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PI3-kinase regulates survival of chronic lymphocytic leukemia B-cells by preventing caspase 8 activation

Janet M D Plate1

  • 1Department of Medicine, Section of Medical Oncology, Rush University Medical Center, Chicago, IL 60612, USA. jplate@rush.edu

Leukemia & Lymphoma
|September 17, 2004
PubMed

Insights

Chronic lymphocytic leukemia (CLL) cell survival is maintained by signaling pathways preventing apoptosis. PI3-kinase inhibition induces caspase-dependent apoptosis, independent of Akt activity, suggesting extrinsic factors regulate CLL cell survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Chronic lymphocytic leukemia (CLL) cell survival relies on specific signaling pathways.
  • Microarray analysis revealed dysregulated gene expression in CLL cells, including cell cycle regulators.
  • Activated Akt (Protein Kinase B) was identified as a key survival kinase in CLL.

Purpose of the Study:

  • To investigate signal transduction pathways supporting CLL cell viability.
  • To determine the role of PI3-kinase/Akt pathway in CLL cell apoptosis.
  • To elucidate mechanisms preventing caspase activation in CLL B-cells.

Main Methods:

  • Microarray cDNA analysis to identify gene expression patterns.
  • Immunoblotting to detect protein translation and activation.
  • Inhibition of PI3-kinase using LY294002.
  • Caspase activity assays and substrate cleavage analysis.
  • Western blotting for phosphorylated Akt and its substrates.

Main Results:

  • PI3-kinase inhibition with LY294002 induced apoptosis in CLL cells.
  • Apoptosis was caspase 8 dependent but independent of Akt activity.
  • Akt phosphorylation and activity remained high despite PI3-kinase inhibition.
  • GSK-3beta and calpain were not responsible for LY294002-induced apoptosis.
  • Caspase activation, PARP cleavage, and DNA fragmentation were observed.

Conclusions:

  • PI3-kinase-mediated protection against caspase activation in CLL B-cells is not solely dependent on the canonical Akt survival pathway.
  • Extrinsic factors activating membrane receptors may maintain CLL leukemic B-cell survival by inhibiting caspase activation in vivo.

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