Ets-1 Messenger RNA Expression Is a Novel Marker of Poor Survival in Ovarian Carcinoma

Oncogenicity potential was a defining characteristic of v-ets, the first of the large family of ETS transcription factors to be cloned. v-ets was discovered as an oncoprotein fusion with gag and myb in the E26 avian erythroblastosis virus (1). There are now more than 25 ETS family members defined by a DNA binding or ETS domain, which is highly conserved among family members, and binds to the core DNA binding motif C/A GCA A/T. In addition, a subset of ETS family members have a highly conserved PNT domain that, at least in some contexts, acts an as oligomerization motif (2). ETS family members play an important role in mammalian development. For example, targeted disruption of the Fli-1 gene results in hemorrhage from the dorsal aorta to the lumen of the neural tube and brain ventricles on embryonic day 11.0 (E11.0; Ref. 3). Deficiency of Ets2 causes day E8.5 embryonic lethality, with defects in extraembryonic tissue gene expression and function and failure of ectoplacental cone proliferation (4). Loss of function of ETV6/TEL causes E9.5 embryonic lethality with severe defects in yolk sac angiogenesis and apoptosis of neural crest-derived ganglia (5). In addition, ETS family members play important roles in hematopoietic development. Disruption of Ets-1 causes defects in natural killer cell development (6), loss of function of PU.1 causes defects in myelopoiesis as well as B-lymphopoiesis (7–9), and loss of ETV6/TEL causes inability for the transition of definitive hematopoietic cells from the liver to the bone marrow (10). In addition to playing an important role in mammalian development, ETS family members have been directly implicated in the pathogenesis of a spectrum of human cancers; ETS involvement in human malignancy is notable for pleiotropic structural and functional contributions to the contributions to the malignant phenotype (Fig. 1). For example, there is a spectrum of cancers that include soft tissue sarcomas and leukemias in which balanced reciprocal translocations result in fusion proteins that contain the ETS DNA binding domain. Examples include the EWS-FLI1 and EWS-ERG (11) fusion associated with Ewing’s sarcoma and the TLS/ERG (12) and ETV6/MN1 (13) fusion associated with human leukemia. In addition, there is a broad spectrum of hematological malignancies in which the PNT oligomerization motif is involved in chromosomal translocations with a diverse group of partners that include transcription factors, tyrosine kinases, and genes of unknown function. For example, the ETS translocation variant 6 (also known as TEL) gene is known to be involved in . 40 different translocations in human hematological malignancies. In most of these cases, balanced reciprocal chromosomal translocations result in expression of a fusion protein in which the PNT domain is fused in-frame to the respective partners. Examples of TEL fusions to tyrosine kinases include TEL/PDGFbR (14, 15), TEL/TRKc (16–19), TEL/ABL (20–22), and TEL/JAK2 (23–26), among others. TEL may also be fused to transcription factor partners such as AML1 (27–31), EVI1 (32), and others. In these examples, there is strong epidemiological support for a direct role in transformation of cells. Although these diseases are rare, with an incidence of approximately 1 per 100,000 individuals/year, the chromosomal translocations are highly conserved and in most cases result in expression of identical in-frame fusions. In addition, in some cases it has been possible to demonstrate that the ETS fusion protein is both necessary and sufficient for disease pathogenesis. For example, the TEL/PDGF bR, TEL/TRKc, TEL/ABL, and TEL/JAK2 fusion proteins are each capable of causing myeloproliferative disease in murine bone marrow transplant models of leukemia. These observations have prompted further analysis of downstream targets that may contribute to malignant transformation of cells. For example, TEL/ JAK2 and other TEL tyrosine kinase fusion molecules activated STAT5, a member of the STAT family of latent cytoplasmic transcription factors. In the case of TEL/JAK2, activation of STAT5 is both necessary and sufficient to transform hematopoietic cells. STAT5, in turn, is known to transactivate a number of genes that regulate cellular proliferation and survival, such as oncostatin M, Bcl-Xl, cyclin D1, andPim1 (26). Thus, direct or indirect transcriptional targets of the ETS fusion proteins contributes directly to the transformed phenotype of the cells. Loss of function of ETS family members may also contribute to the pathogenesis of human cancers. For example, in TEL/AML1 leukemias, there is nearly invariable deletion of the residualTEL allele (27–31, 33, 34). Thus, as a consequence of translocation and deletion, there is no functional TEL present in leukemic cells, suggesting that TEL may have tumor suppressor function. Recently, Muelleret al. (35) have reported the presence of mutations in PU.1 associated with human leukemias, indicating that the loss of function of PU.1 may also contribute to the pathogenesis of disease. In the current report, Davidson et al. (see this issue, pp. 551–557) have provided new and important clinical therapeutic 1 To whom requests for reprints should be addressed, at Howard Hughes Medical Institute, Brigham and Women’s Hospital, Harvard Institute of Medicine, Harvard Medical School, 4 Blackfan Circle, Room 418, Boston, MA 02115. 2 The abbreviations used are: TEL, translocation ETS leukemia; PDGFbR, platelet-derived growth factor b receptor. 451 Vol. 7, 451–453, March 2001 Clinical Cancer Research