Role of Dok-1 and Dok-2 in leukemia suppression

Masaru Niki, Antonio Di Cristofano, Mingming Zhao, Hiroaki Honda, Hisamaru Hirai, Linda Van Aelst, Carlos Cordon-Cardo, Pier Paolo Pandolfi

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70 Scopus citations

Abstract

Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210bcr/abl substrates have been identified, their relevance in the pathogenesis of the disease is unclear. We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. Members of this family such as p62dok (Dok-1) and p56dok-2 (Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210 bcr/abl as well as receptor and nonreceptor tyrosine kinases. Here, we report the generation and characterization of single and double Dok-1 or Dok-2 knockout (KO) mutants. Single KO mice displayed normal steady-state hematopoiesis. By contrast, concomitant Dok-1 and Dok-2 inactivation resulted in aberrant hemopoiesis and Ras/MAP kinase activation. Strikingly, all Dok-1/Dok-2 double KO mutants spontaneously developed transplantable CML-like myeloproliferative disease due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p21bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML. These findings unravel the critical and unexpected role of Dok-1 and Dok-2 in tumor suppression and control of the hematopoietic compartment homeostasis.

Original languageEnglish (US)
Pages (from-to)1689-1695
Number of pages7
JournalJournal of Experimental Medicine
Volume200
Issue number12
DOIs
StatePublished - Dec 20 2004

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Keywords

  • Apoptosis
  • CML leukemogenesis
  • Cell proliferation
  • Knockout
  • Signal transduction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Niki, M., Di Cristofano, A., Zhao, M., Honda, H., Hirai, H., Van Aelst, L., Cordon-Cardo, C., & Pandolfi, P. P. (2004). Role of Dok-1 and Dok-2 in leukemia suppression. Journal of Experimental Medicine, 200(12), 1689-1695. https://doi.org/10.1084/jem.20041306