The Core Apoptotic Pathway Controlling Glucocorticoid-induced Apoptosis in ALL

Dana-Farber Cancer Inst, Boston MA

Investigators

Linked publications & trials

Abstract

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