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How Fusion Proteins Cause Leukemia
By Nancy Touchette

Human acute myeloid leukemia cells.

Many leukemias begin when a large piece of one chromosome becomes loose and reattaches to another chromosome. This can bring together two unrelated genes that can wreak havoc on the cell.

New studies suggest that some of these fused genes produce proteins that deliver a double whammy. They shut down genes that help repair mistakes in DNA, and they activate genes that help the cells proliferate. The result is uncontrolled growth of cells with lots of genetic mistakes.

Myriam Alcalay of the European Institute of Oncology in Milan, Italy, and her colleagues used DNA microarray analysis to see how three different fusion proteins associated with three subtypes of acute myeloid leukemia (AML) affect gene activity in human blood cells.

They found 50 genes that were activated, or turned on, by all three proteins and 113 genes that were shut down by the fusion proteins.

The researchers found that the fusion proteins turned on many genes important in the renewal of stem cells. And many genes that repair mutations in just one “letter” of DNA were blocked.

The loss of healthy DNA-repair genes can cause many mistakes in the genome. And the activation of the self-renewal genes can cause the cells to behave more like stem cells, actively proliferating. Eventually, mutations may accumulate that cause the cells to multiply out of control and become malignant.

“One cell goes crazy and doesn’t mature, but rapidly divides,” says Alcalay. “These intermediate, immature cells accumulate and invade the bone marrow. Eventually the patient dies.”

The next step, says Alcalay, is to identify genes in the pathways that will cause the cells to mature, or differentiate, and behave less like stem cells.

“Experience has shown us that differentiation is the way to go in leukemia,” she says. “We need to identify the proteins that will cause the cells to differentiate and stop dividing.”

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Alcalay, M. et al. Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. J. Clin. Invest. 112, 1751-1761 (December 2003).


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