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20 March 1997, Volume 14, Number 11, Pages 1259-1268
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Article
Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias
Ho-keun Yi1,2, Yasuo Fujimura1,2, Momaru Ouchida1, D D K Prasad1, Veena N Rao1,2 and E Shyam P Reddy1,2,a

1Division of Cancer Genetics, Department of Human Genetics, Allegheny University of the Health Sciences, M.S. 481, Broad and Vine Streets, Philadelphia, Pennsylvania 19102

2Department of Microbiology and Immunology, Jefferson Medical College, Kimmel Cancer Institute, 233 South 10th Street, Philadelphia, Pennsylvania 19107-5541, USA

aAuthor for correspondence

Abstract

Two ets family members, namely erg and Fli-1 are fused with two EWS familiy members namely EWS and TLS/FUS as a result of chromosome translocation in human solid tumors and leukemias. EWS-erg and EWS-Fli-1, which are involved in greater than 95% of Ewing family of tumors, were shown to function as transcriptional activators. TLS/FUS-erg, which is involved in human myeloid leukemias also functions as a transcriptional activator. Expression of these fusion proteins (EWS-erg and EWS-Fli-1) are shown to be essential for maintaining the oncogenic and tumorigenic properties of tumor cells. Cancer is thought to be caused not only by uncontrolled cell proliferation but also by deregulation of programmed cell death. Therefore, we have studied the role of normal (Fli-1 and erg) and aberrant fusion proteins (EWS-erg, EWS-Fli-1 and TLS/FUS-erg) in apoptosis. We have found that expression of normal (Fli-1 and erg) and aberrant fusion proteins inhibit the apoptosis of NIH3T3 cells induced by either serum deprivation or by treatment with calcium ionophore. We have also observed similar suppression of apoptosis in Ewing's sarcoma cells expressing EWS-Fli-1 and EWS-erg proteins suggesting that these fusionproteins may be responsible for the decreased ability of these tumor cells to undergo apoptosis. Inhibition of the expression of these aberrant fusion proteins by antisense RNA technique resulted in increased susceptibility to apoptosis leading to the death of tumor cells. Therefore, our results suggest that one can use therapeutic agents which can down regulate the expression of fusion proteins in combination with chemotherapeutic agents as an effective treatment for these human solid tumors and leukemias.

Keywords

Ewing's sarcoma; human myeloid leukemias; EWS- and TLS-fusion proteins; apoptosis; therapy

Received 25 July 1999; revised 13 February 1999; accepted 14 February 1999
20 March 1997, Volume 14, Number 11, Pages 1259-1268
Table of contents    Previous  Abstract  Next   Article  PDF