DESCRIPTION: (provided by applicant): Interferon alpha (IFNa) has significantclinical activity in the treatment of chronic myelogenous leukemia (CML), butthe mechanisms by which it exhibits its antileukemic effects remain unknown. Wehave identified a novel signaling cascade activated by the Type I IFN receptor,involving the small GTPase Rac1 and the p38 Map kinase. This pathway actsindependently of the Stat-pathway, but in cooperation with it, to regulatetranscriptional regulation of IFNa-sensitive genes. Our data demonstrate thatthis signaling cascade is activated in primary granulocytes from CML patientsand that pharmacological blockade of its activation reverses the growthinhibitory effects of IFNa on primary leukemia bone marrow progenitors. Thisproposal is a systematic approach to identify the signaling mechanisms by whichIFNa exhibits its antileukemic effects. Specific aim A is to determine themechanisms of regulation of activation of the p38 pathway by the Type I IFNreceptor in BCR-ABL expressing cells and to identify downstream effectormechanisms. Studies will be performed to determine the roles of Jak kinases andthe vav proto-oncogene product on the activation of the Rac1/p38 pathway inBCR-ABL expressing cells and to define the role of p38-dependent nuclearhistone serine phosphorylation in the induction of IFNa-responses in CML cells.Specific aim B is to determine the biological consequences of activation ofp38 in CML. It will involve studies to determine whether Rac1 and p38 areessential for the generation of the growth inhibitory effects of IFNa onprimary leukemic progenitors and whether defective activation of this pathwaycorrelates with IFNa-resistance. It will also examine the hypothesis that IFNadownregulates BCR-ABL protein expression via a p38-dependent mechanism.Specific aim C includes studies to identify the mechanisms by which theBCR-ABL-tyrosine kinase antagonizes IFNa-dependent gene transcription anddetermine whether the BCR-ABL specific inhibitor, STI571, augments the growthinhibitory effects of IFNa via regulatory effects on the Rac1/p38 and Jak/Statpathways. Altogether, these studies should provide important information on themechanisms by which signals are transduced by the Type 1 IFN receptor in CMLcells and advance our knowledge on the mechanisms of development of IFNaresistance. Identifying such mechanisms will facilitate the development ofnovel therapeutic approaches to overcome IFNa-resistance and the design of newpharmacologic agents for the treatment of CML.
|Effective start/end date||9/1/02 → 8/31/07|
- National Cancer Institute (5 R01 CA094079-04)
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.