TEL is a gene frequently involved in specific chromosomal translocations in human leukemia and sarcoma that encodes a member of the ETS family of transcriptional regulators. TEL is unusual among other ETS proteins by its ability to self-associate in vivo, a property that is essential to the oncogenic activation of TEL-derived fusion proteins. We show here that TEL is a sequence-specific transcriptional repressor of ETS-binding site-driven transcription of model and natural promoters. Deletion of the oligomerization domain of TEL or its substitution by the homologous region of monomeric ETS1 impaired the ability of TEL to repress. In contrast, substitution of the oligomerization domain of TEL by unrelated oligomerization domains resulted in an active repressor, showing that the ability of TEL to repress depends on its ability to self-associate. The study of the properties of TEL fusions to the heterologous DNA binding domain of Gal4 identified two autonomous repression domains in TEL, distinct from its oligomerization domain, that are essential to the ability of TEL to repress ETS-binding site-containing promoters. These results have implications for the normal function of TEL, its relation to other ETS proteins, and its role in leukemogenesis.Genes of the ETS family encode transcriptional regulators that are essential for a variety of developmental processes and for the response of cells to extracellular stimuli (for review see Ref. 1).Specific ETS genes are frequently rearranged in human solid tumors and leukemias as the result of chromosomal translocations. TEL 1 (ETV6) is an ETS family member that was originally identified by virtue of its fusion to the 3Ј-half of the gene encoding the platelet-derived growth factor ␤ receptor in chronic myelomonocytic leukemia harboring a t(5;12)(q33;p13) chromosomal translocation (2). Other translocations in either leukemia or sarcoma also result in the fusion of TEL either to genes encoding other protein tyrosine kinases, including c-ABL (3, 4), JAK2 (5, 6), and TRKC (7) or to genes encoding known or alleged transcriptional regulators (8 -11).TEL is widely expressed throughout mouse embryonic development and in most human and mouse tissues and cell lines (12, 13). It is essential to mouse development as its inactivation by homologous recombination results in early lethality. Embryos show defects in yolk sac angiogenesis and in the survival of select mesenchymal and neural cells (13). TEL shares with other ETS proteins an evolutionarily conserved domain (ETS domain) that is responsible for its ability to bind consensus ETS-binding site (EBS) DNA elements (12). It also shares with a subset of other ETS proteins a conserved amino-terminal domain that is referred to as the B domain, the pointed domain, or the helix-loop-helix domain (2, 14). The recent elucidation of the structure of the B/pointed domain of ETS1 by NMR shows that this domain identifies a novel fold, unrelated to the helixloop-helix motif (15). Although its precise function is unknown, the B/pointed domain of s...

y These authors contributed equally to this work. Persistent ATG-induced CD4þ T cell lymphopenia is associated with serious clinical complications. We tested the hypothesis that ATG induces accelerated immune senescence in renal transplant recipients (RTR). Immune senescence biomarkers were analyzed at transplant and one-year later in 97 incident RTR À62 patients receiving ATG and 35 receiving anti-CD25 mAb (a-CD25). This consisted in: (i) thymic output; (ii) bone marrow renewal of CD34 þ hematopoietic progenitor cells (CD34 þ HPC) and lymphoid (l-HPC) and myeloid (m-HPC) progenitor ratio; (iii) T cell phenotype; and (iv) measurement of T cell relative telomere length (RTL) and telomerase activity (RTA). Clinical correlates were analyzed with a 3 year follow-up. Thymic output significantly decreased oneyear posttransplant in ATG-treated patients. ATG was associated with a significant decrease in l-HPC/m-HPC ratio. Late stage differentiated CD57 þ /CD28 À T cells increased in ATG-treated patients. One-year posttransplant T cell RTL and RTA were consequently lower in ATG-treated patients. ATG is associated with accelerated immune senescence. Increased frequency of late differentiated CD4 þ T cell frequency at transplantation tended to be predictive of a higher risk of subsequent opportunistic infections and of acute rejection only in ATG-treated patients but this needs confirmation. Considering pretransplant immune profile may help to select those patients who may benefit from ATG to prevent severe infections and acute rejection.