Enzyme That Slows Colon Cancer Found to Promote Lethal Form of Leukemia

Cancer researchers have found that the enzyme glycogen synthase kinase 3 (GSK3), a multifunctional serine/threonine kinase that participates in numerous signaling pathways, promotes the growth of a lethal form of leukemia.

Previous studies on colon cancer had shown that GSK3 slowed tumor growth, so investigators at Stanford University (Palo Alto, CA, USA) were surprised when their data showed that the enzyme stimulated the growth of mixed-lineage leukemia (MLL). MLL cells display markers for both lymph nodes and bone marrow and are especially resistant to classical chemotherapy.

The investigators reported in the September 17, 2008, issue of the journal Nature that GSK3 supported MLL leukemia cell proliferation and transformation by a mechanism that ultimately involved destabilization of the cyclin-dependent kinase inhibitor p27Kip1.
Inhibition of GSK3 in a mouse model of MLL leukemia provided promising evidence of effectiveness and earmarked GSK3 as a candidate cancer-drug target. "This finding was quite unexpected," said senior author Dr. Michael Cleary, professor of pathology and of pediatrics at Stanford University. "GSK3 has never been implicated in promoting cancer."

"Newly diagnosed leukemia patients have their cancer cells tested to see which genes are driving the cancer. Mutated MLL genes are viewed as a bad prognostic marker," said Dr. Cleary. "There is intense interest in coming up with better ways to treat these patients. Most current cancer drugs target both the normal and the aberrant cells. It would be a big advantage in cancer treatment if a drug were developed that could selectively kill cancer but help healthy cells grow. Of course, the danger with GSK3 inhibitors would be that they might also cause other cancers if given long-term. There will be a lot of hard work required to get better anti-GSK3 compounds, test them in preclinical models, and translate them to human trials."

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