St. Jude finds factors that accelerate resistance to targeted therapy in lymphoblasti...( Results of a study by investigators ...)

Results of a study by investigators at St. Jude Childrens Research Hospital provide strong evidence for why the targeted therapy drug, imatinib, or Gleevec, which has revolutionized the treatment of chronic myelogenous leukemia, (CML) is often unable to prevent relapse of a particularly aggressive form of acute lymphoblastic leukemia (ALL). Targeted therapy drugs are designed to block the activity of a specific molecule, a strategy aimed at making treatments more effective and less toxic.

The findings may shed new light on why a small percentage of children with ALL do not benefit from treatment, while more than 90 percent of children treated with the latest therapies survive. The discovery could also help researchers better understand both the origins of this form of aggressive ALL as well as why it becomes resistant to imatinib; and this knowledge may lead to more effective treatments for patients who are not helped by current therapies.

CML and an aggressive form of ALL share the same critical mutationthe Philadelphia chromosome (Ph). Cells that have this mutation (Ph+ cells) produce a rogue growth-promoting enzyme called BCR-ABL. Now, work by a team headed by Charles J. Sherr, M.D., Ph.D., a Howard Hughes Medical Institute investigator and co-chair of the St. Jude Department of Genetics and Tumor Cell Biology, has shown that these two forms of leukemia part company in a crucial respect.

Many Ph+ ALL cells lack a tumor-suppressor gene called Arf, which is normally present in CML cells at the time the disease is first diagnosed, said Sherr. Stripped of the anti-tumor effects of Arf and nurtured by growth factors produced in the bone marrow, these ALL cells become less responsive to imatinib and more difficult to eliminate. Sherr reasons that the cells survival advantage increases their opportunity to develop mutations in the BCR-ABL protein, which prompt imatinib resistance.

A report on these results appears in the Septe
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