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Babies' Leukemia a Separate Disease

Genetic study points to need for new drugs for fatal infant cancer

MONDAY, Dec. 3, 2001 (HealthDayNews) -- Certain infants diagnosed with the most common and curable kind of childhood leukemia still do not do well on the same drugs that cure up to 80 percent of their peers. Now researchers may know why.

These children may have a rare variation of acute lymphocytic leukemia (ALL) that is, in fact, a totally separate disease that probably should have its own name and be treated with specially designed drugs, say the researchers at Dana-Farber Cancer Institute. They say their findings could lead to new ways to diagnose and treat the disease they propose to name mixed-lineage leukemia (MLL).

Leukemia, a cancer of bone marrow cells, can lead to easy bruising or bleeding, fatigue due to anemia and repeated minor infections. The MLL variant affects only about 100 babies, usually under 1 year old, in the United States annually, but it kills about 60 percent of those it strikes.

Overall, about 144,000 people in the United States have leukemia, and while the leukemia death rate for American children has declined 61 percent in the last three decades, it still is a leading cause of death among children under age 15. More than 670 deaths from childhood leukemia are expected in 2001.

There are two major types of leukemia, depending on which kind of cell is affected, and each type can be further divided into acute and chronic variants, including acute lymphocytic leukemia (ALL). However, certain children with ALL show signs that a piece of chromosome 11 has broken off and attached itself to another chromosome.

This anomaly is called the mixed-lineage leukemia gene on chromosome 11q23, report the scientists in today's issue of Nature Genetics.

The researchers, led by senior investigator Dr. Todd Golub, assistant professor of pediatric oncology at the Dana-Farber Cancer Institute, in Boston, tested genetic samples from 20 children with ALL and 17 children with the MLL variant.

Using gene microarrays, which reveal the levels of expression of individual genes, the researchers found that roughly 1,000 genes were underexpressed in the MLL versus the ALL samples, while about 200 of the MLL genes were comparatively overexpressed.

Currently, children with MLL are treated as ALL patients, but they tend to relapse faster after chemotherapy, and Golub hoped to learn why. The cure rate is between 10 percent and 50 percent for children with this type of leukemia, compared with up to 90 percent for other children with ALL.

A clue to this mortality rate may lie in the fact that marrow cells in MLL patients appear to become cancerous at a stage when they are closer to becoming blood stem cells, and have not progressed as far along the pathway to differentiating into myeloid or lymphoid cells, the researchers say.

"What this appears to be is the MLL gene causes the cell to be frozen in a very early developmental state, where they have the potential to become lymphocyte-like as well as myeloid-like," says Alan Kinniburgh, vice president of research at the Leukemia & Lymphoma Society, in White Plains, N.Y.

Golub describes the MLL leukemia as more "primitive" or "immature." "These more primitive ones seem to respond less well [to chemotherapy]," he says.

Kinniburgh says the findings are an important advance in understanding childhood leukemia and could lead to new therapies. However, he says its first application will be in diagnosing which patients will respond in a certain way to medications.

While the researchers claim to be able to correctly identify 95 percent of patients with the MLL gene anomaly, Kinniburgh says that figure needs to be more than 99 percent before it could be used to test children. And he says telling the difference between ALL and MLL is irrelevant until therapies are specially designed to treat MLL.

Golub says, "This might be a useful approach to both diagnosing different types of leukemia and also to figuring out better therapeutic strategies for treating these subtypes of leukemia."

The researchers also say they hope the subtype's genetic characteristics could provide new targets for future therapies, replacing the multiple "poisons" that Golub says are now used to fight the cancer. "What we really would like to do is have more elegant, highly specific drugs that target the specific mechanism underlying each type of leukemia. That is likely to be the most effective and have the fewest side effects," he says.

But because this research is at an early stage, Golub says the findings don't support changing the therapy regimen for patients with ALL. "More studies are required before routine clinical care is changed," he says.

What To Do

For more information about leukemia, contact the Leukemia & Lymphoma Society, the Leukemia Research Foundation, the National Cancer Institute or the American Cancer Society.

SOURCES: Interviews with Todd R. Golub, M.D., assistant professor, division of pediatric oncology, Dana-Farber Cancer Institute, Boston, and director, Cancer Genomics, Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Mass.; Alan J. Kinniburgh, Ph.D., vice president of research, The Leukemia & Lymphoma Society, White Plains, N.Y.; Dec. 3, 2001, Nature Genetics
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