Niki, M., Di Cristofano, A., Zhao, M. M., Hirai, H., Van Aelst, L., Cordon-Cardo, C., Pandolfi, P. P. (November 2004) Critical role of Dok-1 and Dok-2 in leukemia suppression. Blood, 104 (11). 807A-807A. ISSN 0006-4971
Abstract
Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein which shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. While 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 p210bcr/abl as well as receptor and non-receptor tyrosine kinases. Here we report the generation and characterization of single and double Dok-2 or Dok-1/Dok-2 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 leukemia due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210bcr/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 2 in tumor suppression and control of the hematopoietic compartment homeostasis.
| Item Type: | Paper |
|---|---|
| Additional Information: | Meeting Abstract |
| Subjects: | diseases & disorders > cancer diseases & disorders > cancer > cancer types > leukemia |
| CSHL Authors: | |
| Communities: | CSHL labs > Van Aelst lab |
| Depositing User: | Matt Covey |
| Date: | November 2004 |
| Date Deposited: | 18 Dec 2013 21:56 |
| Last Modified: | 18 Dec 2013 21:56 |
| URI: | https://repository.cshl.edu/id/eprint/29095 |
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