Investigators at St. Jude have used mouse models to determine why some forms of acute lymphoblastic leukemia (ALL) are very aggressive and resistant to a drug that is effective in treating a different type of leukemia.

The investigators found that the combination of a mutation called Bcr-Abl and the loss of both copies of the tumor suppressor gene Arf in bone marrow cells triggers an aggressive form of ALL. Inactivation of both Arf genes allowed the multiplication of leukemic cells that did not respond to the drug imatinib (Gleevec(R)). Imatinib is already successfully used to treat chronic myelogenous leukemia (CML), another blood cell cancer caused by the Bcr-Abl mutation.

The St. Jude team also found that Arf is not inactivated in CML patients who respond to imatinib. This is in contrast to ALL, in which Arf loss frequently occurs and imatinib treatment is far less effective. "This suggested to us that inactivation of Arf in ALL cells expressing the Bcr-Abl enzyme gives these cells a strong proliferative (cell multiplication) advantage. This advantage might contribute to imatinib resistance in some way," said Charles 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. Sherr is senior author of a report on this work that appears in the April 17 issue of the Proceedings of the National Academy of Sciences.

The Arf gene was discovered at St. Jude in 1995 in the laboratory of Sherr and Martine Roussel, Ph.D., a member of the Department of Genetics and Tumor Cell Biology. Roussel is a co-author of the paper.

Moreover, the study provided evidence that imatinib resistance in mouse models of ALL did not depend strictly on the presence of Bcr-Abl and the loss of Arf genes in the cancer cells themselves. Rather, drug resistance reflected an interaction of the tumor cells with specific growth-promoting factors produced in the mice. After removal of leukemic cells from mice that had failed imatinib therapy, compounds that inhibited enzymes called JAK kinases restored the cells' sensitivity to imatinib.

The findings of this study are important because they suggest why imatinib may fail to cause remission of ALL in patients with the Bcr-Abl mutation, and they point to a strategy for overcoming this resistance, according to the researchers. "Although our efforts to block JAK enzymes were limited to cell cultures, our mouse model provides an inexpensive and efficient way to test newly developed JAK kinase inhibitors and other drugs," said Richard Williams, M.D., PhD, a research fellow in Sherr's laboratory and the lead author of the paper.

This work was supported in part by the Howard Hughes Medical Institute, a National Institutes of Health Cancer Center Core Grant and ALSAC.

About: 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 fund-raising organization.