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


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