Interferon alpha (IFNa) has significant clinical activity in the treatment of chronic myelogenous leukemia (CML), but the mechanisms by which it exhibits its antileukemic effects remain unknown. We have identified a novel signaling cascade activated by the Type I IFN receptor, involving the small GTPase Rac1 and the p38 Map kinase. This pathway acts independently of the Stat-pathway, but in cooperation with it, to regulate transcriptional regulation of IFNa-sensitive genes. Our data demonstrate that this signaling cascade is activated in primary granulocytes from CML patients and that pharmacological blockade of its activation reverses the growth inhibitory effects of IFNa on primary leukemia bone marrow progenitors. This proposal is a systematic approach to identify the signaling mechanisms by which IFNa exhibits its antileukemic effects.
Specific aim A is to determine the mechanisms of regulation of activation of the p38 pathway by the Type I IFN receptor in BCR-ABL expressing cells and to identify downstream effector mechanisms. Studies will be performed to determine the roles of Jak kinases and the vav proto-oncogene product on the activation of the Rac1/p38 pathway in BCR-ABL expressing cells and to define the role of p38-dependent nuclear histone serine phosphorylation in the induction of IFNa-responses in CML cells.
Specific aim B is to determine the biological consequences of activation of p38 in CML. It will involve studies to determine whether Rac1 and p38 are essential for the generation of the growth inhibitory effects of IFNa on primary leukemic progenitors and whether defective activation of this pathway correlates with IFNa-resistance. It will also examine the hypothesis that IFNa downregulates BCR-ABL protein expression via a p38-dependent mechanism.
Specific aim C includes studies to identify the mechanisms by which the BCR-ABL-tyrosine kinase antagonizes IFNa-dependent gene transcription and determine whether the BCR-ABL specific inhibitor, STI571, augments the growth inhibitory effects of IFNa via regulatory effects on the Rac1/p38 and Jak/Stat pathways. Altogether, these studies should provide important information on the mechanisms by which signals are transduced by the Type 1 IFN receptor in CML cells and advance our knowledge on the mechanisms of development of IFNa resistance. Identifying such mechanisms will facilitate the development of novel therapeutic approaches to overcome IFNa-resistance and the design of new pharmacologic agents for the treatment of CML.
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