Dana-Farber Cancer Institute (44 Binney St., Boston, MA 02115; Tel: 866/408-3324; Website: www.danafarber.org) scientists have discovered that a rare but lethal blood cancer that strikes infants in their first year is a genetically distinct type of leukemia. The discovery will help researchers single out the abnormal genes that make the leukemia so difficult to treat, as well as identifying new targets within the cancer cells for drugs that would be more selective than those used today. The results of the study will be published in the January 2002 issue of Nature Genetics.
Currently, physicians diagnose and treat the infant cancer as a particularly aggressive form of the more common Acute Lymphoblastic Leukemia, or ALL.
"This finding is very exciting to us because it forces us to think about this as a separate disease and to think about other therapies," says Scott Armstrong, lead author of the paper.
The Dana-Farber scientists and collaborators propose the name Mixed Lineage Leukemia, or MLL, for the newly identified disease, which affects fewer than 100 hundred babies annually in the United States but is fatal in approximately 60% of the cases.
Using "gene chips," the Dana Farber team found that the gene expression in the cells of this infant cancer is dramatically different from ALL, and also from Acute Myelogenous Leukemia (AML), the other common type of childhood leukemia.
In addition to Armstrong, who is an instructor in pediatric oncology at Dana-Farber and Harvard Medical School, the team included Dana-Farber's Stanley Korsmeyer and Todd Golub, as well as other colleagues.
Golub is a pioneer in using data from the Human Genome Project to obtain genetic "profiles" of different cancers-that is, determining which genes in the cancer cell are active and which are not-as a way of classifying and diagnosing them. The genetic profiles, or "signatures," not only provide a new system of classification but also may lead to the identification of particular genetic abnormalities in each cancer.
The gene activity pattern in the infant cancer cells was captured by so-called gene chips that can determine the "off" or "on" status of thousands of genes in the cell. The chips, glass or silicon wafers with 12,600 DNA segments (about one-third of all the cell's genes) attached to them, are used to probe RNA from cancer cells to determine which of the genes are being expressed.
In their study, the scientists found that about 1,000 genes were silent or underactive in the MLL cells compared with cells from patients with conventional ALL, while approximately 200 genes were overactive compared with ALL.
"When we look at these patterns of gene expression and also at the cells of origin of MLL, we see a pattern indicating that they are very early lymphoid progenitor cells," says Korsmeyer. "This suggests that MLL is caused by arrested maturation of lymphocytes. Once we saw that these cells were nothing like those in ALL, we understood why these children don't respond well at all to standard chemotherapy for ALL.
The gene snapshots also singled out a single gene that may prove critical in causing the leukemia's uncontrolled growth. It "jumped off the page" in the data analysis, says Golub. The gene, called flt-3 encodes a tyrosine kinase (FLT3) that stimulates cell division. In MLL, the flt-3 gene is stuck in the "on" position and may contribute to the defective growth regulation.
"So if you can block flt-3 you might be able to treat MLL," says Armstrong.
"The beauty of the gene chip is that, much to our surprise, we could deal from the genomic equivalent of a whole deck of cards and come up with such a distinctive hand," adds Korsmeyer. "We couldn't have imagined that amidst this vast amount of data, we could not only clearly distinguish MLL, but come up with FLT3 as a testable drug target for treating the disease."
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