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Study Finds MicroRNA Signature That May Reflect Progression to Myeloma

NEW YORK (GenomeWeb) – Researchers from the US National Institutes of Health have uncovered a microRNA signature for myeloma that's detectable in the blood.

Katherine Calvo from the Clinical Center at NIH and her colleagues identified the miRNA signature in bone marrow, a portion of which could be detected in the serum of myeloma patients. As they reported in the Journal of Molecular Diagnostics today, a subset of those myeloma-related miRNAs were also aberrantly expressed in patients with precursor diseases like monoclonal gammopathy of undetermined significance or smoldering myeloma, suggesting that the signature could gauge disease progression.

Some 27,000 people in the US are diagnosed each year with myeloma, and before the onset of disease, most myeloma patients first have monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic disease, or smoldering myeloma (SMM). Only 5 percent of patients with myeloma, though, are diagnosed with stage I disease.

"Currently, there is no single factor that can predict patients with MGUS or SMM who are likely to progress to myeloma," Calvo said in a statement. "A biomarker of disease progression in the peripheral blood could assist in the early identification of patients evolving to multiple myeloma."

She and her colleagues profiled the miRNAs in the extracellular bone marrow of 20 patients with myeloma and eight healthy controls. Using an miRNA array, they identified 111 miRNAs that were differentially expressed between the two groups. Of those, 69 were down-regulated and 42 were up-regulated in the bone marrow of myeloma patients.

Through hierarchical clustering, they homed in on a unique miRNA signature in myeloma. They focused on some two dozen of those miRNAs, 18 of which they validated as down-regulated in the bone marrow microenvironment of 18 myeloma patients as compared to seven controls.

Calvo and her colleagues then examined whether this myeloma signature could also be detected in patients' blood. Eleven of the 18 marker miRNAs, they reported, were also down-regulated in the serum of 13 myeloma patients compared to 12 controls, as determined through qPCR. Hierarchical clustering further indicated that eight of those miRNAs could distinguish myeloma patients from controls.

To validate and extend this eight-miRNA signature, the researchers assessed it in the serum andplasma of 17 myeloma patients and 20 controls, again with a qPCR approach. Six of these miRNAs, they reported, were significantly decreased in the plasma of myeloma patients.

These six miRNAs included let-7a, let-7b, let-7i, miR-15a, miR-15b, and miR-20a. Let-7 miRNAs, the researchers noted, target a number of proteins that regulate oncogenesis, cell cycle, proliferation, and apoptosis.

They then gauged whether these myeloma-related miRNAs — particularly the 11 miRNAs down-regulated in the peripheral blood of myeloma patients — were also aberrantly expressed in myeloma precursor disease.

They performed serum miRNA analysis on a set of 17 MGUS, 17 SMM, and 13 myeloma patients and 12 healthy controls. All 11 of those miRNAs were decreased in peripheral blood samples from myeloma patients, as expected. However, only 36 percent of them were decreased in MGUS peripheral blood samples and 73 percent were decreased in SMM peripheral blood samples. Some 27 percent of the miRNAs were significantly decreased in myeloma but not in MGUS or SMM.

This suggested to the researchers that the down-regulation of these miRNAs might be linked to events that occur later in disease progression.

"Our findings suggest that the antiproliferative and proapoptotic miRNAs, such as the let-7 family members, are down-regulated in multiple myeloma's microenvironment," Calvo said. "These findings suggest that measuring expression of miRNAs associated with myeloma progression in the peripheral blood may hold promise for predicting disease progression in MGUS and SMM."