Seed Grant Profile
Evaluation and Modeling of Redox Regulation of NF-kappaB in Acute Lymphoblastic Leukemia cells: Role in Drug Resistance
There has been increasing interest in the relationship between the NF-kB anti-apoptosis signaling pathway and the generation of reactive oxygen species (ROS) in pediatric acute lymphoblastic leukemia (ALL) post-therapy. Our previous results suggest that ALL cells with high levels of constitutively activated NF-kB have increased resistance to ROS-generating chemotherapeutic agents like doxorubicin. In particular, we have studied two patient-derived ALL cells lines which show differential regulation of NF-kB-activation levels post-treatment with doxorubicin: EU-1 (drug-resistant line) shows high levels of activated NF-kB post-therapy in contrast to EU-3 (drug-sensitive).
We hypothesize that key redox buffering components protect ALL cells from ROS-generating agents by preventing ROS-mediated downregulation of NF-kB. This hypothesis is supported by studies showing increased intracellular glutathione is associated with poor prognosis in pediatric lymphoblastic leukemias. We will evaluate the effect of redox-buffering components on the level of ROS induced by doxorubicin in the two patient-derived cell lines (EU-1 and EU-3). We then will use differences between the cell lines to generate redox-balance computational models of dox-sensitive and dox-insensitive cells. This will permit cell-line specific simulation of redox-conditions and identification of variations in key redox enzyme levels involved in regulating NF-kB activation in the two model cell lines. These results may have clinical significance in elucidating the role of redox-regulatory components in creating resistance to important ROS-generating chemotherapeutic agents used to treat acute lymphoblastic leukemia.
Investigators: Melissa Kemp (GT/Emory, Biomedical Engineering), Harry Findley (Children's Healthcare of Atlanta/Emory, Pediatrics)