The use of plasma miRNAs as potential biomarkers is a growing research area,12, 13, 14
and this is the first study to look at plasma miRNAs in MM. Our findings indicate the possible clinical utility of plasma miRNA level in MM patients. The recent introduction of new agents has improved the response rate and survival in patients with MM.21
In MM treatment, the decision to start chemotherapy usually depends on the presence of clinical symptoms with high evidence level, so-called CRAB (hypercalcemia, renal failure, anemia, bone lesion) symptoms.22
Moreover, the therapeutic target point in MM patients has been proposed,23
and practical guidelines for the therapeutic strategy have been helpful in clinical decision-making for MM treatment.24, 25
However, there are some MM patients for whom the timing and combination of chemotherapy are difficult to decide,26
although high-risk MM patients can be classified.27, 28
Because, decisions regarding chemotherapy are occasionally difficult in non-secretory or asymptomatic MM patients, a novel diagnostic marker is urgently required, in addition to the conventional diagnostic tool.21
In the current study, we demonstrated the downregulation of plasma miR-92a in symptomatic MM patients, irrespective of the presence or absence of renal damage or M-protein, suggesting that the measurement of the plasma miR-92a could be helpful for deciding when to initiate chemotherapy.
Chromosomal abnormalities and molecular alterations in MM cells have been extensively investigated, and some of them are currently incorporated into the risk analysis.23, 27, 29
In addition, pathogenesis of extracellular circumstances, including angiogenesis,30
in MM patients is an important issue not only for understanding the biology of myeloma but therapeutic strategies as well.21
In myeloma cells, overexpression of the miR-17-92a has been noted in the transformation from MGUS to MM.15
Therefore, miR-17-92a expression is thought to correlate with tumor burden in MM patients. In contrast, we found no difference in plasma miR-92a levels between MGUS and SMM patients. Because the plasma miR-92a level was significantly different between patients with SMM and symptomatic myeloma, the level of plasma miR-92a level could reflect the pathological condition of patients rather than the tumor burden of myeloma cells in the body. Moreover, normalization of the plasma miR-92a level after obtaining CR suggests that the plasma miR-92a level might serve as an indicator for therapeutic response. The number of treated patients studied was small, however, and further research is needed to clarify this possibility.
Studies have shown that some circulating miRNAs in cancer-bearing patients are tumor-derived,7
and thus such miRNAs might be used as biomarkers of cancer.12, 13, 14
The downregulation of plasma miR-92a has been recognized in patients with hematologic neoplasia, including acute leukemia,16, 17
and hepatocellular carcinoma,31
as well as in patients with cardiovascular diseases.32
Because miR-17-92a is essential in the development and ontogeny of the lymphoid system,33, 34
we examined the correlation between miR-92a levels in separated lymphocytes and plasma. The plasma miR-92a levels was correlated with the miR-92a level in T lymphocytes, especially CD8+
lymphocytes. Some MM patients in CR/VGPR showed normalization of the plasma miR-92a level, in combination with upregulation of T-cell miR-92a. A recent study reported that the miR-17-92a cluster was critical for optimal T-lymphocyte co-stimulation via CD28 and was thereby essential for regulatory T function under certain conditions.35
Moreover, it is reported that the type-1-skewing tumor microenvironment induces downregulation of miR-17-92a expression, with decreased levels of miR-17-92a noted in both CD4+
cells in tumor-bearing mice and in CD4+
cells in patients with glioblastoma multiforme.36
Together, these findings suggest that the low level of miR-92a in T lymphocytes may represent dysregulation of immunity and the downregulated plasma miR-92a level in MM patients may reflect the dysfunction of T lymphocytes in vivo
. In addition to miR-17-92a downregulation, the TaqMan low-density array screening revealed downregulation of miR-223, a regulator of neutrophil proliferation and activation.37
The ultimate downregulation of plasma miR-223 in MM patients might also be related with granulocyte dysfunction.
In conclusion, the plasma miR-92a level may serve as a biomarker for monitoring therapeutic response in MM patients and disease progression in asymptomatic MM patients. The downregulated plasma miR-92a level may be linked to the expression level of T-cell-derived miR-92a. Although we examined a small number of patients, especially MM patients who had been treated, these initial findings suggest that plasma miR-92a levels in monoclonal gammopathy patients may be a promising parameter not only for determining disease status but also whether further treatment is required.