CML found to wield 'death factor' that kills normal blood marrow cells
ANAHEIM - Based on surprising results from animal experiments, researchers at The University of Texas M. D. Anderson Cancer Center have revamped common beliefs about how chronic myeloid leukemia (CML) functions within bone marrow - a discovery they hope may some day lead to additional therapeutic strategies.In a study presented at the annual meeting of the American Association for Cancer Research (AACR), they found that CML does not "crowd out" normal blood cells in the bone marrow, as has long been thought, but actually kills those healthy cells through use of a unique cell "death factor."
Those destructive proteins, known as lipocalin 24p3, work to promote the development of leukemia by giving the cancer room to grow and spread, making it easier to invade the bone marrow and spleen, say the researchers.
Because they also show in this study that blocking the protein with an antibody in mouse cell experiments will restrain the ability of the cell death protein to kill normal bone marrow cells, the researchers suggest that a therapy that could disable 24p3 might prove useful to CML patients when combined with traditional treatment, such as with Gleevec.
"We don't yet have a therapy that can be tested in humans, but our hope is that this work can lead to development of such a one-two punch," says the study's principal investigator, Ralph Arlinghaus, Ph.D., a professor and chair of the Department of Molecular Pathology.
In the least, the research demonstrates that CML is much craftier than had been suspected, he says. Before this study, no one knew that the 24p3 mouse protein (known in humans as neutrophil gelatinase-associated lipocalin, or NGAL) had any involvement in leukemia, Arlinghaus says.
The protein is a normal component of cells and is believed to have a variety of functions. But the "BCR-ABL oncoprotein (encoded by the Philadelphia chromosome, a translocation of genetic material responsible for most CML) appears to hijack 24p3 and change it structurally to become a cell killer," he says.
The secreted proteins appear to destroy bone marrow stem cells responsible for producing red blood cells as well as platelets, but leukemia cells are believed to be resistant to the effects of 24p3, the researchers found. "This provides an understanding of how Philadelphia chromosome-positive cells can overcome and grow effectively in a crowded marrow environment," Arlinghaus says.
"The disease may begin with a single translocation, but with the death factor helping to continuously clear the way, the leukemia cells can take over the entire marrow," he says. "And when you block the protein, leukemia cells have a hard time growing in the marrow. The goal now is to study this active process further in human leukemia cells.
The study, funded by a grant from the National Cancer Institute, will be presented by its first author at AACR by Hui Lin, research investigator in the Department of Molecular Pathology.
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