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St. Jude investigators have found that a protein called Puma, which normally protects the body by triggering cancer cells to commit suicide through a process called apoptosis, is suppressed in Burkitt lymphoma. The discovery raises the possibility of treating the cancer using drugs that switch on the gene that makes the Puma protein.
Burkitt lymphoma is a cancer in which immune cells called B lymphocytes turn malignant and proliferate uncontrollably. It is the most widespread form of childhood cancer in Africa, but is rare in the United States.
Researchers have known that Burkitt lymphoma is caused by the activation of a master regulatory gene called c-Myc, which releases normal control of B cell proliferation. However, for such cancer cells to survive, they must also disable a key mechanism controlled by a protein called p53 that protects the body against abnormal cells. This p53 mechanism normally triggers apoptosis in damaged or aberrant cells such as cancer cells. A key cog in the p53 apoptosis process is the Puma protein, which stands for “p53 upregulated modulator of apoptosis.”
In their studies, the investigators explored whether production of the Puma protein was suppressed in Burkitt lymphoma, which would unleash B cell proliferation. They found that, in mice engineered to overexpress c-Myc, also knocking out Puma accelerated lymphomagenesis. When the researchers analyzed cells from humans with Burkitt lymphoma, they found that in most cases Puma expression had been lost.
“This finding represents a key extension of other studies on Puma, because such loss had never been shown before in human cancer,” said Gerard Zambetti, PhD, Biochemistry, senior author of a study that appears in the advanced online publication of the journal Molecular and Cellular Biology.
The researchers also tackled the question of how the Puma gene is “silenced” in the cancer. Their analysis of the structure of the Puma gene and of lymphoma cells suggested that, while the Puma gene was intact, its function was being shut down by an epigenetic mechanism. In epigenetic silencing, a gene is masked from being read by the cell’s protein-producing machinery. This masking consists of attaching molecules called methyl groups to the DNA—a process called methylation. The researchers’ studies of the Puma gene in human lymphoma cells revealed such masking by methylation of a specific region of the Puma gene.
The researchers also found that they could switch the silenced Puma gene back on in lymphoma cells by using a drug to inhibit the gene’s masking methylation. These findings suggest that using such drugs to restore Puma expression and activity could be clinically important, Zambetti added.
“On the one hand, patients receiving traditional chemotherapy can suffer the loss of immune cells, and this loss occurs in part because Puma induces the death of these cells,” Zambetti said. “In this case, the goal would be to protect patients’ bone marrow by developing drugs to inhibit Puma. On the other hand, for patients with a lymphoma in which Puma was inactivated, drugs could be used to reactivate the gene, to trigger apoptosis and kill the tumor cells.”
Other authors of this study include Sean Garrison, PhD, and John Jeffers, of Biochemistry; Jerold Rehg, DVM, Mihaela Onciu, MD, of Pathology; and Jeffery Sample (formerly of St. Jude).
This work was supported in part by National Institutes of Health grants, a National Institutes of Health /National Cancer Institute Cancer Center Support CORE Grant and ALSAC.