title: Role of Dok-1 and Dok-2 in leukemia suppression.
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 p210bcr/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-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 Dok-2 in tumor suppression and control of the hematopoietic compartment homeostasis.
authors.affiliation: Cancer Biology and Genetics Program and Dept. of Pathology, Box 110, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA.
authors.forename: Masaru
authors.initials: M
authors.lastname: Niki
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Cristofano
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.forename: Hisamaru
authors.initials: H
authors.lastname: Hirai
authors.forename: Linda
authors.initials: L
authors.lastname: Van Aelst
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020729:p120 GTPase Activating Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D020729:p120 GTPase Activating Protein; D016044:Fusion Proteins, bcr-abl; D019950:Mitogen-Activated Protein Kinase 1