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  • Original Paper
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Progressive changes in the leukemogenic signaling in BCR/ABL-transformed cells

Oncogene volume 19, pages 4117–4124 (2000)Cite this article

Abstract

Our previous study indicated that BCR/ABL SH2 domain and BCR/ABL SH3 domain+SH2 domain complex are required for immediate activation of the phosphatidylinositol-3 kinase PI-3k)→ Akt serine/threonine kinase pathway and of the signal transducer and activator of transcription 5 (STAT5), respectively, in hematopoietic cells. We show here that the defect in activation of PI-3k/Akt by BCR/ABL ΔSH2 mutant (SH2 domain deleted) and of STAT5 by BCR/ABL ΔSH3+ΔSH2 mutant (SH3 and SH2 domains deleted) is not permanent and both Akt and STAT5 could be ‘re-activated’ by in vitro culture. This phenomenon was responsible for increased resistance to apoptosis, growth factor-independent proliferation and leukemogenesis in SCID mice. Incubation of cells with BCR/ABL tyrosine kinase inhibitor STI571 abrogated the ‘re-activation’ of Akt or STAT5 by BCR/ABL SH3+SH2 mutants in some clones, in the others Akt and STAT5 activation became independent on BCR/ABL kinase activity. The immediate upstream activators of Akt and STAT5 such as PI-3k and Jak-2 were also activated. In addition, the common β subunit of IL-3/IL-5/GM-CSF receptor was tyrosine phosphorylated in the clones in which ‘re-activation’ was dependent on the BCR/ABL kinase activity. These results suggested that ‘re-activation’ of Akt and STAT5, in the absence of functional BCR/ABL SH3+SH2 domains, may be achieved by two different mechanisms: (i) BCR/ABL kinase-dependent activation of alternative pathway(s) and (ii) additional genetic changes stimulating Akt and STAT5 independently of BCR/ABL.

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Acknowledgements

This work was supported by the grants from ACS (RPG 98-348-01 LBC) and Elsa U Pardee Foundation. T Skorski is a Scholar of the Leukemia and Lymphoma Society. A Slupianek is a recipient of the Young Investigator Award from the Foundation for Polish Science.

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  1. M Nieborowska-Skorska and A Slupianek: M Nieborowska-Skorska and A Slupianek contributed equally to this work

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  1. Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, 19122, Pennsylvania, PA, USA

    M Nieborowska-Skorska, A Slupianek & T Skorski

  2. Department of Cancer Immunology, University School of Medical Sciences at Great Poland Cancer Centre, Poznan, Poland

    A Slupianek

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Nieborowska-Skorska, M., Slupianek, A. & Skorski, T. Progressive changes in the leukemogenic signaling in BCR/ABL-transformed cells. Oncogene 19, 4117–4124 (2000). https://doi.org/10.1038/sj.onc.1203754

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