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

Research output: Contribution to journalArticle

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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
Externally publishedYes

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TYK2 Kinase
Protein-Tyrosine Kinases
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Myeloproliferative Disorders
Oncogene Proteins
Hematopoiesis
Receptor Protein-Tyrosine Kinases
Hematopoietic Stem Cells
Knockout Mice
Transgenic Mice
Homeostasis
Phosphotransferases
Phosphorylation
Cell Proliferation
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

Niki, M., Di Cristofano, A., Zhao, M., Honda, H., Hirai, H., Van Aelst, L., ... 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

Role of Dok-1 and Dok-2 in leukemia suppression. / Niki, Masaru; Di Cristofano, Antonio; Zhao, Mingming; Honda, Hiroaki; Hirai, Hisamaru; Van Aelst, Linda; Cordon-Cardo, Carlos; Pandolfi, Pier Paolo.

In: Journal of Experimental Medicine, Vol. 200, No. 12, 20.12.2004, p. 1689-1695.

Research output: Contribution to journalArticle

Niki, M, Di Cristofano, A, Zhao, M, Honda, H, Hirai, H, Van Aelst, L, Cordon-Cardo, C & Pandolfi, PP 2004, 'Role of Dok-1 and Dok-2 in leukemia suppression', Journal of Experimental Medicine, vol. 200, no. 12, pp. 1689-1695. https://doi.org/10.1084/jem.20041306
Niki M, Di Cristofano A, Zhao M, Honda H, Hirai H, Van Aelst L et al. Role of Dok-1 and Dok-2 in leukemia suppression. Journal of Experimental Medicine. 2004 Dec 20;200(12):1689-1695. https://doi.org/10.1084/jem.20041306
Niki, Masaru ; Di Cristofano, Antonio ; Zhao, Mingming ; Honda, Hiroaki ; Hirai, Hisamaru ; Van Aelst, Linda ; Cordon-Cardo, Carlos ; Pandolfi, Pier Paolo. / Role of Dok-1 and Dok-2 in leukemia suppression. In: Journal of Experimental Medicine. 2004 ; Vol. 200, No. 12. pp. 1689-1695.
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