St. Jude unlocks mystery of very aggressive leukemiaInvestigators 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."
To investigate this hypothesis, the researchers used a virus-like piece of DNA to carry the Bcr-Abl oncogene into bone marrow-derived lymphocytes obtained from mice that either retained Arf or were previously engineered to lack this gene. These pre-B lymphocytes represent one type of white blood cell that can become cancerous and cause ALL.
The researchers then transplanted these "transformed" cells carrying Bcr-Abl back into normal mice. Animals that received transformed pre-B cells that had both copies of the Arf gene intact were highly resistant to disease development. However, mice injected with cells that carried Bcr-Abl and lacked Arf rapidly developed an aggressive form of ALL that could not be cured with high doses of imatinib.
"Intriguingly, tumor cells removed from these resistant mice and treated with imatinib in cell cultures were still very sensitive to this drug," noted Richard T. Williams, M.D., Ph.D., a fellow in Sherr's laboratory and the paper's lead author. "This suggested to us that the failure of imatinib to cure the mice depended on some substance in the animal that stimulated tumor cell replication or survival."
Sherr's team guessed that one such factor might be the B lymphocyte stimulating protein IL-7. Normally produced in the bone marrow, IL-7 further enhanced the proliferation of cultured leukemic cells removed from the mice and made the cells resistant to imatinib's growth inhibitory effects.
IL-7 binds to receptors on the surface of lymphocytes, which triggers the activity of the JAK kinases. The activated JAK kinases then stimulate cell growth through a signaling pathway that operates alongside the one controlled by the Bcr-Abl kinase, Sherr said. Therefore, the St. Jude investigators used a chemical inhibitor of JAK kinases to block the effect of IL-7 on leukemic cells in culture. This treatment restored the ALL cells' sensitivity to imatinib.
"Our study of mice with ALL containing both Bcr-Abl and Arf mutations has provided unexpected insights into how factors in the mice--and potentially in humans--might contribute to imatinib resistance," Williams said. "Although our efforts to block IL-7 were limited to cell cultures, our mouse model provides an inexpensive and efficient way to test newly developed JAK kinase inhibitors and other drugs."
This work was supported in part by the Howard Hughes Medical Institute, a National Institutes of Health Cancer Center Core Grant and ALSAC.
St. Jude Children's Research Hospital
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. For more information, please visit www.stjude.org.
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