St. Jude discovers factors that accelerate resistance to Gleevec targeted therapy in lymphoblastic leukemia

Results of a study by investigators at St. Jude Children's Research Hospital provide strong evidence for why the drug imatinib (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).

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 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 mutation -- the 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 Department, 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 September 15 issue of "Genes & Development."

"The findings also imply that doctors might identify patients at high risk of failing this treatment by determining whether their leukemia cells lack the Arf gene," said Richard T. Williams, M.D., Ph.D., an assistant member in the St. Jude Department of Oncology and the paper's first author.

This study strongly suggests that a widely held explanation for how leukemias arise is not universally applicable. "This view holds that leukemias arise from rare 'cancer stem cells,' which do not make up the bulk of the tumor, but are the only cells required to regenerate the cancer after treatment," Williams said. "However the new St. Jude study reveals that the combination of BCR-ABL activity and inactivation of Arf are sufficient to generate a uniform population of leukemia-initiating cells -- any one of which can expand and induce rapidly fatal disease."

The other author of the paper was Willem den Besten (St. Jude).

This was supported by funding from Howard Hughes Medical Institute, a Cancer Center Core Grant and ALSAC.

St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization.

http://www.stjude.org