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Fusion tyrosine kinase mediated signalling pathways in the transformation of haematopoietic cells

Leukemia volume 20, pages 572–582 (2006)Cite this article

Abstract

The fusion tyrosine kinases (FTKs) are generated by chromosomal translocations creating bipartite proteins in which the kinase is hyperactivated by an adjoining oligomerization domain. Autophosphorylation of the FTK generates a ‘signalosome’, an ensemble of signalling proteins that transduce signals to downstream pathways. At the earliest stages of oncogenesis, FTKs can mimic mitogenic cytokine signalling pathways involving the GAB-2 adaptor protein and signal transducers and activators of transcription (STAT) factors, generating replicative stress and thereby promoting a mutator phenotype. In parallel, FTKs couple to survival pathways that upregulate prosurvival proteins such as Bcl-xL, so preventing DNA-damage-induced apoptosis. Following transformation, FTKs induce resistance to genotoxic attack by upregulating DNA repair mechanisms such as STAT5-dependent RAD51 transcription. The phenomenon of ‘oncogene addiction’ reflects the continued requirement of an active FTK ‘signalosome’ to mediate survival and mitogenic signals involving the PI 3-kinase and mitogen-activated protein stress-activated protein kinase pathways, and the nuclear factor-kappa B, activator protein 1 and STAT transcription factors. The available data so far suggest that FTKs, with some possible exceptions, induce and maintain the transformed state using similar panoplies of signals, a finding with important therapeutic implications. The FTK signalling field has matured to an exciting phase in which rapid advances are facilitating rational drug design.

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Acknowledgements

We thank the Leukaemia Research Fund, the Leukaemia and Lymphoma Society, and the British Biological Sciences Research Council for their financial support, and also apologise to those authors whose work has not been cited due to space constraints. SDT is supported by funding from the Leukaemia Research Fund (UK) and DRA from the Biotechnology and Biological Sciences Research Council.

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  1. Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Lab Block Level 3, Addenbrooke's Hospital, Cambridge, UK

    S D Turner

  2. Laboratory of Lymphocyte Signalling and Development, Babraham Research Campus, The Babraham Institute, Babraham, Cambridge, UK

    D R Alexander

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Turner, S., Alexander, D. Fusion tyrosine kinase mediated signalling pathways in the transformation of haematopoietic cells. Leukemia 20, 572–582 (2006). https://doi.org/10.1038/sj.leu.2404125

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