Dan Jones, M.D., Ph.D. University of Texas MD Anderson Cancer Center

GENETICS

Proteomic characterization of activation induced TCL1-complexes and their targeting as a therapeutic strategy in CLL

Grant awarded in 2006

Abstract:

This project is a collaboration between MD Anderson Cancer Center and the University of Cologne in Germany and focuses on the role of the leukemia-causing gene TCL1 in CLL. Abnormal activation of the gene TCL1 leads to a T-cell variant of human CLL, produces CLL-like tumors in mice and has been implicated as a cancer gene in the more common human B-cell CLL. We have shown that TCL1 is found at high levels in a genetic subset of CLL patients with poor outcome. Consequently, TCL1 represents a promising therapeutic target for aggressive variants of this leukemia.

The exact function of TCL1 is still not completely understood. We are using a range of analysis techniques to find which proteins TCL1 interacts with and how its presence alters the growth response of CLL cells to external stimulatory factors. In particular, we have shown in CLL cells that TCL1 interacts with and regulates a key cellular protein, called Akt, which controls tumor cell growth and death. We have shown that inhibitors of Akt alter its association with TCL1 and shift TCL1-containing protein complexes to different locations within the tumor cell.

We are utilizing our range of antibodies developed against TCL1 to isolate novel TCL1-interacting proteins and to track changes in TCL1-containing complexes within CLL cells as the tumor grows. The project will use small molecule inhibitors, TCL1 gene silencing, and TCL1 mimetic peptides to test the effects of interfering with TCL1-complex formation / localization as a therapeutic approach in CLL.

Useful Definitions:
TCL1: a human gene that is associated with the development of T-cell and B-cell leukemias and lymphomas
Akt: a cellular protein that functions in growth signaling and prevention of tumor cell death