Opposing regulation of BIM and BCL2 controls glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells

D Jing, VA Bhadri, D Beck, JAI Thoms… - Blood, The Journal …, 2015 - ashpublications.org
D Jing, VA Bhadri, D Beck, JAI Thoms, NA Yakob, JWH Wong, K Knezevic, JE Pimanda
Blood, The Journal of the American Society of Hematology, 2015ashpublications.org
Glucocorticoids are critical components of combination chemotherapy regimens in pediatric
acute lymphoblastic leukemia (ALL). The proapoptotic BIM protein is an important mediator
of glucocorticoid-induced apoptosis in normal and malignant lymphocytes, whereas the
antiapoptotic BCL2 confers resistance. The signaling pathways regulating BIM and BCL2
expression in glucocorticoid-treated lymphoid cells remain unclear. In this study, pediatric
ALL patient-derived xenografts (PDXs) inherently sensitive or resistant to glucocorticoids …
Abstract
Glucocorticoids are critical components of combination chemotherapy regimens in pediatric acute lymphoblastic leukemia (ALL). The proapoptotic BIM protein is an important mediator of glucocorticoid-induced apoptosis in normal and malignant lymphocytes, whereas the antiapoptotic BCL2 confers resistance. The signaling pathways regulating BIM and BCL2 expression in glucocorticoid-treated lymphoid cells remain unclear. In this study, pediatric ALL patient-derived xenografts (PDXs) inherently sensitive or resistant to glucocorticoids were exposed to dexamethasone in vivo. Microarray analysis showed that KLF13 and MYB gene expression changes were significantly greater in dexamethasone-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 expression 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 opposing BCL2 and BIM gene regulation that control glucocorticoid-induced apoptosis in pediatric ALL cells in vivo.
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