Biomedical Research 2, Rm. 708
421 Curie Blvd.
Philadelphia, PA 19104-6160

215-573-5217 office phone
215-573-7617 lab phone
215-573-7049 fax

Signal Transduction in Myeloid Malignancies

My laboratory studies the role of signal transduction "events" in the pathogenesis of acute and chronic myeloid leukemias. There are currently two primary areas of work in the laboratory. One is study of signal transduction by the TEL/PDGFbR fusion protein associated with CMML. TEL/PDGFbR is a tyrosine kinase fusion protein.

Tyrosine kinase fusion proteins are a group of proteins, which are generated as the result of chromosomal translocations, implicated in the development of hematologic malignancies. Constitutive expression of these proteins as a result of the chromosomal translocation leads to constitutive activation of the tyrosine kinase activity and activation of signal transduction pathways that may lead to the development of leukemia. We are interested in understanding the molecular biology of how these proteins lead to transformation. In addition, we have begun studying signal transduction in acute myeloid leukemia. Here are brief descriptions of what we know and available projects.

Signal transduction by TEL/PDGFbR: We have previously shown that TEL/PDGFbR activates STAT5, phosphotidyl-inositol 3 phosphate (PI3 kinase) and Ras. In the case of PI3 kinase, we know that inhibition of PI3 kinase in TEL/PDGFbR transformed cells leads to a cessation of cell growth. This occurs because of a decrease in the activity of the cdk4 kinase which regulates the cell cycle. Current expereiments are aimed at understanding the signal transduction pathways which regulate the interaction between PI3 kinase and cdk4. In the case of Ras and STAT5, we have not yet demonstrated a critical role for these pathways in transformation. Available projects would include studying inhibition of Ras or STAT 5 in transfromed cells and studying the effect of these interventions on cell growth and transfromation.

Signal transduction in AML: Although many fusion proteins have been identified with AML, most of these proteins are transcription factor proteins which probably function to block differentiation. Very little is known about the regulation of cell growth in AML however. There are several technical reasons why this is so and we have been working to resolve these. Patient's cells are now brought back to the lab and studied for their growth in tissue culture conditions. We have shown that several signaling pathways are activated in these cells including STAT5, a MAP kinase known as p38 and possibly PI3 kinase. We want to continue to characterize these signalling pathways. In particular, we are interested in using pharmacologic inhibitors of signaling pathways and expression of dominant negative proteins to study their effects on growth of the AML cells. The eventual goal of this project is to develop reagents for use in the treatment of AML. There are several areas here that are wide open for investigation including investigation of culture techniques both in vitro and using NOD/SCID animals, further development of the technolgy to analyze signaling in primary cells, studies of the effects of inhibiting signaling pathways in various models.