Functional studies of the ETS protein TEL

The human TEL gene is rearranged in several chromosomal translocations that cause a variety of human leukemias. In each case the region of the gene that encodes the PNT domain is retained in the oncogenic fusion protein. These leukemias include >20% of pediatric acute lymphoblastic leukemia (pre-B cell ALL). This disease is caused by the translocation t(12;21) that creates the fusion gene product TEL-AML1. An understanding of the progression from the initial translocation to leukemia requires additional mechanistic insight into the biochemistry of this chimeric, oncogenic protein. The PNT domain of TEL is proposed to function in oligomerization. This oligomerization is implicated in the oncogenic properties of TEL. We are investigating how the oligomerization state affects the DNA binding activity of TEL. We plan to extend this work to the oncogenic fusion protein TEL-AML1. Several lines of evidence suggest that wild-type TEL and TEL-AML1 function act as transcriptional repressors and that this repression function maps to the PNT domain. We are searching for the co-repressors that function with TEL and how their binding interfaces with oligomerization.