One-Two Drug Punch Trips Up Leukemia

The source of leukemia’s evil may lead to its downfall. By pushing leukemia cells’ cancer-promoting proteins into their nuclei and trapping them there, researchers have tricked the cells into committing suicide. Physicians may someday employ this ruse to treat the late, acute stage of some adult leukemias.

Scientists at the University of California, San Diego Cancer Center used a two-drug punch to ferry the aberrant proteins into the leukemia-cell nuclei and trap them there. The cells, for some reason intolerant of such intimate contact with these proteins, self-destruct. Normal cells lack the cancer proteins and remain unharmed.

“It’s a really nifty finding, and we love it because it shows that cancer cells have their weaknesses-their strength is also their weakness,” says Jean Y.J. Wang. She and Paolo Vigneri reported their results in the February Nature Medicine.

Leukemia, a cancer of the immune system, begins when immature white blood cells in the bone marrow proliferate out of control. The excess cells interfere with the blood’s ability to transport oxygen and to clot.

The early stage of chronic myelogenous leukemia (CML), a form of the disease accounting for 15 percent of adult cases, is fairly mild, says Vigneri. After a few years, however, it invariably progresses to the acute stage, “when it becomes deadly,” he says.

The progression through this final stage is rapid and brutal. Once patients have entered what physicians call the “blast phase,” death may come in as little as 2 to 3 months. Patients over 50 rarely survive the bone marrow transplants that can help some younger people with the disease.

The telltale protein of both stages of CML is a hybrid of two damaged products of the BCR (breakpoint cluster region) and ABL (Abelson murine leukemia) genes. ABL protein normally acts as a messenger molecule and can initiate a cell’s natural self-destruct program when the cell is damaged or endangers other cells. BCR’s normal protein function isn’t known. When damaged, the two molecules join to create a single protein, BCR-ABL, that ignites leukemia.

In the cytoplasm of a leukemia cell, BCR-ABL directs the cell to reproduce faster. It also stops the cell’s program of self-destruction. It’s as if in acquiring the BCR-ABL complex, the leukemia cell gains an internal shield “like a missile-defense system,” says Wang.

Last year, other researchers hailed the compound STI571, which blocks BCR-ABL, after early-stage CML patients improved dramatically during treatment in clinical trials (SN: 12/11/99, p. 372). Unfortunately, STI571 didn’t help patients in the acute stage of the disease.

Using cell cultures, Wang and Vigneri discovered that STI571 can carry BCR-ABL from the cytoplasm of a leukemia cell into the nucleus. They also found that the nucleus ships the dangerous protein complex back to the cytoplasm.

Vigneri hit upon the idea of using the drug leptomycin B, which disables the nucleus’ export mechanism, to trap BCR-ABL. The researchers found that the trapped BCR-ABL initiates the leukemia cell’s suicide program.

Carlo M. Croce, director of the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, is optimistic. He says, “The results are already spectacular with STI571, so if they can find a better way to treat [CML], it will have a major impact on cancer treatment.”