Genetic Mapping of Leukemia May Lead to Better Treatment

With more than 13,000 new cases diagnosed annually in the United States, acute myelogenous leukemia (AML) is the most common type of acute leukemia in adults. AML is a cancer of the blood and bone marrow, arising in either granulocytes or monocytes, which are white blood cells that battle infectious agents throughout the body. The word "acute" in this case denotes the rapid progression of the disease and the fact that it affects immature blood cells, rather than mature ones. Although the exact cause of AML is unknown, cigarette smoking, exposure to benzene, and prior exposure to chemotherapy drugs are linked to the disease. Because of its complexity, there has been little change in the treatment for AML for decades. However, a team of American researchers have uncovered eight genes that may play a role in AML, which could lead to better ways of treating the deadly disease.

Dr. Richard Wilson and colleagues at the Genome Sequencing Center and the Siteman Cancer Center at Washington University School of Medicine in St. Louis, using a recently developed sequencing method, mapped the malignant blood cells from a 50+-year-old woman who died of AML, and then compared them with the genes in a normal cell from her skin. This process allowed them to see exactly how the DNA of the cancer differed from the healthy DNA, explained author Timothy Ley, a professor of medicine and genetics at the Washington University School of Medicine.

The comparison of 20,000 genes uncovered 10 that differed between the tissues. Two of the 10 were known to be involved in leukemia, but the other eight had never before been linked to this type of cancer. One of the newly discovered genes was found to block chemotherapy drugs from getting inside the cancer cells to kill them, while 4 others appear to disable a cell’s defense system that prevents it from turning into a cancer cell. “If those genes are mutated or de-activated, there’s a very good chance the cancer can start to grow out of control,” Dr. Wilson said.

The researchers also examined tumor samples from 187 other patients with AML, hoping to find many genes in common—making it easier to design one drug that would work for everyone. Unfortunately, none of the other patients had the same eight new mutations found in the woman’s tumor, suggesting that even cancers that look alike may actually be caused by completely different genetic mutations. “There are probably many, many ways to mutate a small number of genes to get the same result, and we’re only looking at the tip of the iceberg in terms of identifying the combinations of genetic mutations that can lead to AML,” Richard Wilson said in a statement.

Wilson attributes the breakthrough to an increase in the speed of whole-genome sequencing, along with a drop in its cost. He says he hopes in twenty years or less, scientist will be able to perform DNA sequencing by using only a drop of blood that would be analyzed by a computer. “A genome-wide understanding of cancer, which is now possible with faster, less expensive DNA sequencing technology, is the foundation for developing more effective ways to diagnose and treat cancer,” he said.

The researchers are already mapping another patient’s "cancer genome" and hope to quickly map ten more. After mapping enough individual genomes, scientists will have a good idea of all the mutations that can make a cell malignant, allowing them to design drugs that block the bad genes. “We need to do hundreds, if not thousands, of each of the major cancer types,” Ley said.

Brian Druker, a professor at the Oregon Health and Science University Knight Cancer Institute, called Ley’s techniques “incredibly promising.” Druker developed a drug called Gleevec, which is used to treat chronic myeloid leukemia. Gleevec works so well because it blocks the very first mutation involved in that type of cancer. Researchers have also developed a drug that blocks one of the well-known mutations in the woman’s AML cells, called FLT-3. However, that drug has had limited success because the mutation happens relatively late in the cancer process, after a cell has already become abnormal, Druker says.

The study was published in the November 12 issue of Nature.