Researchers show how aggressive form of multiple myeloma resists chemotherapy

Published on July 3, 2012 at 1:54 AM · No Comments

Researchers at Washington University School of Medicine in St. Louis have shown how an aggressive form of multiple myeloma resists chemotherapy.

Multiple myeloma is a rare cancer of plasma cells in the bone marrow. Though the finding has no immediate benefit for patients, the scientists say it could help guide research into better treatments.

The results appear online July 2 in the Journal of Clinical Investigation.

About 20 percent of patients with multiple myeloma have a specific genetic abnormality that is associated with a poor prognosis. Patients with this "translocation" — in which a broken section of chromosome 14 is swapped into chromosome 4 — show resistance to certain chemotherapy drugs and shorter survival than multiple myeloma patients without this particular translocation.

"Even in this cancer that has no cure, patients with the 4, 14 translocation tend to do very poorly with treatment," says Michael H. Tomasson, MD, associate professor of medicine. "But no one really knew why. For a number of years, we have been studying the gene at the chromosome's breakpoint, without much success in explaining how it could lead to cancer."

The gene at the breakpoint, called WHSC1, makes proteins that guide how DNA is packaged, an important method for regulating which genes are turned on or off in a given cell. This type of gene is a prime suspect in cancer because an error in DNA packaging could lead to uncontrolled cell division. Patients with this translocation also make the gene's proteins in extremely high amounts, another hallmark of cancer. But even after extensive experiments, the researchers couldn't show how these proteins might make a cell cancerous.

"So we took a step back and asked what's missing?" Tomasson says. "What is different between what we're doing in the lab and what is going on with our patients?"

In the lab, they had used common techniques that only examine the small portion of the WHSC1 gene that codes for proteins. Patients, of course, are living with the entire gene. In this case, the missing piece of the puzzle lay in the so-called non-coding regions of the gene. Tomasson and his colleagues designed an unbiased method to examine these non-coding regions, specifically measuring the RNA made by the gene. RNA is closely related to DNA and plays broad roles in regulating cellular processes.

"It turns out, hidden inside this gene is a non-coding RNA that's expressed at very high levels in patients with the translocation," Tomasson says.

This particular RNA is called ACA11 and is classified as a small nucleolar RNA, or snoRNA. Generally, snoRNAs are well known only for helping the cell regulate other RNAs.

In an interesting twist, fellow Washington University researcher Jean E. Schaffer, MD, the Virginia Minnich Distinguished Professor of Medicine, had recently found the first evidence that snoRNAs are not limited to their previously defined roles. Schaffer and her colleagues showed that some snoRNAs are also involved in the cellular damage seen in metabolic diseases such as diabetes. Reporting in Cell Metabolism last year, they demonstrated that some snoRNAs regulate how a cell responds to oxidative stress, stress caused by highly reactive molecules that contain oxygen.

"Jean published a paper showing that another type of snoRNA modified oxidative stress not in cancer, but in cardiac metabolism," Tomasson says. "That put us on to the idea that perhaps our snoRNA, ACA11, is also regulating the oxidative stress that can damage cells."

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