The Leukemia-Associated Gene TEL Encodes a Transcription Repressor Which Associates with SMRT and mSin3A

HDAC3: taking the SMRT-N-CoRrect road to repression

“…Many of these fusion proteins have been shown to interact with N-CoR/SMRT corepressors and compelling evidence shows that aberrant recruitment of the correpressor proteins correlates with the oncogenic activities of the fusion proteins. For instance, N-CoR/SMRT-HDAC3 and other corepressors are aberrantly recruited to the promoters of AML1 (renamed RUNX1) target genes via their interaction with the TEL moiety of TEL-AML1 (Chakrabarti and Nucifora, 1999;Fenrick et al, 1999;Guidez et al, 2000). The latter is the fusion protein generated in about one fourth of pediatric B-cell ALL patients, as a result of the t(12;21) translocation (Romana et al, 1995;Shurtleff et al, 1995).…”

RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription

“…The t(12;21) is found in up to 25% of pediatric B-cell acute leukemia and creates a chimeric gene encoding the TEL-RUNX1 fusion protein (Golub et al, 1995;Nucifora et al, 1995;Raynaud et al, 1995;Romana et al, 1995). TEL-RUNX1 also appears to act as a transcriptional repressor that dominantly interferes with RUNX1-specific transactivation (Hiebert et al, 1996;Chakrabarti and Nucifora, 1999;Fenrick et al, 2000;Guidez et al, 2000). RUNX1 function is also impaired by the inv(16), which fuses the RUNX1 associating factor, core binding factor b (CBFb or polyoma enhancer binding protein 2 beta) to the smooth muscle myosin heavy-chain gene MYH11, in approximately 8% of acute myeloid leukemia (Liu et al, 1993).…”

The MN1-TEL myeloid leukemia-associated fusion protein has a dominant-negative effect on RAR-RXR-mediated transcription

“…This fusion protein was shown to activate TEL-responsive transcription, whereas TEL itself is a repressor (Buijs et al, 2000;Chakrabarti and Nucifora, 1999). Now, we have compared the properties of MN1 and MN1-TEL with respect to RAR-RXR-mediated transcription, crucial for the proliferation and differentiation of blood cell lineages.…”

“…Corepressor complexes can be released from PML-RARa with pharmacological doses of ATRA, or can be counteracted by histone deacetylase inhibitors in the case of the PLZF-RAR fusion (Guidez et al, 1998). As TEL is a transcriptional repressor that recruits corepressors and histone deacetylases (Chakrabarti and Nucifora, 1999), MN1-TEL could recruit such corepressor complexes to RAR-RXR. Nonetheless, even pharmacological doses of ATRA only marginally relieved the repression in our transfection assays, and experiments with histone deacetylase inhibitors showed that tight or irreversible binding of corepressor complexes is not the cause of MN1-TEL's inhibitory activity.…”

“…This indicates that, in contrast to MN1, MN1-TEL does not interact productively with p160 or p300. Given that TEL represses transcription by recruiting a histone deacetylase complex (Chakrabarti and Nucifora, 1999), it is conceivable that these deacetylases counteract coactivators bound to MN1-TEL. To test this hypothesis, GAL4-MN1-TEL and the reporter were transfected in the absence or presence of trichostatin A (TSA), a potent inhibitor of histone deacetylases (Yoshida et al, 1990).…”