Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia

Tomoharu Yasuda, Masaki Shirakata, Atsushi Iwama, Asuka Ishii, Yasuhiro Ebihara, Mitsujiro Osawa, Kazuho Honda, Hisaaki Shinohara, Katsuko Sudo, Kohichiro Tsuji, Hiromitsu Nakauchi, Yoichiro Iwakura, Hisamaru Hirai, Hideaki Oda, Tadashi Yamamoto, Yuji Yamanashi

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78 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1681-1687
Number of pages7
JournalJournal of Experimental Medicine
Volume200
Issue number12
DOIs
Publication statusPublished - Dec 20 2004

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Yasuda, T., Shirakata, M., Iwama, A., Ishii, A., Ebihara, Y., Osawa, M., Honda, K., Shinohara, H., Sudo, K., Tsuji, K., Nakauchi, H., Iwakura, Y., Hirai, H., Oda, H., Yamamoto, T., & Yamanashi, Y. (2004). Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia. Journal of Experimental Medicine, 200(12), 1681-1687. https://doi.org/10.1084/jem.20041247