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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA065797-09
Application #
6624718
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mccarthy, Susan A
Project Start
1994-12-08
Project End
2004-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
9
Fiscal Year
2003
Total Cost
$330,725
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093