St. Jude unlocks mystery of very aggressiv...( rf rapidly developed an aggressive form...),Health

"Intriguingly, tumor cells removed from these resistant mice and treated with imatinib in cell cultures were still very sensitive to this drug," noted Richard T. Williams, M.D., Ph.D., a fellow in Sherr's laboratory and the paper's lead author. "This suggested to us that the failure of imatinib to cure the mice depended on some substance in the animal that stimulated tumor cell replication or survival."

Sherr's team guessed that one such factor might be the B lymphocyte stimulating protein IL-7. Normally produced in the bone marrow, IL-7 further enhanced the proliferation of cultured leukemic cells removed from the mice and made the cells resistant to imatinib's growth inhibitory effects.

IL-7 binds to receptors on the surface of lymphocytes, which triggers the activity of the JAK kinases. The activated JAK kinases then stimulate cell growth through a signaling pathway that operates alongside the one controlled by the Bcr-Abl kinase, Sherr said. Therefore, the St. Jude investigators used a chemical inhibitor of JAK kinases to block the effect of IL-7 on leukemic cells in culture. This treatment restored the ALL cells' sensitivity to imatinib.

"Our study of mice with ALL containing both Bcr-Abl and Arf mutations has provided unexpected insights into how factors in the mice--and potentially in humans--might contribute to imatinib resistance," Williams said. "Although our efforts to block IL-7 were limited to cell cultures, our mouse model provides an inexpensive and efficient way to test newly developed JAK kinase inhibitors and other drugs."

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Contact: Kelly Perry
media@stjude.org
901-495-3306
St. Jude Children's Research Hospital
19-Apr-2006