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Malignant MicroRNAs

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Thanks to Carlo Croce and his collaborators, scientists are several steps closer to understanding the biological underpinnings of multiple myeloma — and a microRNA expression panel may be starting its path to the clinic. The disease, which is diagnosed in approximately 75,000 new patients around the world each year, is the second most common blood cancer after non-Hodgkin's lymphoma.

Croce, director of the Human Cancer Genetics Program in the Department of Molecular Virology, Immunology, and Medical Genetics at Ohio State University, has been studying multiple myeloma and the genetic causes of cancer since the '70s. Before joining Ohio State in 2005, Croce was director of the Kimmel Cancer Institute at Jefferson Medical College, part of Thomas Jefferson University in Philadelphia. He started out in 1970 as a scientist at the Wistar Institute, and is a member of the National Academy of Sciences.

In the early days, Croce says, multiple myeloma was studied by analyzing chromosome translocation. More recently, his team members switched over to evaluating microRNAs, developing in the process their own microarray tool, originally published in 2004 in the Proceedings of the National Academy of Sciences. That tool was an oligo array including 245 miRNAs taken from the genomes of human and mouse. The chip was originally used to find an miRNA expression signature specific to a particular kind of tissue, and was considered useful for analyzing normal versus disease state samples.

Using an upgraded version of that technology — an approach Croce calls the "most comprehensive" way to look at global microRNA expression — in addition to qPCR, Croce's team has now described an miRNA expression signature for multiple myeloma. That team included scientists from Ohio State, the National Cancer Institute, the University of Torino, and Louisiana State University. Flavia Pichiorri and Sung-Suk Suh served as lead authors on the paper, which came out in PNAS in late August.

The research began by trying to assess whether miRNAs played a part in transforming plasma cells to malignant myeloma cells. That their studies showed regulation of certain miRNAs "was not that surprising," Croce says. "What was surprising was which microRNAs were regulated."

The research implicated several miRNAs, including miR-19a and miR-19b, which have been shown to down-regulate expression of the SOCS-1 gene. That gene tends to be silenced in multiple myeloma cases and, when active, serves to inhibit IL-6 growth signaling. Those miRNAs might turn out to be "critical in the transition to multiple myeloma," Croce says.

To test the findings, Croce and his collaborators performed xenograft studies using cell lines representing multiple myeloma in humans and treated them with antagonists for the regulatory miRNAs. The result was noticeable suppression of tumor growth in mice.

Croce says this work will require follow-up studies — in particular, to develop mouse models "and see whether the mice with these regulated microRNAs develop multiple myeloma." The validation process using mouse models could take a couple of years, Croce predicts.

And if that approach pans out, Croce says the next step would be to figure out how to use the relevant miRNAs as targets for a therapeutic. He suspects that these miRNAs are "critically important" and could indeed be controlling the expression of proteins that lead to the onset of multiple myeloma. If that's true, targeting the miRNAs in question could be an effective way to prevent the transition from plasma cells to the myeloma stage.

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