The Secret of Resistant Leukemia

A rare, untreatable type of leukemia appears to be due to a mutant cell receptor that binds one signaling molecule so tightly that it is deaf to the signals that normally halt cell division. The researchers who discovered the mutant receptor hope that the finding, reported in tomorrow's issue of Nature, may shed light on more prevalent forms of the leukemias.

Acute promyelocytic leukemia (APL) is an aggressive form of bone marrow cancer that strikes about 3000 people in the United States each year. The trouble starts when immune cells called leukocytes divide and two of their chromosomes fuse to create a mutant gene. The leukocytes then make a mutant receptor that cannot fully respond to retinoic acid--one signal for a cell to stop dividing. As a result, their growth accelerates and becomes cancerous. In most cases, however, heavy doses of vitamin A--which produces retinoic acid--can slow the cancerous growth. But about 4% of patients do not respond to the therapy.

To find out why, a joint research team from the University of Pennsylvania Medical Center in Philadelphia and the European Institute of Oncology in Milan, Italy, analyzed gene fusion in cell lines of untreatable APL patients. They found that in these patients, the fusion had yielded a different mutant receptor. This receptor, it turned out, has a fatal affinity for a signaling protein called N-CoR that represses cell division. When the researchers added N-CoR to cultured cells with the rarer mutant gene, the receptors bound it so tightly that N-CoR couldn't respond to retinoic acid at all and the cells began to divide out of control. "Now we know the mechanism that causes APL, and we know why in some cases the treatment doesn't help," says team member Iris Zamir.

"It's an intriguing finding," says Thomas Waldmann, chief of the National Cancer Institute's Metabolism Branch in Bethesda, Maryland. While researchers have known for some time that retinoic acid treats leukemia, this research explains why. "It doesn't provide all the molecular details," says Waldmann, "but it's an opening" to uncovering future treatments.

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