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Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia

Oncogene volume 23, pages 2287–2297 (2004)Cite this article

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) is a malignant disease characterized by an accumulation of monoclonal CD5+ mature B cells, with a high percentage of cells arrested in the G0/G1 phase of the cell cycle, and a particular resistance toward apoptosis-inducing agents. Dok1 (downstream of tyrosine kinases) is an abundant Ras-GTPase-activating protein (Ras-GAP)-associated tyrosine kinase substrate, which negatively regulates cell proliferation, downregulates MAP kinase activation and promotes cell migration. The gene encoding Dok1 maps to human chromosome 2p13, a region previously found to be rearranged in B-CLL. We have screened the Dok1 gene for mutations from 46 individuals with B-CLL using heteroduplex analysis. A four-nucleotide GGCC deletion in the coding region was found in the leukemia cells from one patient. This mutation causes a frameshift leading to protein truncation at the carboxyl-terminus, with the acquisition of a novel amino-acid sequence. In contrast to the wild-type Dok1 protein, which has cytoplasmic/membrane localization, the mutant Dok1 is a nuclear protein containing a functional bipartite nuclear localization signal. Whereas overexpression of wild-type Dok1 inhibited PDGF-induced MAP kinase activation, this inhibition was not observed with the mutant Dok1. Furthermore the mutant Dok1 forms heterodimers with Dok1 wild type and the association can be enhanced by Lck-mediated tyrosine-phosphorylation. This is the first example of a Dok1 mutation in B-CLL and the data suggest that Dok1 might play a role in leukemogenesis.

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Acknowledgements

We thank Drs A-M Pendergast, A August, W Eckhart, R Perlmutter, R Kobayashi, and J Cambier for reagents, Mrs S Pauly for EBV transformation assay, Drs H Huang, V Krutovskikh, M Tommasino, S Tavtigian, J Hall, O Serova and G Lenoir for advice and critical reading of the manuscript. We are also grateful to Dr Z-Q Wang for support and comments, Dr J Cheney and Mrs T Perdrix-Thoma for editing and G Mollon for illustrations.

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Authors and Affiliations

  1. International Agency for Research on Cancer, 150 Cours Albert-Thomas, Lyon, 69008, France

    Sanghoon Lee, François Roy, Rosita Accardi, Jocelyne Michelon, Alexandra Viller & Bakary S Sylla

  2. INSERM U 590 and Hospices Civils de Lyon, Lyon, 69008, France

    Carlos M Galmarini, Emeline Cros & Charles Dumontet

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  1. Sanghoon Lee
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Correspondence to Bakary S Sylla.

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Lee, S., Roy, F., Galmarini, C. et al. Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia. Oncogene 23, 2287–2297 (2004). https://doi.org/10.1038/sj.onc.1207385

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