Despite the constellation of abnormal genetic changes that drive multiple myeloma, these cancer cells are controlled by a single protein, researchers reported online in Nature this week.

The study suggests that multiple myeloma cells are dependent upon the cancer-promoting genetic activities controlled by a protein called IRF4. It further suggests that breaking their "addiction" to this protein could possibly treat the disease.

In 10 different laboratory models of multiple myeloma, Dr. Louis M. Staudt of NCI's Center for Cancer Research and his colleagues found that interfering with the production of IRF4 caused the myeloma cells to die.

"We were surprised to find that multiple myeloma cells with many different genetic abnormalities were all exquisitely sensitive to IRF4 inhibition," says Dr. Staudt. "This suggests that therapeutic targeting of IRF4 might be broadly effective in this disease."

The IRF4 protein, a transcription factor that regulates the activity of multiple genes, is normal in most myeloma cells. But it acquires an expanded genetic repertoire and directs a broad program of activity, including genes that are active in cell metabolism and other basic functions. The loss of IRF4 in myeloma cells, then, results in widespread disruptions to these essential functions, a process the researchers call "death by a thousand cuts."

Multiple myeloma is a cancer that involves a type of white blood cells called plasma cells, which are antibody-producing cells that develop from the immune system's B cells.

The disease currently has no cure, but patients may benefit from chemotherapy, stem cell transplantation, or newer treatments such as bortezomib (Velcade) or thalidomide.

To discover the role of IRF4, the researchers screened a genetically diverse collection of myeloma cells for "essential" genes using a technique known as RNA interference. They observed the dependence on IRF4 in myeloma cells across genetic subtypes of the disease.

The list of oncogenes regulated by IRF4 in myeloma cells includes MYC, which plays an important role in multiple myeloma and other cancers. In an unexpected finding, IRF4 and MYC form a feedback loop: IRF4 activates MYC, and MYC, in turn, activates IRF4, as well as abnormal gene networks regulated by IRF4.

The study is an example of so-called "non-oncogene addiction." In this situation, cancer cells become dependent on the activity of a gene that does not have mutations or other hallmarks of oncogenes.

Based on studies of mice with a form of IRF4 and laboratory experiments, the researchers are hopeful that a therapeutic window may exist in which treatments directed at the production of IRF4 might kill myeloma cells while sparing normal cells.

Transcription factors are considered challenging molecules to inhibit, but recent success in targeting the transcription factors p53 and BCL-6 "provides hope that IRF4 can be exploited as the Achilles' heel of multiple myeloma," the researchers note.

—Edward R. Winstead