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¹ Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
² Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
³ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
⁴ Department of Developmental Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
⁵ Department of Hematology & Oncology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan

Address correspondence to Pier Paolo Pandolfi, Cancer Biology and Genetics Program and Dept. of Pathology, Box 110, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-6168; Fax: (212) 717-3102; email: p-pandolfi{at}ski.mskcc.org

Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210^bcr/abl oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210^bcr/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 p62^dok (Dok-1) and p56^dok-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-p210^bcr/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.

Key Words: cell proliferation • apoptosis • knockout • CML leukemogenesis • signal transduction

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