Lack of adhesion molecule key to tumor cell homing in leukemia
| Date: July 20, 2004 | 
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Bar Harbor, Maine--Scientists at The Jackson Laboratory discovered a property of leukemia cells that may lead to a new way to treat one form of the cancer.
It appears that leukemia cells lack a molecule that helps maturing white blood cells attach to bone marrow. Without the adhesion molecule, the immature cells enter the blood stream too soon and accumulate in organs, leading to hemorrhaging.
The gene BCR-ABL1 causes chronic myelogeneous leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). Previous research indicated that immature blood cells expressing the BCR/ABL gene exhibited altered adhesion properties. However, no studies in a live organism had shown whether the altered adhesion properties affect the progression of the two forms of leukemia.
A research team headed by Shaoguang Li, M.D., Ph.D., deactivated the genes responsible for production of two adhesion molecules and found that one form of leukemia progresses at a much faster rate in mice without the adhesion molecules. The research has been pre-published online by the journal Blood.
The team employed the new mouse models of both forms of BCR-ABL1-induced leukemia that Dr. Li had developed. By testing mice lacking two adhesion molecules-P-selectin and intercellular adhesion molecule-1 (ICAM1)-the scientists showed that the deficient mice develop BCR/ABL-induced CML at a significantly faster rate than do mice with the normal adhesion molecules. They found no significant effect on the development of B-cell acute lymphoblstic leukemia (B-ALL).
CML, which accounts for almost 20 percent of all adult leukemia cases, is one of four diseases characterized by a proliferation of immature white blood cells, which can accumulate in organs and cause damages. Using mice deficient for P-selectin or ICAM1 alone, they found that it is P-selectin that plays a major role in the acceleration of CML-like leukemia. Lack of P-selectin resulted in early release of immature white blood cells from bone marrow.
"P-selectin appears to alter the biological properties of leukemic cells rather than affect their growth rate," explained Dr. Li. According to the oncologist-turned-researcher: "This suggests that improving the adhesion between the immature BCR/ABL-expressing cells and bone marrow stroma may be of therapeutic value for human CML."
In 2001, the Swiss-based pharmaceutical company Novartis developed Gleevec, the first kinase inhibitor used to fight cancer by blocking the errant kinase enzyme. It proved effective against chronic phase of CML, but not the advanced phase. In some patients, it seems, CML can develop a resistance to Gleevec.
In the May 2004 issue of the journal Nature Genetics, Dr. Li's team announced that they had identified another kinase inhibitor that blocks B-cell acute lymphoblastic leukemia (B-ALL) and that, when combined with Gleevec, may provide more effective treatment in later phases of CML.
"Studying the effects of adhesion-restoring drugs including interferons and tryrphostins can help reveal the mechanisms through which they restore adhesive properties," suggested Dr. Li. " It will be interesting to investigate whether Gleevec can improve adhesion of the cells to the bone marrow, and how using combinations of the drugs affects the progression of the disease," he concluded.
With more than 1,300 employees and an FY05 operating budget of $130.1 million, the 75-year-old Jackson Laboratory is one of Maine's largest employers. Its research staff of more than 350 investigates the genetic basis of cancers, heart disease, osteoporosis, Alzheimer's disease, glaucoma, diabetes and many other human diseases and disorders. The Laboratory is also home of the Mouse Genome Database and many other publicly available information resources, and is also an international hub for scientific courses, conferences, training and education-including programs for Maine high school, college and graduate students.
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Lack of the adhesion molecules P-selectin and Intercellular adhesion molecule-1 accelerates the development of BCR/ABL-induced chronic myeloid leukemia-like myeloproliferative disease in mice. Blood, June 2004. Shawn D Pelletier, Daniel S Hong, Yiguo Hu, Yuhua Liu, and Shaoguang Li*
Contact(s): Joyce Peterson, joyce@jax.org, 207-288-6058
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