Most cases of pediatric T cell acute lymphoblastic leukemia (T-ALL) involve tumor-specific activation of TAL-1/SCL. TAL-1, a basic helix-loop-helix (bHLH) protein expressed in hematopoietic progenitors and erythroid cells, binds DNA once bound to E proteins (e.g., E12, E47, HEB), critical bHLH transcription factors, which regulate lymphoid development. Stable tal-1/E47 or HEB heterodimers are detected in human and mouse leukemic cells, suggesting that tal-1 contributes to leukemia by interfering with E protein function(s). Consistent with this idea, E2A-deficient mice develop T cell leukemia/lymphoma, and mice expressing a DNA binding mutant of tal-1 develop disease. The TAL-1E/2A transformation pathway is implicated in human T-ALL involving the LIM-only genes LMO1/LM02, recently found activated in gene therapy-induced T-ALL. The overall goal of this research program is to define the mechanism(s) of leukemogenesis by tall/ scl using the mouse as a model system. Our preliminary studies of tal-1/E2A+l- and taI-1/HEB+I- mice provide genetic evidence that tal-1 transforms by interfering with E47/HEB. How tal-1/scl inhibits E47/HEB transcriptional activity and whether novel taI-1/E47/LMO2 target genes contribute to disease are objectives of the work proposed (Aim 1). An additional goal is to examine the immediate and direct effects of tal-1 expression on thymocyte differentiation, apoptosis, and gene expression, using a conditional tal-1 transgenic model (Aim 2). Using retroviral insertional mutagenesis, we identified activated notch 1, dominant negative ikaros, and myc as cooperating genes in tal l1-induced leukemia. A final objective is to determine how activated notch 1, dominant negative ikaros, and myc contribute to tal-1 leukemogenesis and whether tal-1 tumors remain dependent on the continuous expression of these secondary mutations (Aim 3)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096899-02
Application #
6925472
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mufson, R Allan
Project Start
2004-08-01
Project End
2009-05-31
Budget Start
2005-08-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$332,186
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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