TEL, a member of the ETS family of transcription factors, is frequently involved in aberrations targeting chromosome 12, band 13 in human leukemia. One of these aberrations consists of a recurrent t(12;22), which is found in myeloproliferative disorders and is associated with a poor clinical prognosis. This translocation results in a chimeric gene that encodes a fusion protein, in which the N-terminus of TEL has been replaced by almost the entire sequence of MN 1, a nuclear protein of unknown function. This N-terminal substitution of TEL creates a protein containing MN 1-derived glutamine/proline-rich sequences linked to the ETS DNA-binding moiety of TEL, a configuration carrying the hallmarks of an activated transcription factor. Preliminary studies have shown that MN 1-TEL transforms NIH3T3 cells, which is in agreement with the hypothesis that the fusion protein plays a direct role in leukemogenesis. To understand how the fusion protein alters both MN1 and TEL function, we will first test the influence of functionally different domains of the fusion protein on DNA binding and transcription transactivation, and correlate these with transformation of NIH3T3 cells. Second, we will determine the transforming activity of the MN 1-TEL protein in vivo, using a transgenic mouse model. In addition, we will use overexpression of a dominant negative TEL protein to define the role of TEL in mouse lymphpoiesis. This animal model will also be analyzed to assess whether TEL may function as a tumor suppressor, as suggested by genetic evidence found in children with precursor B-cell acute leukemia. Finally, we will unravel the biologic pathway controlled by MN 1-TEL by identifying genes in NIH3T3 cells and myeloid cells whose altered expression in response to the fusion protein directly contributes to tumorigenesis. Results from these studies will provide a better insight into the role of MN I-TEL in tumorigenesis as well as the normal functions of TEL. Hopefully this basic research will lead to the development of novel approaches for treatment of t( I 2;22) myeloid diseases, thereby improving their poor prognosis.
