Researchers in Japan, Bar Harbor find 25 potential leukemia targets
|Date: February 10, 2010||
Bar Harbor, Maine -- Researchers in Japan, in collaboration with Jackson Laboratory Professor Leonard Shultz, Ph.D., have figured out how to identify molecules that are present in leukemia stem cells but not in normal blood stem cells. The 25 molecules thus discovered are each a potential target for treating acute myeloid leukemia (AML).
The discovery may help scientists develop effective treatments for rare leukemia stem cells, which are not only resistant to chemotherapy but thought to be responsible for high rates of often fatal relapse. In the introduction to their study, published in Science Translational Medicine, the researchers note, "Despite advances in cancer therapeutics and supportive care, long-term outcomes of patients with AML remain dismal. Even after complete remission in which the whole-body leukemia burden is reduced to nearly undetectable values, most patients eventually succumb to disease relapse."
In the study, Fumihiko Ishikawa of the RIKEN Research Center for Allergy and Immunology and colleagues set out to isolate molecules that are present in leukemia stem cells--a tricky endeavor because leukemia stem cells share many similarities with normal blood stem cells.
The researchers purified both leukemia and blood stem cells from patients and healthy individuals. Using microarray gene chips, they compared all the genes expressed in the leukemia stem cells to those expressed in the normal blood stem cells. They found 25 molecules that are highly expressed in leukemia stem cells but not in blood stem cells, indicating that these molecules can serve as unique markers to pinpoint the cancer stem cells that may be the root cause of AML relapse.
An important part of the discovery process was transplanting the isolated leukemia stem cells into special, immunodeficient mice developed by Dr. Shultz, "to show that the cells that grow up are all leukemia cells," he says. "Most of the primary AML tumors grew in the mice, which had never before been demonstrated."
The researchers then found that two of the 25 molecules stood out as the most promising drug targets to prevent relapse--these molecules were found in the leukemia stem cells of over half of the 61 patients screened. Two other features of these particular molecules highlight their potential as good targets for therapy: they are barnacle-like, remaining stuck to leukemia stem cells even after treatment with a common chemotherapy drug, and their inhibition does not interfere with normal blood cell development.
Dr. Shultz also notes that several of the targets are antibodies already used in treatments for other diseases, and so have already been approved by the FDA for safety.
The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a facility in Sacramento, Calif. Its mission is to discover the genetic basis for preventing, treating and curing human diseases, and to enable research and education for the global biomedical community.
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Saito et al.: Identification of Therapeutic Targets for Quiescent, Chemotherapy-Resistant Human Leukemia Stem Cells. Science Translational Medicine, Volume 2, Issue 17, 17ra9, published online Feb. 3, 2010.
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