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    Changing Places

    Children do it. Young practical jokers swap desks—and identities—while their substitute teacher studies a seating chart.

    Chromosomes do it, too. Parts of these molecular pranksters can break off and swap places. But the outcome may be much more serious than classroom mischief. When chromosomes relocate and fuse, the results can be cataclysmic.

    In a quiet corner of the Danny Thomas Research Center, Gerard Grosveld, PhD, investigates what happens when pieces of chromosomes wander from their assigned places. For years, his research has been affecting the health of people worldwide. For instance, before coming to St. Jude he led an international team of researchers that discovered how the famed “Philadelphia chromosome” is created by the fusion of the c-ABL gene to part of a gene called BCR. This new fusion gene produces a protein that is a critical player in the formation of chronic myeloid leukemia and some cases of acute lymphoblastic leukemia.

    The Philadelphia chromosome breakthrough eventually led to development of the anti-cancer drug Gleevec™.

    Today, Grosveld chairs the Genetics and Tumor Cell Biology department at St. Jude Children’s Research Hospital, where he continues to delve into the secrets of gene fusion and its role in pediatric cancers, particularly leukemias and a muscle tumor called alveolar rhabdomyosarcoma.

    Alveolar rhabdomyosarcoma is a malignant tumor that usually affects muscles in the trunk and limbs. Mutations in a gene called FKHR (pronounced “forkhead”) contribute to this disease. If a piece of the chromosomes containing the PAX3 or PAX7 genes breaks off and attaches to FKHR, a PAX-FKHR fusion gene is formed that gives rise to cancer.

    Scientists knew that the FKHR protein causes mature cells to commit suicide, but in 2003 Grosveld and his colleagues discovered another role for this molecule: It helps primitive cells called myoblasts to fuse and develop into muscles. By better understanding FKHR’s normal role, researchers have gained insight into how mutated forms of FKHR cause cancer. But Grosveld also found that expression of the PAX3-FKHR fusion gene is not enough to cause cancer; for that to happen, mutations must also exist in two tumor suppressor pathways. And he learned that the overexpression of certain genes that normally cause cells to proliferate also helps make cancer cells expressing PAX3-FKHR more aggressive.

    Grosveld says the discoveries may offer hope to children with the disease.

    “We have identified a way that would cure alveolar rhabdomyosarcoma,” he says. FKHR holds the key to wiping out these tumors. Now scientists must figure out how to do just that. The answer may lie in gene therapy or in a procedure that interferes with the breakdown of the protein expressed by FKHR. Grosveld favors the latter method. “We’ve still got a long way to go,” he admits. “But if we make a small molecule that interferes with the breakdown of this particular protein, I’m pretty sure that it will work.”

    Members of Grosveld’s department are helping scientists across the institution understand the abnormalities that underlie the diseases treated at St. Jude. The Genetics staff is conducting research on topics ranging from the genetic alterations in cancer and lysosomal storage disorders to the genetic changes that affect our ability to repair mutagenic insults. Researchers in his department also study the genes that are important for the formation of the eyes, the lymphatic system, the liver and the pancreas in mammals.

    “The work done in that department is having an incredible impact on our understanding of the mechanisms that go wrong and lead to the diseases we see,” says James Downing, MD, St. Jude scientific director. “This research provides us with a much more detailed understanding so that we can then devise more rational approaches to diagnose, treat or ultimately prevent these diseases.”

    Several years ago, Grosveld discovered a new gene that’s involved in acute lymphoblastic leukemia (ALL). Called TEL2, this gene regulates the action of a cell protein called mTOR. That molecule can activate a biochemical pathway that leads to cell proliferation. Grosveld and Peter Houghton, PhD, chair of St. Jude Molecular Pharmacology, are trying to understand how TEL2 regulates mTOR.

    Grosveld has also been involved in research on TEL gene rearrangements. He and a team of other scientists discovered that children with ALL who have a specific TEL mutation have a favorable prognosis. That means those children do not need aggressive treatment and thus can avoid the side effects that often accompany cancer treatment.

    When it comes to acute myeloid leukemia, Grosveld focuses on two chromosomal translocations—the fusion of the CAN and DEK genes and the fusion of the MN1 and TEL genes. He and his colleagues recently discovered that overexpression of the MN1 gene is important in certain forms of acute myeloid leukemia called core binding factor (CBF) leukemias.

    “We’re trying to find out why the cells are overexpressing MN1,” Grosveld explains. “If you find out why they’re doing that, you can interfere with the process, cut out the overexpression of MN1 and the tumors won’t grow any more.”

    Downing says Grosveld’s work is having a profound impact on scientific knowledge. “His work on alveolar rhabdomyosarcoma is providing key insights into the genetic alterations that underlie the formation of these tumors; similarly, his work on acute myeloid leukemia is providing critical insights into the combinations of genetic lesions that are involved in establishing leukemia,” Downing observes.

    Those genetic pranksters had better watch out. Like substitute teachers who whip around and nab errant chair-swappers, St. Jude scientists are becoming savvy to the antics of certain chromosomes. And they’re using that knowledge to send catastrophic diseases to the back of the class.

    Reprinted from spring 2005 Promise magazine

     

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