Plasma Mir-92a Levels in Multiple Myeloma Correlate with T-Cell-Derived Mir-92a and Restored in Bortezomib Responder

The oncomir micro-RNA (miR) 17–92a, especially miR-92a, is highly expressed in multiple myeloma (MM) and possibly affects neoplastic proliferation resulting from inhibition of apoptotic effect of BIM. Recent studies have demonstrated that circulating miRNAs can be detected in the plasma and serum of healthy subjects and cancer patients. Therefore, circulating miRNAs are thought to be possible diagnostic or prognostic biomarkers in human diseases. In order to gain more insight into biological and clinical relevance of plasma miR-92a expression, we sought to evaluate plasma miR-92a levels in MM patients at various phases and related disorders.

We evaluated peripheral blood obtained from 168 patients with monoclonal gammopathies; 138 patients with symptomatic MM, 8 smoldering MM (SMM), and 22 monoclonal gammopathy of undermined significance (MGUS). The plasma miR-92a expression was measured by Q-RTPCR, and normalized to miR-638 expression, as reported previously (Ohyashiki K, et al. PloS ONE, 2011 6(2) :e16408). The CD4+ or CD8+ T-cell fractions were separated with an isolation kit for humans (Miltenyi Biotec, Bergisch Gladbach, Germany) and AutoMACS Pro Separator (Miltenyi Biotec), according to the supplier's instruction. Cellular miR-92a expression level was also determined as reported previously (Ohyashiki JH, et al. BMC Res Notes, 2010, 3 :347).

MiR-17-92a clusters (miR-19b, miR-17, miR-92a, miR-20a, and miR-19a) were significantly decreased in plasma samples obtained from MM patients. The plasma miR-92a level in symptomatic MM patients was significantly down-regulated compared with normal subjects (P < 0.0001), regardless of immunoglobulin subtypes or disease stage at diagnosis. Patients in complete remission (CR: n = 8) had a significant increase in plasma miR-92a compared with those at diagnosis (P < 0.0001), and 7 of 8 patients were normalized (≥ 0.2593 cut-off level).

By contrast, cellular miR-92a in circulating CD8+ cells (P = 0.0004) or CD4+ cells (P = 0.0013) from MM patients significantly decreased compared with normal subjects, and the patients' values tended to correlate with plasma miR-92a levels. The plasma miR-92a level in complete remission group became normalized, whereas the partial response and very good partial response groups did not reach to the normal range. Of particular interest is that some MM bortezomib-responder patients and non-responders sustained low levels of plasma miR-92a level after short-courses of the therapy, and then the plasma miR-92a levels up-regulated at 8 or more injections in the responder group. Therefore, the down-regulated plasma miR-92a level elevated after bortezomib therapy in therapy responders but not in non-responders. Our observation suggests that measurement of the plasma miR-92a level in MM patients is a useful indicator for monitoring therapeutic response, and the level may represent, in part, the T-cell immunity status of patients with MM.

No relevant conflicts of interest to declare.