Abstract
The t(15;17) chromosomal translocation in acute promyelocytic leukemia (APL) generates the PML-RARα fusion protein. The recruitment of nuclear receptor corepressor SMRT/N-CoR and subsequent repression of retinoid target genes is critical for the oncogenic function of PML-RARα. Here we show that the ability of PML-RARα to form homodimers is both necessary and sufficient for its increased binding efficiency to corepressor and inhibitory effects on hormonal responses in myeloid differentiation. We further provide evidence that altered stoichiometric interaction of SMRT with PML-RARα homodimers may underlie these processes. Finally, we demonstrate that a RXR AF2 mutant recapitulates many biochemical and functional properties of PML-RARα. Taken together, our results provide an example that altered dimerization of a transcription factor can be directly linked to cellular transformation and implicate dimerization interfaces of oncogenes as potential drug targets.
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