TEL (ETV6) is a frequent target of chromosomal translocations in hematopoietic malignancies and some solid tumors. The recurrent t(1 2;22), which is associated with myeloproliferative disorders and acute myeloid leukemia, results in the creation of the MN 1-TEL fusion gene in which the sequence encoding the N-terminal region of the transcription factor TEL is replaced by almost the entire coding sequence of the transcriptional coactivator MN1. MN1-TEL can transform fibroblasts, and recent findings suggest that this fusion protein increases the proliferation rate of primitive hematopoietic progenitors in vitro. However, transplantation of mouse bone marrow cells transduced with an MN1-TEL--containing retrovirus into lethally irradiated recipients does not result in overt hematologic abnormalities or leukemia. This result suggests that secondary genetic lesions must cooperate with MN1-TEL to transform primitive hematopoietic progenitors. Therefore, retroviral rnutagenesis of MN1-TEL--expressing boneS marrow cells will be performed to identify those genetic lesions that cooperate with MN 1-TEL in the induction of leukemia (Specific Aim 1). Earlier work has identified a novel TEL homolog, TEL2, which is primarily expressed in human fetal liver and bone marrow cells. TEL2 has extensive sequence homology with TEL; although both proteins form oligomers via their pointed domains and repress transcription through the same DNA recognition sequence, they have distinct biological activities. Notably, overexpression of TEL2 stimulates the proliferation of murine hematopoietic progenitors in vitro. Because genetic evidence suggests that TEL acts as tumor suppressor, experiments will test the hypothesis that the loss of TEL results in an altered ratio of TEL:TEL2 to TEL2:TEL2 oligomers and that this alteration directly results in increased proliferation of affected cells (Specific Aim 2). Together the results of the proposed studies should provide insight into the pathways involved in MN1-TEL-associated leukemia and TEL's mechanism of tumor suppression. The murine models generated in these studies should be valuable tools in the development of new therapies for t(1 2;22)-associated myeloid diseases.
