ANAHEIM, CALIFORNIA--Chronic myeloid leukemia (CML) cells invade the bone marrow and spleen by destroying healthy cells with a toxic protein, according to a new study. The findings challenge the long-held theory that leukemia cells simply outperform healthy cells by living longer and suggest that targeting this “death factor” may be a viable way of combating the disease.
CML is caused by the activity of BCR-ABL, an oncogene formed by a swapping of genetic material between chromosomes 9 and 22, in white blood cells. People in an acute stage of the disease often develop severe anemia, because the leukemia cells, which live almost ten times as long as their normal counterparts, replace healthy cells in the bone marrow. When Ralph Arlinghaus, a molecular biologist at the University of Texas MD Anderson Cancer Center in Houston, learned that growth factor–starved healthy cells release a protein called 24p3 that causes them to die, he wondered if leukemia cells also use the molecule to kill off their competition.
To test the theory, Arlinghaus and colleagues first demonstrated that BCR-ABL positive cells expressed 24p3 and secreted it into the surrounding tissue, causing cell death. Then, the team created an antisense 24p3 inhibitor and delivered it into leukemia cells. When the researchers injected untreated leukemia cells into mice, nearly 70% of the animal's bone marrow and spleen cells were found to be cancerous after 16 to 18 days. Mice injected with the blocker-treated leukemia cells, however, only exhibited cancer in 2% of their bone marrow cells. Instead, the leukemia cells in these mice invaded the liver and abdomen.
"The antisense changed the course of the disease from leukemia to a lymphoma," says Arlinghaus, who presented his findings here this week at a meeting of the American Association for Cancer Research.
The study nicely demonstrates how leukemia cells create space for themselves in the bone marrow by inducing cell death, says Michael Kharas, a molecular biology graduate student at the University of California, Irvine. And, even though the 24p3 inhibitor increased the proportion of healthy cells in the bone marrow, it did not decrease the leukemia cells overall, according to Kharas. While this limits the clinical implications of using a 24p3 inhibitor as a sole treatment for leukemia, adding it to a cancer drug such as Gleevec might prove effective, he says.