Chronic myelomonocytic leukemia (CMML) is a form of myelodysplastic syndrome that is characterized by clonal proliferation of myeloid cells and frequent progression to acute leukemia. A recurring cytogenetic abnormality in CMML is the t(5;12)(q33;pl3) chromosomal translocation, and the resulting gene rearrangement fuses the 5'- region of TEL to the gene encoding the protein-tyrosine kinase domain of the platelet-derived growth factor receptor. The Ba/F3 murine hematopoietic cell line can be transformed to IL3 factor independence by expression of the TEL/PDGFbetaR fusion, and this assay has provided a useful system for the study of TEL/PDGFbetaR signal transduction. The following proposal is founded on the hypothesis that diseases of myeloid proliferation are caused by alterations in common signaling pathways. The first specific aim of this proposal is to characterize signaling events that contribute to transformation of hematopoietic cells by TEL/PDGFbetaR. A panel of TEL/PDGFbetaR variants that contain one or more mutations at phosphotyrosine interaction sites will be used to identify those potential signaling intermediates that are necessary for hematopoietic transformation. After identification of phosphotyrosine residues in TEL/PDGFbetaR that are necessary for transformation of Ba/F3 cells, the requirement of such downstream signal transducers as PI 3-kinase, phospholipase C-gamma, the SHP-2 tyrosine phosphatase, the STAT transcriptional regulators, Ras, and the Akt/PKB kinase will be evaluated for their role in transformation of Ba/F3 cells by TEL/PDGFbetaR. The second specific aim is to identity signaling events that contribute to leukemogenesis in the murine transplantation model of TEL/PDGFbetaR transformation. Transplantation of murine bone marrow cells that are transformed with TEL/PDGFbetaR into syngeneic mice causes a disease that resembles CMML. TEL/PDGFbetaR variants that are selective in activation of distinct signaling pathways will be used in the mouse transplantation model to confirm the relevance of these signaling intermediates in CMML. The third specific aim is to identity common signaling pathways that are engaged by TEL/tyrosine kinase fusion proteins. The information gained from this research will deepen the understanding of CMML pathogenesis and will serve to identify rational targets for therapeutic intervention. The candidate's career goals and research career development plan are detailed in Section II of this proposal.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA082261-02
Application #
6173599
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$139,320
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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