Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma.
Histiocytic sarcoma (HS), a rare hematological malignancy, is an aggressive neoplasm that responds poorly to therapy. The molecular etiology and pathology of this disease remain unclear, hampering the development of an effective therapy, and there remains a need for more, and more realistic, animal models. HS cells typically show a histiocytic (ie, tissue macrophage-like) morphology and express histiocyte/macrophage markers in the absence of lymphocyte markers. In this study, we report that Dok-1(-/-)Dok-2(-/-)Dok-3(-/-) mice develop HS, but do not exhibit elevated incidence of other types of tumors. These mutant mice showed earlier mortality than wild-type (WT) or the other mutant mice, and this mortality was associated with HS. In total, 17 of 21 tumor-bearing Dok-1(-/-)Dok-2(-/-)Dok-3(-/-) mice necropsied at 25-66 weeks of age showed multiple organ spread, with osteolytic lesions and orthotopic invasion from the bone marrow to skeletal muscle. Tumors from the mice were transplantable. In addition, all Dok-1(-/-)Dok-2(-/-)Dok-3(-/-) mice, but only a small proportion of Dok-3(-/-) mice and no Dok-1(-/-)Dok-2(-/-) mice, exhibited abnormal accumulation of macrophages in the lung on necropsy at 8-12 weeks of age. Macrophages derived from Dok-1(-/-)Dok-2(-/-)Dok-3(-/-) mice displayed an exaggerated proliferative response to macrophage colony-stimulating factor (M-CSF) or granulocyte- macrophage colony-stimulating factor (GM-CSF) compared with WT and mutant controls. Together, these findings indicate that Dok-1, Dok-2, and Dok-3 cooperatively suppress aggressive HS, and commend Dok-1(-/-)Dok-2(-/-)Dok-3(-/-) mice as a useful model for the study of this neoplasia.
Mashima
Ryuichi
R
Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Honda
Kazuho
K
Yang
Yi
Y
Morita
Yohei
Y
Inoue
Akane
A
Arimura
Sumimasa
S
Nishina
Hiroshi
H
Ema
Hideo
H
Nakauchi
Hiromitsu
H
Seed
Brian
B
Oda
Hideaki
H
Yamanashi
Yuji
Y
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D003115:Colony-Stimulating Factors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D054747:Histiocytic Sarcoma / Q000235:genetics* / Q000473:pathology; D008168:Lung / Q000473:pathology*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D013047:Specific Pathogen-Free Organisms
D048868:Adaptor Proteins, Signal Transducing; D003115:Colony-Stimulating Factors; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; C406768:Dok3 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor