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Molecular and Cellular Biology, July 2005, p. 6235-6246, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6235-6246.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Oncogenic TLS-ERG Fusion Protein Exerts Different Effects in Hematopoietic Cells and Fibroblasts

Junhui Zou,1 Hitoshi Ichikawa,4 Michael L. Blackburn,3 Hsien-Ming Hu,1 Anna Zielinska-Kwiatkowska,1 Qi Mei,3 Gerald J. Roth,2,3 Howard A. Chansky,1,3 and Liu Yang1,2,3*

Department of Orthopedics,1 Department of Medicine/Hematology, University of Washington, Seattle, Washington 98195,2 Medical Research Service, VA Puget Sound Health Care System, Seattle, Washington 98108,3 Cancer Transcriptome Project, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan4

Received 16 September 2004/ Returned for modification 20 October 2004/ Accepted 1 April 2005

The oncogenic TLS-ERG fusion protein is found in human myeloid leukemia and Ewing's sarcoma as a result of specific chromosomal translocation. To unveil the potential mechanism(s) underlying cellular transformation, we have investigated the effects of TLS-ERG on both gene transcription and RNA splicing. Here we show that the TLS protein forms complexes with RNA polymerase II (Pol II) and the serine-arginine family of splicing factors in vivo. Deletion analysis of TLS-ERG in both mouse L-G myeloid progenitor cells and NIH 3T3 fibroblasts revealed that the RNA Pol II-interacting domain of TLS-ERG resides within the first 173 amino acids. While TLS-ERG repressed expression of the luciferase reporter gene driven by glycoprotein IX promoter in L-G cells but not in NIH 3T3 cells, the fusion protein was able to affect splicing of the E1A reporter in NIH 3T3 cells but not in L-G cells. To identify potential target genes of TLS-ERG, the fusion protein and its mutants were stably expressed in both L-G and NIH 3T3 cells through retroviral transduction. Microarray analysis of RNA samples from these cells showed that TLS-ERG activates two different sets of genes sharing little similarity in the two cell lines. Taken together, these results suggest that the oncogenic TLS-ERG fusion protein transforms hematopoietic cells and fibroblasts via different pathways.

* Corresponding author. Present address: Department of Pathology, University of Arkansas for Medical Sciences, BRCII, Room 641-B2, 4301 W. Markham Street, Little Rock, AR 72205. Phone: (501) 526-5300. Fax: (501) 526-4601. E-mail: lyang{at}uams.edu.

Molecular and Cellular Biology, July 2005, p. 6235-6246, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6235-6246.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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