The t(8;21) is one of the most common chromosomal aberrations in acute myelogenous leukemia (AML) and juxtaposes the AML1 gene on chromosome 21 with the ETO gene on chromosome 8, to generate the AML1/ETO chimeric transcription factor (TF). The goals of this project are to determine the role and mechanism of action of AML1/ETO in the neoplastic transformation of hematopoietic progenitor cells and the importance of AML1/ETO to the specific phenotype of leukemic cells with the t(8;21). To accomplish these goals, I propose to 1) Define the transcriptional effects of AML1/ETO, namely its ability to bind DNA and affect the expression of genes that influence normal hematopoietic cell growth and development, 2) Define the ability of AML1/ETO to transform NIH 3T3 cells, and determine the effect of introducing the AML1/ETO fusion gene, by retroviral gene transfer techniques, on the growth and differentiation of normal hematopoietic progenitors, and 3) Determine the importance of AML1/ETO to the growth and differentiation of a t(8;21) containing myeloid leukemia cell line by inhibiting AML1/ETO protein expression using antisense DNA and RNA strategies. The results of this project will provide insight into the pathogenesis of human leukemia and the feasibility of using fusion TFs as targets for developing molecularly based therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA070388-04
Application #
2895523
Study Section
Cancer Research Manpower and Education Review Committee (CRME)
Program Officer
Myrick, Dorkina C
Project Start
1996-05-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Frank, R C; Sun, X; Berguido, F J et al. (1999) The t(8;21) fusion protein, AML1/ETO, transforms NIH3T3 cells and activates AP-1. Oncogene 18:1701-10