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Spotlight on IMATINIB as a Model for Signal Transduction Inhibitors

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

Leukemia volume 16, pages 1589–1595 (2002)Cite this article

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-Abland Baf3p210Bcr-Abl cells as models, we tested whether IL-3 might protect Bcr-Abltransformed, 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.

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Authors and Affiliations

  1. Molecular Oncology and Experimental Therapeutics Programs, H Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, FL, USA

    JF Dorsey, JM Cunnick, R Lanehart, M Huang, KN Bhalla, R Jove & J Wu

  2. Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, FL, USA

    JF Dorsey, JM Cunnick, R Lanehart, M Huang, KN Bhalla, R Jove & J Wu

  3. Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa, FL, USA

    JF Dorsey & J Wu

  4. Cancer Pharmacology, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, MI, USA

    AJ Kraker

  5. Department of Biochemistry and Molecular Biology, University of South Florida College of Medicine, Tampa, FL, USA

    R Jove

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Dorsey, J., Cunnick, J., Lanehart, R. et al. Interleukin-3 protects Bcr-Abl-transformed hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors. Leukemia 16, 1589–1595 (2002). https://doi.org/10.1038/sj.leu.2402678

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