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Chronic lymphocytic leukemic cells exhibit apoptotic signaling via TRAIL-R1

M MacFarlane1, S Inoue, S L Kohlhaas

  • 1MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester, UK.

Cell Death and Differentiation
|April 30, 2005
PubMed

Insights

Histone deacetylase inhibitors (HDACi) shift apoptosis signaling in chronic lymphocytic leukemia (CLL) cells from TRAIL-R2 to TRAIL-R1. This finding suggests combining TRAIL-R1 agonistic antibodies with HDACi may improve CLL treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R1, TRAIL-R2) are targets for cancer therapy.
  • Histone deacetylase inhibitors (HDACi) can modulate apoptosis signaling pathways.

Purpose of the Study:

  • To investigate the differential apoptotic signaling of TRAIL and agonistic antibodies targeting TRAIL-R1 and TRAIL-R2 in chronic lymphocytic leukemia (CLL) cells.
  • To determine the effect of HDAC inhibitors on TRAIL-mediated apoptosis in CLL cells.

Main Methods:

  • Treatment of primary CLL cells and tumor cell lines with Apo2L/TRAIL and agonistic monoclonal antibodies (mAbs) against TRAIL-R1 and TRAIL-R2.
  • Assessment of apoptosis induction in the presence or absence of HDAC inhibitors (HDACi).

Main Results:

  • Apoptosis induction varied significantly between TRAIL preparations, mAbs, and cell types.
  • Contrary to existing literature, CLL cells treated with HDACi showed predominantly TRAIL-R1-mediated apoptosis.
  • Apo2L/TRAIL, which signals mainly through TRAIL-R2, demonstrated minimal activity against CLL cells, especially when combined with HDACi.

Conclusions:

  • The choice of TRAIL-R1 or TRAIL-R2 as the primary signaling pathway is crucial for therapeutic efficacy in CLL.
  • Combining agonistic TRAIL-R1 antibodies with HDAC inhibitors, like sodium valproate, may represent a promising therapeutic strategy for CLL.

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