Selective induction of apoptosis in Philadelphia chromosome-positive chronic myelogenous leukemia cells by an inhibitor of BCR–ABL tyrosine kinase, CGP 57148 (original) (raw)

Cell Death & Differentiation volume 5, pages 710–715 (1998) Cite this article

Abstract

The BCR–ABL tyrosine kinase has been implicated as the cause of Philadelphia chromosome (Ph1)-positive leukemias. We report herein that CGP 57148, a selective inhibitor of the ABL tyrosine kinase, caused apoptosis specifically in **bcr–abl**-positive chronic myelogenous leukemia (CML) cells, K562 and KYO-1. Upon treatment with CGP 57148, CRKL, a specific substrate for BCR–ABL that propagates signals via phosphatidylinositol-3′ kinase (PI3K), was dephosphorylated, indicating inhibition of BCR–ABL tyrosine kinase at the cellular level. Likewise, MAPK/ERK, a downstream mediator of Ras, was also dephosphorylated. Caspase activation and cleavage of retinoblastoma protein (pRB) accompanied the development of CGP 57148-induced apoptosis. Inhibition of caspase suppressed apoptosis and the cleavage of pRB, and in turn arrested cells in the G1 phase. These results indicate that CGP 57148 shows apoptogenic and anti-proliferative effects on **bcr–abl**-positive cells by blocking BCR–ABL-initiated signaling pathways.

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Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo
    Shingo Dan, Mikihiko Naito & Takashi Tsuruo
  2. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
    Takashi Tsuruo

Authors

  1. Shingo Dan
  2. Mikihiko Naito
  3. Takashi Tsuruo

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Correspondence toTakashi Tsuruo.

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Edited by: Y. Kuchino

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Dan, S., Naito, M. & Tsuruo, T. Selective induction of apoptosis in Philadelphia chromosome-positive chronic myelogenous leukemia cells by an inhibitor of BCR–ABL tyrosine kinase, CGP 57148.Cell Death Differ 5, 710–715 (1998). https://doi.org/10.1038/sj.cdd.4400400

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