Chronic lymphocytic leukemic cells exhibit apoptotic signaling via TRAIL-R1

M. MacFarlane, S. Inoue, S. L. Kohlhaas, A. Majid, N. Harper, D. B.J. Kennedy, M. J.S. Dyer, G. M. Cohen

Research output: Contribution to journalArticlepeer-review


Clinical trials have been initiated with Apo2L/TRAIL (Genentech) and agonistic mAbs to TRAIL receptors, -R1 and -R2 (Human Genome Sciences). The apoptosis-inducing ability of these mAbs and different TRAIL preparations, in the presence or absence of histone deacetylase inhibitors (HDACi), varied markedly against primary chronic lymphocytic leukaemia (CLL) cells and various tumor cell lines, demonstrating an unanticipated preferential apoptotic signaling via either TRAIL-R1 or -R2. Contrary to literature reports that TRAIL-induced apoptosis occurs primarily via signaling through TRAIL-R2, CLL cells, in the presence of HDACi, undergo predominantly TRAIL-R1-mediated apoptosis. Consequently, Apo2L/TRAIL, which signals primarily through TRAIL-R2, is virtually devoid of activity against CLL cells. To maximize therapeutic benefit, it is essential to ascertain whether a primary tumor signals via TRAIL-R1/-R2, prior to initiating therapy. Thus combination of an agonistic TRAIL-R1 Ab and an HDACi, such as the anticonvulsant sodium valproate, could be of value in treating CLL.

Original languageEnglish
Pages (from-to)773-782
Number of pages10
JournalCell Death and Differentiation
Issue number7
Publication statusPublished - 2005 Jul
Externally publishedYes


  • Chronic lymphocytic leukaemia
  • Histone deacetylase inhibitors
  • TRAIL-R1
  • Tumor necrosis factor-apoptosis inducing ligand

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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