TREATMENT OF BCR/ABL CAUSED LEUKEMIAS WITH FTIs

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DESCRIPTION: The Bcr/Abl oncoprotein causes the development of Ph-chromosome-positive leukemias. Bcr/Abl P210 and P190 share a domain of Abi which encodes a deregulated tyrosine kinase. This activity perturbs a number of downstream signal transduction pathways including that of the small GTPase Ras. Inhibitors of the enzyme farnesyltransferase (FTIs) have been tested as possible therapeutic agents against Ras-associated solid tumors in man. We have generated a transgenic mouse model which clinically mimics Ph-positive acute lymphoblastic leukemia and tested the potential therapeutic properties of an FTI in this model. Our data show that FTIs are surprisingly potent in preventing the emergence of overt leukemia in our mice. We therefore hypothesize that Ffls are effective in the treatment of Bcr/AbI caused leukemias by interfering with specific small CTPases necessary for disease progression. We will explore this by determining which cellular characteristics known to be altered by Bcr/AbI expression including apoptosis, cytokine independence, mitogenesis and adhesion are affected by the FTIs in BaF3 lymphoid cells with regulatable Bcr/Abl expression. It will also be investigated which small GTPases including Ras are activated by Bcr/Abl in cell line and animal models, and which are targeted by treatment with the FTIs. In addition, we will evaluate whether the FTls are effective against terminal-stage disease in the Bcr/AbI P190 transgenic mouse model, whether they can cure P190-caused leukemia/lymphoma in a bone marrow transplant model and whether Bcr/Abl-expressing cells develop resistance to FTIs. By utilizing a compound which apparently acts on downstream targets of Bcr/Abl in vivo, these experiments will provide unique insights into the mechanisms by which Bcr/AbI causes leukemia. These studies will also help pinpoint which pathway(s) are critical in transducing the oncogenic signals of Bcr/Abl, which could provide additional targets for therapeutic intervention. Finally, data will emerge which will be invaluable in the assessment nf Using FTIs in the treatment nf Ph-positive leukemia in man