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PLZF/ZBTB16, a glucocorticoid response gene in acute lymphoblastic leukemia, interferes with glucocorticoid-induced

Muhammad Wasim1, Michela Carlet, Muhammad Mansha

  • 1Division Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.

The Journal of Steroid Biochemistry and Molecular Biology
|May 4, 2010
PubMed

Insights

Glucocorticoids (GCs) induce apoptosis in lymphoid cells, but mechanisms are unclear. PLZF/ZBTB16, a transcriptional repressor, protects against GC-induced apoptosis by interfering with GC gene regulation, including Bim.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Immunology

Background:

  • Glucocorticoids (GCs) are crucial for treating lymphoid malignancies by inducing apoptosis in lymphoid cells.
  • The precise molecular mechanisms underlying GC-induced apoptosis in leukemia remain incompletely understood.
  • Previous expression profiling identified PLZF/ZBTB16 as a GC-regulated gene potentially involved in GC resistance.

Purpose of the Study:

  • To investigate the role of the transcriptional repressor PLZF/ZBTB16 in the anti-leukemic effects of GCs.
  • To elucidate how PLZF/ZBTB16 influences GC-induced apoptosis in acute lymphoblastic leukemia (ALL) cells.

Main Methods:

  • Overexpression and knock-down experiments of PLZF/ZBTB16 in CCRF-CEM childhood ALL cells.
  • Assessment of cell proliferation, survival, and apoptosis induction by GCs, Fas/CD95 antibodies, and chemotherapeutics.
  • Whole genome expression profiling using Affymetrix Exon arrays to analyze gene expression changes.

Main Results:

  • Overexpression of PLZF/ZBTB16 reduced sensitivity to GC-induced apoptosis but not to other apoptotic stimuli.
  • Knock-down of ZBTB16 significantly increased GC-induced cell death.
  • PLZF/ZBTB16 interfered with the regulation of GC response genes, notably BCL2L11/Bim, without altering the overall expression profile.

Conclusions:

  • PLZF/ZBTB16 plays a protective role against GC-induced apoptosis in lymphoid cells.
  • The protective effect is mediated by interference with GC-driven transcriptional regulation, specifically impacting key apoptosis-related genes like Bim.
  • Understanding PLZF/ZBTB16's function offers insights into GC resistance mechanisms in lymphoid malignancies.

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