Although large series of genes have been identified that are translocated in human leukemic cells, the mechanism how they are involved in the promotion of leukemias is poorly understood. The objective of this propose is focused on a class of homeodomain proteins, designated as TALE proteins. The TALE proteins include Pbx, Meis and Prep-1. The gene encoding pbx-1 is consistently rearranged in pediatric pre-B acute lymphoblastoid leukemia (ALL) due to a t (1;19) chromosomal translocation Specifically, in pre-B ALL, the pbx-1 N-terminal domain has been replaced with a transactivation domain derived from E2A, normally a helix-loop-helix protein. The consistent presence of a translocated pbx gene in pre-B ALL makes it likely that the E2A/pbx fusion protein contributes to the malignant transformation of human pre- B cells. We have recently identified a down-stream target gene of E2A/Pbx-1 encoding a growth factor, designated Wnt-16. We propose in this research application to understand the mechanism by which E2A/pbx-1 promotes the aberrant growth of human pre-B cells and how Wnt-16 contributes to the development of the leukemia. First, we would characterize Pbx and Prep-1 in normal. We would examine how Wnt-16 is regulated by E2A/Pbx-1. The oncogenic potential of Wnt-16 would be tested in cell lines employing dominant-negative LEF and Wnt-gene products. To determine how Wnt-16 promotes lymphoid malignancies we would test the ability of Wnt-16 to induce leukemias in mice. These studies should provide important information of how pbx molecules contribute to childhood leukemias and may suggest new avenues for the treatment of pre-B cell ALL.
| McWhirter, J R; Neuteboom, S T; Wancewicz, E V et al. (1999) Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia. Proc Natl Acad Sci U S A 96:11464-9 |
| Li, X; Murre, C; McGinnis, W (1999) Activity regulation of a Hox protein and a role for the homeodomain in inhibiting transcriptional activation. EMBO J 18:198-211 |
