Previous studies from our lab identified a distinct gene expression signature associated with MLL-rearranged ALL (MLL), and identified FLT3 as a potential therapeutic target in this disease and ALL destined for relapse. These findings have prompted a broader assessment of pathways that influence drug resistance in MLL and ALL. As glucocorticoid resistance is associated with a poor prognosis, and has been shown to be regulated by components of the apoptotic pathway, we propose to study the mechanisms of glucocorticoid sensitivity and resistance in normal lymphocytes, MLL and ALL. We will interrogate gene expression signatures associated with glucocorticoid sensitivity and resistance in MLL and ALL. Initial experiments suggest that members of the apoptotic pathway, particularly MCL-1, are differentially expressed between blasts that are either sensitive or resistant to glucocorticoids in vitro. We will now compare these signatures to those from leukemias that are either sensitive or resistant to glucocorticoid treatment in vivo. As glucocorticoids are potent modulators of gene expression, we will analyze gene expression changes that occur in sensitive and resistant ALL samples after glucocorticoid treatment and compare these signatures to those obtained from lymphocytes isolated from BAX/BAK double knock-out mice that eliminate any secondary signatures as they possess a complete block to the intrinsic pathway of cell death. These studies should pinpoint, a gene expression signature for glucocorticoid-induced apoptosis. We will characterize the role of anti-apoptotic MCL-1 in glucocorticoid-induced apoptosis, drug resistance and leukemogenesis;and we will characterize the pro-apoptotic BCL-2 family members BAX and BAK, and especially """"""""BH3-only"""""""" members including BIM that participate in glucocorticoid and drug-induced apoptosis pathways. The recognition of the differences in apoptotic pathways between the glucocorticoid sensitive and resistant populations holds the promise of identifying targets for drug resistant leukemia.
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