Key Points

• The glucocorticoid receptor coordinately regulates the antiapoptotic BCL2 and proapoptotic BIM genes in pediatric ALL cells in vivo. • GR binding at a novel intronic region is associated with BIM transcription and dexamethasone sensitivity in pediatric ALL cells in vivo. Glucocorticoids are critical components of combination chemotherapy regimens in pediatricacute lymphoblastic leukemia (ALL). TheproapoptoticBIMprotein is an important mediator of glucocorticoid-induced apoptosis in normal and malignant lymphocytes, whereas theantiapoptoticBCL2confers resistance. Thesignalingpathways regulatingBIM andBCL2expression inglucocorticoid-treated lymphoidcells remainunclear. In thisstudy, pediatric ALL patient-derived xenografts (PDXs) inherently sensitive or resistant to glucocorticoids were exposed to dexamethasone in vivo. Microarray analysis showed thatKLF13andMYBgeneexpressionchangesweresignificantlygreater indexamethasone-sensitive than-resistant PDXs. Chromatin immunoprecipitation (ChIP) analysis detected glucocorticoid receptor (GR) binding at the KLF13 promoter to trigger KLF13 expression only in sensitive PDXs. Next, KLF13 bound to the MYB promoter, deactivating MYB ex-pression only in sensitive PDXs. Sustained MYB expression in resistant PDXs resulted in maintenance of BCL2 expression and inhibition of apoptosis. ChIP sequencing analysis revealed a novel GR binding site in a BIM intronic region (IGR) that was engaged only in dexamethasone-sensitive PDXs. The absence of GR binding at the BIM IGR was associated with BIM silencing and dexamethasone resistance. This study has identified novel mechanisms of opposingBCL2 and BIM gene regulation that control glucocorticoid-induced apoptosis in pediatric ALL cells in vivo. (Blood. 2015;125(2):273-283