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    The hunt for Puma

    While stalking Puma, investigators learned that this protein is suppressed in one type of cancer. This discovery opens the door for the creation of drugs that switch on the Puma gene.

    Nine-year-old Matthew Fox doesn’t talk much about the fact that he was found to have cancer when he was 4 years old. His mother, Freda, says most people have a hard time believing that the third-grader battled Burkitt lymphoma, a cancer in which immune cells called B lymphocytes turn malignant and proliferate uncontrollably.

    When an egg-shaped knot developed on his neck and Matthew complained of a sore throat, Freda took her son to a specialist. Surgeons removed Matthew’s abscessed tonsils, but a biopsy revealed cancer. The physician referred Matthew to St. Jude Children’s Research Hospital.

    “It floored me when I found out,” Freda says. “My family had no dealings with cancer. It was something new to me.”

    In the past few years, the Fox family has learned much about the clinical aspects of Burkitt lymphoma. Meanwhile, in a research laboratory, one biochemist has been exploring the gene that contributes to this disease. Gerard Zambetti, PhD, of St. Jude Biochemistry and his colleagues recently made a discovery that may someday help kids like Matthew. The research centers around a gene with a feline name: Puma.

    When Puma runs silent

    Although cases such as Matthew’s are rare in the United States, Burkitt lymphoma is the most widespread form of childhood cancer throughout the African continent. St. Jude researchers recently made a discovery that could lead to the treatment of this cancer by using drugs to switch on the Puma gene. The Puma protein usually protects the body by triggering cancer cells to self-destruct. But Zambetti and his team found that Puma is suppressed in Burkitt lymphoma.

    Puma is an acronym for “p53 upregulated modulator of apoptosis.” Apoptosis is the process by which cells undergo programmed death. The p53 protein prevents cancer by functioning as a tumor suppressor. One way p53 performs this function is by inducing genes such as Puma to target abnormal cells to commit suicide.

    In addition to regulating Puma, p53 is responsible for modulating the expression of more than 100 other genes. “p53 can control whether an abnormal cell is halted or killed through the regulation of a series of downstream target genes,” Zambetti explains.

    In search of Puma

    In Burkitt lymphoma, the protein-encoding c-Myc gene swaps places in the chromosome with an antibody-producing immunoglobulin gene and becomes abnormally expressed.

    “When the c-Myc gene is moved into the immunoglobulin position on the chromosome in B cells, it is constantly expressed at high levels,” Zambetti says. Although the elevated level of c-Myc inappropriately drives the growth of these blood cells, it also triggers p53-mediated killing. To fully develop into tumors, these abnormal B cells must overcome the death response.

    As they studied Puma production in Burkitt lymphoma, the researchers found that in models created to overexpress c-Myc, Puma inactivation accelerated the cancer’s growth and development.

    The researchers also discovered that Puma expression had been lost in most human Burkitt lymphoma cells. Such a loss had never been shown before in human cancer, according to Zambetti.

    Manipulating Puma

    The next question for the St. Jude researchers to answer was how the Puma gene was being silenced in Burkitt lymphoma. By analyzing the structure of the Puma gene and of lymphoma cells, investigators found that while Puma was intact, its function was being masked so that it could not be read by the cell’s protein-producing machinery.

    This silencing occurs through DNA methylation, which occurs when molecules known as methyl groups attach directly to the DNA.

    “The human Burkitt lymphoma cell lines that we grew in the lab were consistent with what we found in the tumors,” Zambetti says. “The cell lines that had low Puma message also had Puma gene methylation, which would explain why Puma expression is diminished.”

    Zambetti and a team that included postdoctoral fellow Sean Garrison, PhD, of Biochemistry used a drug to switch the silenced Puma gene back on by inhibiting the cell’s machinery responsible for DNA methylation. This finding suggests that drugs could be developed for clinical use to restore Puma expression and activity.

    “On the one hand, patients receiving traditional chemotherapy can suffer the loss of immune cells. This loss occurs in part because Puma induces the death of these cells,” Zambetti says. “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.”

    Taming the beast

    During his treatment for Burkitt lymphoma, Matthew received six months of chemotherapy at St. Jude. His check-ups now occur only once a year.

    “St. Jude was so overwhelming because everybody there was so nice,” Freda says. “Every time we go for his yearly check-up, he has to go upstairs and see his nurses.”

    Now, when the family comes to St. Jude, they will also glance up at the fourth-floor windows of the Danny Thomas Research Center. Matthew and his parents know that in a laboratory high above them, researchers continue their quest to understand—and eradicate—Burkitt lymphoma.

    Reprinted from Promise Winter 2009

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