Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia.
Dok-1 and Dok-2 are closely related rasGAP-associated docking proteins expressed preferentially in hematopoietic cells. Although they are phosphorylated upon activation of many protein tyrosine kinases (PTKs), including those coupled with cytokine receptors and oncogenic PTKs like Bcr-Abl, their physiological roles are largely unidentified. Here, we generated mice lacking Dok-1 and/or Dok-2, which included the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia. The double-deficient mice displayed medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyperproliferation and hypo-apoptosis upon treatment and deprivation of cytokines, respectively. Consistently, the mutant myeloid cells showed enhanced Erk and Akt activation upon cytokine stimulation. Moreover, loss of Dok-1 and/or Dok-2 induced blastic transformation of chronic phase CML-like disease in mice carrying the bcr-abl gene, a cause of CML. These findings demonstrate that Dok-1 and Dok-2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and suppression of leukemia.
Yasuda
Tomoharu
T
Dept. of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Shirakata
Masaki
M
Iwama
Atsushi
A
Ishii
Asuka
A
Ebihara
Yasuhiro
Y
Osawa
Mitsujiro
M
Honda
Kazuho
K
Shinohara
Hisaaki
H
Sudo
Katsuko
K
Tsuji
Kohichiro
K
Nakauchi
Hiromitsu
H
Iwakura
Yoichiro
Y
Hirai
Hisamaru
H
Oda
Hideaki
H
Yamamoto
Tadashi
T
Yamanashi
Yuji
Y
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D042381:Granulocyte Precursor Cells / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D038042:Myelopoiesis / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3