The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published 20 December 2004. doi:10.1084/jem.20041247
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 12, 1681-1687
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Brief Definitive Report

 Role of Dok-1 and Dok-2 in Myeloid Homeostasis and Suppression of Leukemia

Tomoharu Yasuda1, Masaki Shirakata1, Atsushi Iwama2, Asuka Ishii1, Yasuhiro Ebihara3, Mitsujiro Osawa2, Kazuho Honda7, Hisaaki Shinohara1, Katsuko Sudo4, Kohichiro Tsuji3, Hiromitsu Nakauchi2, Yoichiro Iwakura4, Hisamaru Hirai6, Hideaki Oda7, Tadashi Yamamoto5, and Yuji Yamanashi1

1 Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
2 Laboratory of Stem Cell Therapy, Institute of Medical Science
3 Department of Clinical Oncology, Institute of Medical Science
4 Center for Experimental Medicine, Institute of Medical Science
5 Department of Oncology, Institute of Medical Science
6 Department of Cell Therapy and Transplantation Medicine, Faculty of Medicine, University of Tokyo, Tokyo 108-8639, Japan
7 Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan

Address correspondence to Yuji Yamanashi, Dept. of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Phone: 81-3-5803-5814; Fax: 81-3-5803-0241; email: yamanashi.creg{at}mri.tmd.ac.jp

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.

Key Words: hematopoiesis • granulocyte • macrophage • cytokine • bcr-abl

T. Yasuda and M. Shirakata contributed equally to this work.


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