SWI/SNF Complex and Glucocorticoid Resistance in Pediatric Acute Lymphoblastic Leukemia

Steroids are a highly effective component of therapy for acute lymphoblastic leukemia (ALL).  However, patients whose leukemia does not respond to steroid therapy have high risk for relapse and poor prognosis.  New understanding of and therapies for steroid resistance are critical to progress in ALL therapy.  Cells respond to steroids via the glucocorticoid receptor (GR), which binds DNA and cooperates with the SWI/SNF complex to modify gene expression.  The SWI/SNF complex modulates packaging of DNA, thereby controlling access of other proteins necessary for gene expression.  Subunits of the SWI/SNF complex are newly-recognized as tumor suppressors, mutated or deleted in a variety of cancers.  How the SWI/SNF complex regulates gene activity in healthy cells and cancer is just beginning to be understood. Clinical studies show that steroid resistance in pediatric ALL correlates with decreased levels of SWI/SNF subunits, including SNF5.  Experimentally decreasing SNF5 expression in leukemia cell lines causes steroid resistance.  Together, these studies suggest alterations of the SWI/SNF complex may play a central role in steroid resistant pediatric ALL.  We propose to study how GR and SWI/SNF cooperate to control DNA packaging and gene expression, in order to better understand mechanisms by which diminished SWI/SNF subunit expression causes steroid resistance. Using a combination of cutting-edge, genome-wide sequencing technologies and traditional approaches, we will discover targets for potentially novel therapies of steroid-resistant, poor-prognosis pediatric ALL.