The inv(16) encodes an acute myeloid leukemia 1 transcriptional corepressor

The inv(16) is one of the most frequent chromosomal translocations associat ed with acute myeloid leukemia (AML). The inv(16) fusion protein acts by do minantly interfering with AML-1/core binding factor beta-dependent transcri ptional regulation. Here we demonstrate that the inv(16) fusion protein coo perates with AML-1B to repress transcription. This cooperativity requires t he ability of the translocation fusion protein to bind to AML-1B. Mutationa l analysis and cell fractionation experiments indicated that the inv(16) fu sion protein acts in the nucleus and that repression occurs when the comple x is bound to DNA. We also found that the inv(16) fusion protein binds to A ML-1B when it is associated with the mSin3A corepressor. An AML-1B mutant t hat fails to bind mSin3A was impaired in cooperative repression, suggesting that the inv(16) fusion protein acts through mSin3 and possibly other core pressors. finally, we demonstrate that the C-terminal portion of the inv(16 ) fusion protein contains a repression domain, suggesting a molecular mecha nism for AML-1-mediated repression.