Characterization of a novel ETS gene, TELB, encoding a protein structurally and functionally related to TEL

Abstract

The TEL/ETV6 gene is located at 12p13 and is frequently involved in chromosomal translocations in human malignancies usually resulting in the expression of fusion proteins between the amino terminal part of TEL, and either unrelated transcription factors or protein tyrosine kinases. We report here a novel gene named TELB which is located on human chromosomal band 6p21 and encodes a protein highly related to TEL. TELB is widely expressed in dierent tissues and, similarly to TEL encodes a sequence-speci®c transcriptional repressor. Oncogene (2000) 19, 4802 ± 4806. Keywords: transcriptional repression; ETS; TELThe TEL (Translocated Ets Leukemia, also known as ETV6) gene (Golub et al., 1994), which encodes a member of the ETS family of transcription factors, is aected in more than half of the abnormalities of the short arm of the chromosome 12 in various hematopoietic malignancies, and in solid tumours.An intriguing characteristic of TEL-derived fusion oncoproteins is that the contribution of TEL appears variable and that the fusion partners are not functionally homogeneous but they fall in several dierent categories (for a recent review see Rubnitz et al., 1999). In the ®rst category, the amino-terminal domain of TEL is fused to the catalytic domain of several protein tyrosine kinases (PDGFRb, ABL, JAK2, NTRK3). In these examples, the TEL protein provides a speci®c domain which induces the selfassociation of the fusion proteins to constitutively activate their tyrosine kinase activity. In the second category, TEL drives the expression of unrelated transcription factors such as MDS1/EVI1 or CDX2, as a result of t(3;12)(q26;p13) and t(12;13)(p13;q12) chromosomal translocations, respectively. In a third category, exempli®ed by the t(12;22)(p13;q11) and t(4;12)(q11-q12;p13) chromosomal translocations, the transcription of the chimeric gene is driven by the partner chromosome and the fusion proteins contain the ETS DNA binding domain of TEL, indicating that the fusion protein could disregulate TEL target genes.The most frequent TEL fusion is the TEL ± AML1 fusion that results from the childhood B type ALL speci®c t(12;21)(p13;q22). The crucial fusion protein is TEL ± AML1 which contains the 336 aminoterminal residues of TEL, including its oligomerization and repressor domains, and almost all the AML1 protein.As a result, the fusion protein has been proposed to interfere with the normal transcriptional regulation of AML1 target genes. In virtually all cases, the t(12;21) is associated with loss of expression of the untranslocated TEL copy, usually due to total or partial deletion. Whether this is important for TEL ± AML1 malignant function proper or for the achievement of a loss of function for TEL is not established. Regarding this question, several examples have been reported in which translocations do not create fusion products but rather result in the impairment of TEL functions, which is regarded as an additional modality for TEL disregulation.Our understanding of TEL's involvement in leukemogenesis is expected to b...

TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3

“…Although several di erent ETS family members can repress transcription, TEL is the ®rst to be linked to histone deacetylases. Another ETS factor that is homologous to TEL, TEL2 or TELB, was recently identi®ed through sequence homology (Poirel et al, 2000;Potter et al, 2000). This gene encodes a protein of 341 amino acids, which is 38% identical to TEL.…”

Proteins of the ETS family with transcriptional repressor activity

“…ETS-1 is monomeric in solution whereas TEL assemble into oligomers, a property which is exclusively mediated by its B/pointed domain (Jousset et al, 1997). TEL-B/TEL-2 also self-associates in vitro and in vivo through its B/pointed domain and associates with TEL as well (Potter et al, 2000;Poirel et al, 2000).…”

“…Compared to the majority of the other ETS domains both TEL and TEL-2/TEL-B present primary amino-acid sequence deviations in the a1 helix, present at the extreme amino-terminus of the ETS domain, and at the end of the a3 recognition helix. Yet, the isolated ETS domain of TEL and TEL-B/TEL-2 binds conventional EBS in vitro (Poirel et al, , 2000Potter et al, 2000) and regulate EBS-driven transcription (see below). However, in vitro, the DNA binding activity of full-length TEL is considerably lower as compared to that of its isolated ETS domain, suggesting that the DNA binding properties of TEL are subject to an intramolecular repressive mechanism as frequently observed in other ETS proteins (for review, see Ghysdael and Boureux, 1997;Graves and Petersen, 1998).…”

“…TEL, together with the recently identi®ed TEL-B (or TEL-2), a gene encoding a protein closely related to that encoded by TEL, de®nes a new sub-class of the ETS family in mammals (Potter et al, 2000;Poirel et al, 2000). TEL appears to be ubiquitously expressed in mouse and human tissues whereas TEL-B/TEL-2 expression is more restricted (Golub et al, 1994;Wang et al, 1997Wang et al, , 1998Potter et al, 2000;Poirel et al, 2000). TEL is essential to mouse development as its inactivation by homologous recombination is lethal at day 10.5 ± 11.5 of embryonic development.…”

Comparative analysis of the ETV6 gene in vertebrate genomes from pufferfish to human

“…Donaldson et al, 1996). In addition, ETV6 can dimerize through its conserved pointed oligomerization domain (termed PNT domain), located at its Nterminus, with itself or with other partners such as UBC9 , Fli-1, another Ets member (Kwiatkowski et al, 1998), and TEL2, a protein highly related to ETV6 Poirel et al, 2000). Contrary to most of the Ets proteins, ETV6 acts as a transcription repressor by recruiting proteins involved in the histone-deacetylase pathway.…”