Mutation may help cause acute myeloid leukemia

August 01, 2003

St. Louis, Aug. 1, 2003 -- Researchers at Washington University School of Medicine in St. Louis have found that a chromosome defect often seen in human acute myeloid leukemia (AML) can cause the same disease in mice when combined with a genetic defect in a molecule known as a tyrosine kinase receptor. The study is published online and in the Aug. 5 issue of the Proceedings of the National Academy of Sciences.

"The findings indicate that tyrosine kinases may be an important class of cancer-causing genes in leukemia," says principal investigator Michael H. Tomasson, M.D., assistant professor of genetics and of medicine. "It further suggests that drugs designed to inhibit these molecules might provide effective new treatments for this deadly disease."

AML is a cancer of immature white blood cells. It can lead to severe anemia and immune deficiency and often is fatal. Although AML accounts for less than 3 percent of all cancers, it is the leading cause of cancer death among Americans under age 35. It also strikes older people, in whom it can be difficult to treat.

About 12 percent of AML patients have a chromosomal abnormality that fuses a piece of chromosome 21 to chromosome 8. The genetic mutation leads to production of an abnormal protein known as aml1-eto. But this change alone isn't enough to cause AML in humans or animals.

Tomasson and colleagues examined mice transplanted with bone-marrow cells some of which contained both the aml1-eto defect and a defect in a tyrosine kinase receptor gene known as tel-pdgfrb. With these two mutations, the mice developed AML; mice with only the aml1-eto fusion gene did not develop the disease.

"This is the first study to show that an activated tyrosine kinase receptor can cooperate with aml1-eto to produce AML in laboratory animals," says first author Jay L. Grisolano, Ph.D., a post-doctoral fellow in Tomasson's laboratory. "It raises the possibility that a combination of therapies designed to inhibit aml1-eto and tyrosine kinase receptors might one day be used to control this disease."

Tyrosine kinases power chemical reactions in cells, particularly those involved in cell division. Normally, these molecules are carefully regulated to keep a tight lid on cell growth. But they can lose that regulation when tyrosine kinase genes mutate. Instead of powering reactions only when appropriate, for example, the tel-pdgfrb protein runs constantly, like an engine that won't shut off.

"Mutations in tyrosine kinases can push cells to divide," says Grisolano. "If this is combined with a mutation that blocks cells from maturing, as does the aml1-eto gene, it can lead to cancer."

For example, mutations in a gene known as flt3 (pronounced flit 3), also in the tyrosine-kinase gene family, are among the most common mutations in people with AML. Drugs that block flt3 are being developed as a possible treatment for AML. Tel-pdgfrb is closely related to flt3.

"This study further supports the idea that tyrosine kinases may be highly worthwhile targets for new drugs to treat AML," says Tomasson.
-end-
Grisolano JL, O'Neal J, Cain J, Tomasson MH. An activated receptor tyrosine kinase, TEL-PDGFRB, cooperates with AML1-ETO to induce acute myeloid leukemia in mice. Proceedings of the National Academy of Sciences, 100(16), 9506-9511, Aug. 5, 2003.

Funding from the National Cancer Institute and the Leukemia and Lymphoma Society supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Washington University School of Medicine

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