Apoptosis sensitivity in chronic lymphocytic leukemia is determined by endogenous endonuclease content and relative expression of BCL-2 and BAX

David J. McConkey, Joya Chandra, Susan Wright, William Plunkett, Timothy J. McDonnell, John C. Reed, Michael Keating

Research output: Contribution to journalArticle

Abstract

Therapeutic agents used in the treatment of chronic lymphocytic leukemia (CLL) are capable of inducing apoptosis in some (but not all) patient isolates. It is not yet clear whether cells that are resistant to one agent will also be resistant to others, and the mechanisms contributing to differential apoptosis sensitivity are not known. Here we report that glucocorticoid hormone and a clinically relevant chemotherapy combination (fludarabine plus mitoxantrone) fail to induce apoptosis in four of 24 CLL patient isolates. Apoptosis resistance was associated with elevated BCL-2 and BAX expression. Interestingly, incubation in vitro led to down-regulation of BCL-2 expression in both apoptosis-sensitive and apoptosis-resistant cells, whereas parallel down-regulation of BAX occurred only in the resistant samples. Evaluation of nuclear endonuclease content indicated that all of the apoptosis-sensitive samples contained appreciable levels of activity, whereas the endonuclease was not detected in the four populations of resistant cells. Our results indicate that nuclear endonuclease activity represents an excellent prognostic indicator of CLL apoptosis sensitivity that may be controlled by differential BCL-2 family polypeptide expression and signals from the in vivo microenvironment.

Original languageEnglish (US)
Pages (from-to)2624-2630
Number of pages7
JournalJournal of Immunology
Volume156
Issue number7
StatePublished - Apr 1 1996
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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