Blocking A Single Protein Proves Toxic To Myeloma Cells

Researchers have found that cells from a blood-borne cancer called multiple myeloma rely on the activity of a single protein, called IRF4, for the activation of a wide range of genes responsible for cell survival and spread. Blocking the production of this protein can be strikingly effective in eliminating cancer cells in laboratory models of multiple myeloma. Scientists at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), published their results in the June 22, 2008, issue of Nature, which highlight this potentially powerful new therapeutic target in multiple myeloma.

"These findings reveal a hitherto unknown and, for myeloma cells, critical network of gene activity centered on this one protein," said Louis M. Staudt, M.D., Ph.D., deputy chief of the Metabolism Branch at NCI's Center for Cancer Research. "What we have now is a new window of opportunity for therapeutic development in multiple myeloma."

Multiple myeloma arises from blood plasma cells, antibody-producing cells that develop from the immune system's B cells. There is no cure for multiple myeloma, though the disease can sometimes be controlled with chemotherapy, stem cell transplantation, or newer treatments.

To expand the therapeutic options for multiple myeloma patients, Staudt, Arthur Schaffer III, Ph.D., NCI, and collaborators employed a system for identifying potential drug targets that was recently developed in their laboratory on the basis of a phenomenon called RNA interference (RNAi). This system employs small snippets of RNA, called short hairpin RNAs, to effectively turn genes off one at a time, and allows researchers to measure the subsequent effects on cells' survival and proliferation.

The researchers applied this system to 10 laboratory models of multiple myeloma, each representing distinct genetic subtypes of the cancer. In all of these models, the scientists found that quenching IRF4 production caused the myeloma cells to die.

IRF4 is a transcription factor -- a protein that helps to activate other genes. The Staudt team noted that the list of genes that interact with IRF4 in multiple myeloma cells included genes that are normally activated, not in plasma cells but in mature, activated B cells. This finding suggests that myeloma cells are somehow able to redirect IRF4 to activate a genetic program that it would not normally affect in plasma cells.

One gene in particular that stood out from the rest of the list was an oncogene called MYC, known to play a significant role in multiple myeloma and other cancers. Further investigations revealed that IRF4 and MYC form a feedback loop: IRF4 activates MYC, and MYC, in turn, activates IRF4 and -- by extension -- itself and the myeloma-fueling gene networks that rely on IRF4.

The discovery that multiple myeloma cells are dependent on IRF4 for survival puts a new twist on a hypothesis known as oncogene addiction. This hypothesis suggests that certain cancers rely on the activity of a single mutated gene pathway for proliferation and survival. If this Achilles' heel can be identified and shut down therapeutically, the hypothesis contends, the cancer can be eliminated.

However, the case of multiple myeloma and IRF4 differs slightly. Although the gene for IRF4 is not mutated in multiple myeloma, myeloma cells are addicted to the protein's ability to activate normally inactive genetic programs inappropriately. Therefore the dependency of myeloma on IRF4 may be best described as non-oncogene addiction, which is the dysfunction of a normal protein that is required for cancer cell survival or spread.