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Molecular and Cellular Biology, April 2008, p. 2125-2137, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.00740-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inducible Expression of Chimeric EWS/ETS Proteins Confers Ewing's Family Tumor-Like Phenotypes to Human Mesenchymal Progenitor Cells{triangledown} ,{dagger}

Yoshitaka Miyagawa,1 Hajime Okita,1* Hideki Nakaijima,1 Yasuomi Horiuchi,1 Ban Sato,1 Tomoko Taguchi,1 Masashi Toyoda,3 Yohko U. Katagiri,1 Junichiro Fujimoto,2 Jun-ichi Hata,1 Akihiro Umezawa,3 and Nobutaka Kiyokawa1

Department of Developmental Biology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan,1 National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan,2 Department of Reproductive Biology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan3

Received 27 April 2007/ Returned for modification 13 July 2007/ Accepted 7 January 2008

Ewing's family tumor (EFT) is a rare pediatric tumor of unclear origin that occurs in bone and soft tissue. Specific chromosomal translocations found in EFT cause EWS to fuse to a subset of ets transcription factor genes (ETS), generating chimeric EWS/ETS proteins. These proteins are believed to play a crucial role in the onset and progression of EFT. However, the mechanisms responsible for the EWS/ETS-mediated onset remain unclear. Here we report the establishment of a tetracycline-controlled EWS/ETS-inducible system in human bone marrow-derived mesenchymal progenitor cells (MPCs). Ectopic expression of both EWS/FLI1 and EWS/ERG proteins resulted in a dramatic change of morphology, i.e., from a mesenchymal spindle shape to a small round-to-polygonal cell, one of the characteristics of EFT. EWS/ETS also induced immunophenotypic changes in MPCs, including the disappearance of the mesenchyme-positive markers CD10 and CD13 and the up-regulation of the EFT-positive markers CD54, CD99, CD117, and CD271. Furthermore, a prominent shift from the gene expression profile of MPCs to that of EFT was observed in the presence of EWS/ETS. Together with the observation that EWS/ETS enhances the ability of cells to invade Matrigel, these results suggest that EWS/ETS proteins contribute to alterations of cellular features and confer an EFT-like phenotype to human MPCs.

* Corresponding author. Mailing address: Department of Developmental Biology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan. Phone: 81-3-3416-0181. Fax: 81-3-3417-2496. E-mail: okita{at}nch.go.jp

{triangledown} Published ahead of print on 22 January 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2008, p. 2125-2137, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.00740-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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