Four steps to lymphoma.

Four steps to lymphoma

Working with genetically engineered mice, Charles, L. Sidman of the Jackson Laboratory in Bar Harbor has discovered four specific steps in the development of B-cell lymphoma -- a cancer of the immune system -- that occur in mice after activation of a cancer-triggering gene, or oncogene. And in a flip of the usual pattern of finding animal models that mimic human diseases, Sidman has identified a human condition that appears to mimic the mouse malignancy and has joined with physicians to investigate it. "Guided by what we've been learning in the mouse, we're trying to study successive changes in humans that mirror this [mouse] disease," he says.

Sidman uses a strain of transgenic mice that always develop B-lymphocyte tumors. His studies reveal that the mice first experience a proliferation of B-cells, and then the proliferation goes away. In step three, the proliferation returns. In step four, the B-cells transform from normal cells to cancerous ones.

But sometimes step four can precede step three. "That's a striking observation," Sidman says. "The early concept was that cells proliferated wildly and that's the cancer. But we can get cells that can create a cancer [in other mice] before the return of proliferation. The return of proliferation may not be synonymous with the ability of cells to cause a cancerous tumor."

These findings suggest new point where physicians might one day intervene to prevent cancer. Sidman suggests the four-step process applies to human leukemias and lymphomas and may apply to all cancers. He is now trying to decipher the biological mechanisms that regulate the various steps in mice.

Some people develop a condition called benign monoclonal gammopathy, marked by a proliferation of a specific set of B-cells. Each year, about 6 percent of these people go on to develop malignant myeloma, which will strike about 11,600 people in the United States this year. Sidman and a research team at the Maine Cytometry Research Institute in Portland plan to test and follow the B-lymphocyte changes in several dozen patients with benign monoclonal gammopathy. "This gives us a situation in which to explore the events and genes that make a difference," he says.