Awards honor Alt's three decades of genetic cancer research
Discoveries on genomic instability have moved cancer prevention in new directions
Frederick W. Alt, a Howard Hughes Medical Institute investigator at the Children's Hospital Boston Department of Molecular Medicine, has received the Clowes Memorial Award from the American Association for Cancer Research, acknowledging his three decades of seminal discoveries in genomic instability and cancer. The Clowes is the oldest award given by the AACR, and recognizes outstanding recent accomplishments in basic cancer research. The award will be presented at the AACR's 95th Annual Meeting in Orlando, Fla. (March 27-31, 2004). This month Alt, who holds a doctorate in Biological Sciences, also received the prestigious Scientific Leadership Award in Immunology from the Irvington Institute for Immunological Research in New York City.
Alt was the first to elucidate a molecular mechanism for genomic instability (an increased tendency to develop gene mutations) involved in promoting cancer. The human genome is at constant risk for mutations due to environmental insults, errors in gene replication, and other factors that can cause chromosomes to break and bits of DNA to be lost, duplicated, or reshuffled to the wrong chromosomes (translocated). Cells have repair mechanisms that constantly fix this damage, but when the repair process breaks down, the genome becomes unstable and cancers are more likely to develop.
Alt's wide-ranging research has important implications for cancer prevention and has sparked much additional research by other scientists. His work has touched on many aspects of genomic instability and cancer. Several key advancements specifically cited by the AACR are detailed below, followed by a description of Alt's more recent work.
Alt's early work, as a student with Robert Schimke in the 1970s, led to the discovery of a major form of genomic instability known as gene amplification, or creation of many duplicate copies of a gene, sometimes even numbering in the thousands. Studying how cancers become resistant to the chemotherapy drug methotrexate, Alt studied how cancer cells churn out high levels of an enzyme that enables the resistance. He showed that gene amplification endows these cells with many extra copies of the gene encoding this enzyme.
"At the time, people believed the mammalian genome was inviolate and didn't change at all," recalls Alt, who is also the Charles A. Janeway Professor of Pediatrics at Children's and a professor of Genetics at Harvard Medical School. "This discovery showed that cancer cells, at least, could change their genome drastically, and was the first clear-cut molecular demonstration of genomic instability in cancer."
N-myc oncogene amplification
The gene amplification work led Alt to co-discover a specific cancer-causing gene, or oncogene, known as N-myc. He found that N-myc is frequently amplified in neuroblastoma, a childhood brain cancer, making the cancer especially aggressive. "N-myc opened up oncogene amplification as important in cancer prognosis and in mechanisms of cancer progression," he notes. Oncogene amplification has since been found to be fundamental in many advanced-stage cancers, but Alt's N-myc discovery in the early 80s provided one of the first systematic associations with a particular tumor.
The non-homologous DNA end-joining pathway
During the 1980s, Alt also turned his attention to immunology studies, examining how the immune system can recognize and defend against an almost infinite variety of attackers. Serendipitously, this work also led to key discoveries about genomic instability.
The immune cells known as T lymphocytes have receptors that can recognize far more foreign invaders than the genome could possibly anticipate and encode for. The same is true of B lymphocytes, which can make a seemingly limitless variety of antibodies. The genes for these receptors and antibodies come in segments known as Vs, Ds, and Js. In collaboration with Nobel Prize Winner David Baltimore (now president of the California Institute of Technology), Alt helped elucidate how these gene segments are cut and pasted into millions and even billions of combinations through a process known as VDJ recombination.
Baltimore subsequently discovered the proteins that do the cutting, known as recombination activating gene (RAG) proteins, but Alt speculated that some other mechanism was pasting the Vs, Ds, and Js back together. Knowing that cells have a variety of tools for general gene repair, he theorized that those same tools recombine V, D, and J gene segments for the immune system. In the early 1990's his lab studied numerous different kinds of hamster ovary cells that were known to be defective in gene repair, and added RAG proteins to cut apart the V, D, and J segments. They then investigated which cell types could and couldn't reassemble the segments.
Three of the cell types couldn't complete the VDJ recombination, and further studies of these cells led to the discovery of major components of the non-homologous DNA end-joining pathway. This pathway not only joins the severed V, D, and J segments, but also has a key role in maintaining genomic stability by mending double-strand breaks in DNA molecules. Alt and his collaborators immediately identified three proteins involved in this pathway, and later elucidated roles for two more; a total of six end-joining proteins are known today. Alt's team found that mice deficient in these proteins, in combination with certain other mutations, are dramatically susceptible to cancers of the immune system and other cancers.
Mechanisms of oncogene amplification and translocation
Alt's lab also has demonstrated that when a cell is deficient in both end-joining proteins and a protein known as p53, gene amplification, translocations, and tumor formation are greatly enhanced. Normally, p53 sets up a "checkpoint" that detects cells with unrepaired chromosomal breaks, and either kills them outright or prevents them from growing and dividing. In its absence, genomically unstable cells remain in circulation and accumulate more mutations, becoming increasingly malignant. (The p53 protein is known to be mutated in almost half of human cancers, including breast, colon, lung, and prostate cancer.)
When cells lacking both p53 and having defective end-joining proteins fail to repair chromosome breaks, the breaks are replicated along with the chromosome during cell division. The broken ends join to broken ends on other chromosomes, causing cancer-initiating translocations. As chromosomes keep breaking, fusing their broken ends, and replicating, gene amplification results as extra copies accumulate.
Alt's more recent work is exploring further mechanisms of genomic stability in cancer. One mechanism involves H2AX, a structural protein that helps ensure that double-strand DNA breaks are properly repaired by the end-joining proteins. When p53 is also absent, loss of even a single copy of the H2AX gene can lead to translocations. "If you eliminate H2AX and P53 in mice, they get all sorts of cancers – lymphomas, solid tumors, you name it," Alt says. Interestingly, simply reducing H2AX activity is enough to cause genomic instability. "You can't just think that a tumor suppressor gene has to be completely mutated or gone to contribute to cancer," he says. "We need to think in a new way about tumor suppressive genes, particularly those involved in genomic stability." H2AX is a prime candidate for further study, because it maps to a region of human chromosome 11 that is altered in a large percentage of human cancers.
A second mechanism, again drawing on Alt's work in immunology, is class switch recombination. This gene-reshuffling tool is used by the immune system to instruct an antibody where to go in the body and what strategy to use in fighting a pathogen. As with VDJ recombination, genes are cut and pasted, generating different classes of antibodies (IgM, IgG, IgE, etc.). Again as with VDJ recombination, Alt believes that errors in the "pasting" part of the process may lead to translocations and oncogene (cancer gene) activation, a phenomenon already seen in many human B-cell lymphomas. H2AX may play a protective role here as well, Alt believes, by ensuring that cut ends of genes are properly joined.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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