Interleukin-3 protects Bcr-Abl-transformed hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors

J. F. Dorsey, J. M. Cunnick, R. Lanehart, M. Huang, A. J. Kraker, K. N. Bhalla, R. Jove, J. Wu

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Bcr-Abl tyrosine kinase has been validated as a molecular target for the treatment of chronic myelogenous leukemia (CML). More recently, it has been reported that CML patients could develop resistance to the Bcr-Abl tyrosine kinase inhibitor, imatinib (STI571, Gleevec), pointing to the need for development of additional Bcr-Abl tyrosine kinase inhibitors or other therapeutic strategies. It was also found that a significant proportion of patients who received the Bcr-Abl inhibitor did not achieve complete cytogenetic response. Mechanisms for incomplete cytogenetic response to Bcr-Abl inhibition are not entirely clear. We report here three new pyrido[2,3-d]pyrimidine Bcr-Abl tyrosine kinase inhibitors, PD164199, PD173952, PD173958, that induced apoptosis of Bcr-Abl-dependent hematopoietic cells. An interleukin-3 (IL-3) autocrine loop was observed previously in primitive CD34+/Bcr-Abl+ leukemic cells in CML patients. Using 32Dp210Bcr-Abl and Baf3p210Bcr-Abl cells as models, we tested whether IL-3 might protect Bcr-Abl-transformed, IL-3-responsive cells from apoptosis caused by Bcr-Abl tyrosine kinase inhibition. Results of trypan blue exclusion, fluoroisothiocyanate-valyl-alanyl-aspartyl-[O-methyl] -fluoromethylketone (FITC-VAD-FMK), and Annexin-V/7-amino-actinomycin D (7-AAD) binding assays indicate that IL-3 could protect Bcr-Abl-transformed, IL-3 responsive hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors. This finding raises the possibility that the IL-3 autocrine loop found in primitive CD34+/Bcr-Abl+ cells in CML patients could contribute to the incomplete eradication of Bcr-Abl+ cells by Bcr-Abl inhibition.

Original languageEnglish (US)
Pages (from-to)1589-1595
Number of pages7
JournalLeukemia
Volume16
Issue number9
DOIs
StatePublished - 2002
Externally publishedYes

Keywords

  • Apoptosis
  • Bcr-Abl
  • Interleukin-3
  • Leukemia
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

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