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 proposal is focused on pbx-1, a recently identified DNA binding protein that contains a homeobox. 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 transforation of human pre-B cells. We propose in this research application to understand the mechanism by which E2A/pbx-1 promotes the aberrant growth of human pre-B cells. We have recently found that pbx binds DNA either as a homo- or as a heterodimer with homeobox proteins. We propose to continue these studies. First, we will determine the ability of pbx proteins to regulate gene expression in lymphoid cells. Next we propose to map the pbx domains and residues important for regulation of critical pbx target genes in lymphoid cells. We propose to characterize pbx proteins in normal and transformed B lymphocytes, in particular in cells derived from patients with pre-B All. The oncogenic potential of both wild-type and mutant-pbx proteins will be tested using transformation assays. To determine how E2A/pbx promotes lymphoid malignancies we will test the ability of wild-type and mutant E2A/pbx molecules 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.
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