Researchers Unlock Mystery of Very Aggressive Leukemia

Investigators at St. Jude Children's Research Hospital have used mouse models to determine why some forms of acute lymphoblastic leukemia (ALL) are extremely aggressive and resist 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 facilitated the multiplication of leukemic cells that did not respond to the drug imatinib (Gleevec®). Imatinib is already successfully used to treat chronic myelogenous leukemia (CML), another blood cell cancer caused by the Bcr-Abl mutation.

The St. Jude 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 inhibiting enzymes called JAK kinases restored the cells' imatinib sensitivity.

The study's findings suggest why imatinib may fail to cause remission of ALL in patients with the Bcr-Abl mutation and point to a strategy for overcoming this resistance. A report on this work appears in the April 17 issue of Proceedings of the National Academy of Sciences.

The Bcr-Abl oncogene (a cancer-causing gene) is formed when parts of two chromosomes switch places, leading to fusion of a fragment of the Bcr gene from one chromosome to a portion of the Abl gene from the other. Bcr-Abl encodes a type of enzyme called a tyrosine kinase, which then drives the abnormal, uncontrolled multiplication of leukemic cells.

Other researchers had previously shown that inhibiting the Bcr-Abl kinase with imatinib causes durable remissions of cancer with minimal side effects in patients with CML - a finding that has revolutionized the treatment of this form of leukemia. However, imatinib has proven far less effective in treating ALL patients with the Bcr-Abl mutation, and the basis of drug resistance in this disease is unknown.

The Arf gene normally suppresses the proliferation of cells carrying cancer-causing mutations such as Bcr-Abl, according to 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. Arf acts as a safeguard against the cancer-causing effects of Bcr-Abl, Sherr said. Sherr is senior author of the paper. The Arf gene was discovered at St. Jude in 1995 in the laboratory of Sherr and Martine F. Roussel, Ph.D., a member of the Department of Genetics and Tumor Cell Biology. Roussel is also an author of the current paper.

The St. Jude team 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," Sherr said. "And this advantage might contribute to imatinib resistance in some way."