St. Jude unlocks mystery of very aggressiv...( fects in patients with CML--a finding t...),Health

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 A
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Contact: Kelly Perry
media@stjude.org
901-495-3306
St. Jude Children's Research Hospital
19-Apr-2006