title: Opposing regulation of BIM and BCL2 controls glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells.
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.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, and the.
authors.forename: Duohui
authors.initials: D
authors.lastname: Jing
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, and the.
authors.forename: Vivek A
authors.initials: VA
authors.lastname: Bhadri
authors.affiliation: Lowy Cancer Research Centre, and the Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; and.
authors.forename: Dominik
authors.initials: D
authors.lastname: Beck
authors.affiliation: Lowy Cancer Research Centre, and the Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; and.
authors.forename: Julie A I
authors.initials: JA
authors.lastname: Thoms
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, and the.
authors.forename: Nurul A
authors.initials: NA
authors.lastname: Yakob
authors.affiliation: Lowy Cancer Research Centre, and the Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; and.
authors.forename: Jason W H
authors.initials: JW
authors.lastname: Wong
authors.affiliation: Lowy Cancer Research Centre, and the Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; and.
authors.forename: Kathy
authors.initials: K
authors.lastname: Knezevic
authors.affiliation: Lowy Cancer Research Centre, and the Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; and Department of Haematology, Prince of Wales Hospital, Sydney, Australia.
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, and the.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone