Blocking the Activity of a Single Protein Proves Lethal to Myeloma Cells
The Bottom Line
A protein called IRF4 activates a network of genes that is necessary for the growth and survival of multiple myeloma cells and may represent an Achilles' heel that can be targeted for the development of new therapies against this cancer.
The Whole Story
Multiple myeloma is a cancer of the blood system. It originates in antibody-producing cells called plasma cells, which develop from immune cells called B cells. There is no cure for multiple myeloma; however, chemotherapy, stem cell transplantation, and newer treatments can control the disease and may extend survival. In an effort to expand the treatment options for patients with multiple myeloma, investigators at NCI's Center for Cancer Research set out to identify new therapeutic targets for this disease.
To do so, the researchers used a method they had previously developed that takes advantage of a phenomenon called "RNA interference." In this method, small strands of ribonucleic acid (RNA)--called short hairpin RNAs, or shRNAs--are introduced into cancer cells in such a way that they can turn off the expression of a single gene per cell. If a turned-off gene is necessary for cancer cell growth or survival, then the affected cells will fail to proliferate and/or they will die. Such a gene or its product would be viewed as a potential target for drug development.
In the new work, the researchers showed that turning off a gene called IRF4 causes myeloma cells to die. The IRF4 gene produces a protein that functions as a transcription factor, meaning it regulates the expression of other genes.
Specifically, the researchers found that turning off IRF4 expression caused cells from 10 different myeloma cultured cell lines to die but had only a minimal effect on cells from five different lymphoma cultured cell lines. Surprisingly, when IRF4 gene DNA in the myeloma cell lines was examined, no harmful mutations were found, suggesting that myeloma cells depend critically on a normal cell protein for their survival.
To investigate the molecular basis for this dependency, the researchers identified genes whose activity is affected by the presence or absence of IRF4 protein in myeloma cells. They found that, in myeloma cells, IRF4 protein controls the activity of a large network of genes, including the MYC gene, which itself plays an important role in cell growth and proliferation and in the development of myeloma and other cancers.
Further analysis showed that the IRF4 and MYC proteins participate in a feedback loop in which activation of the MYC gene in myeloma cells increases the production of IRF4 protein, which in turn drives increased expression of the MYC gene, as well as the expression of other genes under IRF4's control.
According to Louis M. Staudt, M.D., Ph.D, deputy chief of the Metabolism Branch at CCR, "These findings reveal a hitherto unknown and, for myeloma cells, critical network of gene activity centered on this one protein." The researchers hope to develop new therapeutic approaches to target what they describe as a possible Achilles' heel of multiple myeloma.
More summaries of selected scientific advances from NCI-supported research are available at http://www.cancer.gov/aboutnci/servingpeople/advances.