Mechanisms of transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)-encoded fusion proteins

Citation
Sw. Hiebert et al., Mechanisms of transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)-encoded fusion proteins, CANC CHEMOT, 48, 2001, pp. S31-S34
Citations number
23
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN journal
0344-5704 → ACNP
Volume
48
Year of publication
2001
Supplement
1
Pages
S31 - S34
Database
ISI
SICI code
0344-5704(200108)48:<S31:MOTRBT>2.0.ZU;2-W
Abstract
AML-1 is one of the most frequently translocated genes in human leukemia. A ML-1 binds DNA and activates or represses transcription, while the chromoso mal translocation fusion proteins in acute myeloid leukemia subvert these f unctions. The t(8;21) is the second most frequent translocation in acute my eloid leukemia and creates a fusion between the DNA binding domain of AML-1 and the ETO (also known as MTG8) corepressor. The t(12;21) is found in up to 25% of pediatric B cell acute lymphoblastic leukemias and fuses the ETS family transcription factor TEL to the amino terminus of AML-1. In addition , the inv(16), the most frequent translocation in acute myeloid leukemia, f uses the AML-1 cofactor CBF beta to the smooth muscle myosin heavy chain MY H11. Both the t(8;21) and t(12;21) create transcriptional repressors that i mpair AML-1 target gene expression. We demonstrated that the fusion protein s encoded by these translocations contact the nuclear hormone corepressors (N-CoR/SMRT), mSin3A, and histone deacetylases. We have also found that bot h TEL and AML-1 interact with mSin3A. TEL also binds NCoR and histone deace tylase-3, indicating that wild-type TEL is a transcriptional repressor. The t(12;21) fuses the mSin3A interaction domain of TEL to AML-1 to transform AML-1 from a regulated to an unregulated transcriptional repressor. The rec ognition that AML-1 interacts with mSin3A to repress transcription suggeste d that the inv(16) fusion protein might also repress the transcription of A ML-1-target genes. In fact, the inv(16) encodes a protein that cooperates w ith AML-1 to repress transcription. The inv(16) fusion protein was found in a ternary complex with AML-1 and mSin3A, suggesting that the inv(16) also acts by recruiting transcriptional corepressors and histone deacetylases.