INHIBITION OF APOPTOSIS BY NORMAL AND ABERRANT FLI-1 AND ERG PROTEINSINVOLVED IN HUMAN SOLID TUMORS AND LEUKEMIAS

Two ets family members, namely erg and Fli-1 are fused with two EWS fa miliy members namely EWS and TLS/FUS as a result of chromosome translo cation in human solid tumors and leukemias. EWS-erg and EWS-FLi-1, whi ch are involved in greater than 95% of Ewing family of tumors, were sh own to function as transcriptional activators. TLS/FUS-erg, which is i nvolved 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 tumorige nic properties of tumor cells. Cancer is thought to be caused not only by uncontrolled cell proliferation but also by deregulation of progra mmed 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 cell s induced by either serum deprivation or by treatment with calcium ion ophore. We have also observed similar suppression of apoptosis in Ewin g's sarcoma cells expressing EWS-Fli-1 and EWS-erg proteins suggesting that these fusionproteins may be responsible for the decreased abilit y of these tumor cells to undergo apoptosis. Inhibition of the express ion of these aberrant fusion proteins by antisense RNA technique resul ted in increased susceptibility to apoptosis leading to the death of t umor cells. Therefore, our results suggest that one can use therapeuti c 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.