplastic anemia and patients with a higher relative expression of miR-126-5p at diagnosis had the shortest progression-free survival compared to those with lower or normal levels [114].…”