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

Abstract

TEL (Translocation ± ETS ± Leukemia or ETV 6) is disrupted by multiple chromosomal translocations in acute leukemia. The loss of heterozygosity at the TEL locus in leukemias and the hemizygous deletion of TEL that is observed in various tumors, suggests that TEL is a tumor suppressor. Overexpression of TEL alters cellular morphology and represses the expression of the matrix metalloproteinase stromelysin-1. Based on these studies, deletion analysis was used to de®ne the minimal repression domains of TEL. TEL-mediated repression required both the N-terminal pointed domain and a central region composed of amino acids 268 ± 303. The mSin3A and N-CoR corepressors bind to the pointed domain and the central repression domain of TEL, respectively. Unexpectedly, histone deacetylase-3, but not other histone deacetylases, also associates with the central region of TEL. Histone deacetylase-3 interacts with a TEL mutant that cannot bind N-CoR, suggesting that this is a direct interaction with TEL. In addition, histone H3 was under-acetylated near the TEL-binding sites in the endogenous stromelysin-1 promoter when TEL was expressed. Furthermore, trichostatin A, a potent histone deacetylase inhibitor, impaired TELdependent repression of the stromelysin-1 promoter. Finally, while TEL-expression induced cellular aggregation of Ras-transformed cells, Trichostatin A reversed the TEL-induced cellular aggregation phenotype. Thus, the cumulative data suggests that histone deacetylase-3 activity is required for the transcriptional functions of TEL. Oncogene (2001) 20, 3716 ± 3725.

TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL

“…This region has been shown to recruit the corepressor N-CoR and histone deacetylase-3 (Guidez et al, 2000;Wang and Hiebert, 2001). We found that the region of TEL Cterminal of the HLH domain, which includes the CR domain, is also essential for TEL-AML1 to initiate progenitor B-cell expansion from HSC.…”

Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia

“…30,31 (iii) Acute leukemias with translocations involving TEL also showed an interference with the co-repressor N-CoR. 32 We found that overexpressed SKI inhibits RARa signaling in different cytogenetic subgroups of AML. As described for leukemias (i-iii), where HDAC inhibitors impaired the repression of differentiation, we could show that the HDAC inhibitor VPA partially reverted the effect of overexpressed Ski.…”

Directing oncogenic fusion genes into stem cells via an SCL enhancer

“…The finding that the CFS variant of TEL-TRKC but not the L form interferes with the expression of Flk1 provides a lead in how this selectivity might arise, as does the known activity of central region of TEL (encoded by exon 5) to recruit transcriptional corepressors (40)(41)(42)(43). CFS TEL-TRKC protein mainly localizes in the cytoplasm (data not shown), and, therefore, any transcriptional deregulating activity would presumably be indirect, e.g., by sequestering components in the cytoplasm.…”