The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans

Carrasco, Daniel R.; Fenton, Tim R.; Sukhdeo, Kumar; Protopopova, Marina; Enos, Miriam; You, M. James; Vizio, Dolores Di; Nogueira, Cristina; Stommel, Jayne M.; Pinkus, Geraldine S.; Fletcher, Christopher D.�M.; Hornick, Jason L.; Cavenee, Webster K.; Furnari, Frank B.; DePinho, Ronald A.

doi:10.1016/j.ccr.2006.07.012

Cited by 13 publications

(20 citation statements)

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“…For example, the majority of mice lacking Pten, Ink4A, and Arf in combination develop both lymphoblastic B-cell lymphomas and HS with virtually the same incidence. 30 Similarly, mice lacking the cell-cycle regulator p21 develop a variety of tumors, including HS and B-cell lymphomas, and also suffered from severe renal failure, 31 unlike TKO mice. The syndrome elicited in mice lacking all the three proteins, Dok-1, Dok-2, and Dok-3, more specifically resembles the disease found in humans and hence may serve as a useful model for the study of HS.…”

Section: Discussionmentioning

confidence: 99%

Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma

Mashima

Honda

Yang

et al. 2010

Laboratory Investigation

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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 À/À Dok-2 À/À Dok-3 À/À 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-1À/À Dok-3 À/À 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-1À/À Dok-3 À/À mice, but only a small proportion of Dok-3 À/À mice and no Dok-1 À/À Dok-2 À/À mice, exhibited abnormal accumulation of macrophages in the lung on necropsy at 8-12 weeks of age. Macrophages derived from Dok-1 À/À Dok-2 À/À Dok-3 À/À mice displayed an exaggerated proliferative response to macrophage colony-stimulating factor (M-CSF) or granulocytemacrophage 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 À/À Dok-2 À/À Dok-3 À/À mice as a useful model for the study of this neoplasia.

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Section: Discussionmentioning

confidence: 99%

Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma

Mashima

Honda

Yang

et al. 2010

Laboratory Investigation

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“…Histology, immunohistochemistry (IHC), and terminal deoxynucleotidyl transferase (TdT) deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) assay were performed as in previous studies. 31 Immunofluorescence was performed on paraffin-embedded tissue with antimouse CD19 antibody and 49,6-diamidino-2-phenylindole (DAPI) nuclear counterstain. Apoptotic cells were detected by using the APO-BrdU TUNEL kit (Invitrogen).…”

Section: Cd19mentioning

confidence: 99%

“…32,33 Flow cytometry using antibody against B220/CD45R and proliferation assay using tritiated thymidine ([ 3 H]dThd) incorporation into DNA were performed as described. 31 For a detailed list of antibodies, see supplemental Methods. Figures display means from 3 independent replicates; P values were calculated by using Welch's t test.…”

Section: Cd19mentioning

confidence: 99%

“…31 For a detailed list of antibodies, see supplemental Methods. Genomic DNA collected via the Puregene kit (Gentra Systems) from lymph nodes (LNs) or lungs was used to analyze the immunoglobulin heavy-chain (IgH) gene and the T-cell receptor (TCR) gene by Southern blotting as described.…”

Section: Western and Southern Blottingmentioning

confidence: 99%

“…Genomic DNA collected via the Puregene kit (Gentra Systems) from lymph nodes (LNs) or lungs was used to analyze the immunoglobulin heavy-chain (IgH) gene and the T-cell receptor (TCR) gene by Southern blotting as described. 31 Gene expression analysis, array comparative genomic hybridization, and whole-exome sequencing Duplicate samples of RNA from CD19…”

Section: Western and Southern Blottingmentioning

confidence: 99%

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