PLZF/ZBTB16, a glucocorticoid response gene in acute lymphoblastic leukemia, interferes with glucocorticoid-induced apoptosis
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- 作者：Muhammad Wasim ; Michela Carlet ; Muhammad Mansha ; Richard Greil ; Christian Ploner ; Alex ; er Trockenbacher ; Johannes Rainer ; Reinhard Kofler
- 关键词：Acute lymphoblastic leukemia ; CCRF-CEM cell line ; Exon array-based expression profiling ; Functional gene analysis ; Glucocorticoid-induced apoptosis ; PLZF/ZBTB16
- 刊名：The Journal of Steroid Biochemistry and Molecular Biology
- 出版年：2010
- 出版时间：June 2010
- 年：2010
- 卷：120
- 期：4-5
- 页码：218-227
- 全文大小：1037 K
文摘
Glucocorticoids (GCs) cause cell cycle arrest and apoptosis in lymphoid cells which is exploited to treat lymphoid malignancies. The mechanisms of these anti-leukemic GC effects are, however, poorly understood. We previously defined a list of GC-regulated genes by expression profiling in children with acute lymphoblastic leukemia (ALL) during systemic GC monotherapy and in experimental systems of GC-induced apoptosis. PLZF/ZBTB16, a transcriptional repressor, was one of the most promising candidates derived from this screen. To investigate its role in the anti-leukemic GC effects, we performed overexpression and knock-down experiments in CCRF-CEM childhood ALL cells. Transgenic PLZF/ZBTB16 alone had no detectable effect on cell proliferation or survival, but reduced sensitivity to GC-induced apoptosis but not apoptosis induced by antibodies against Fas/CD95 or 3 different chemotherapeutics. Knock-down of ZBTB16 entailed a small, but significant, increase in cell death induction by GC. Affymetrix Exon array-based whole genome expression profiling revealed that PLZF/ZBTB16 induction did not significantly alter the expression profile, however, it interfered with the regulation of numerous GC response genes, including BCL2L11/Bim, which has previously been shown to be responsible for cell death induction in CCRF-CEM cells. Thus, the protective effect of PLZF/ZBTB16 can be attributed to interference with transcriptional regulation by GC.