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pubmed:abstractText |
In acute promyelocytic leukemia (APL) the retinoic acid receptor alpha (RAR?) becomes an oncogene through the fusion with several partners, mostly with promyelocytic leukemia protein (PML), all of which have in common the presence of a self-association domain. The new fusion proteins, therefore, differently from the wild-type RAR?, which forms only heterodimers with retinoic X receptor alpha, are also able to homo-oligomerize. The presence of such a domain has been suggested to be crucial for the leukemogenic potential of the chimeric proteins found in APL blasts. Whether or not any self-association domain is sufficient to bestow a leukemogenic activity on RAR? is still under investigation. In this work, we address this question using two different X-RAR? chimeras, where X represents the coiled-coil domain of PML (CC-RAR?) or the oligomerization portion of the yeast transcription factor GCN4 (GCN4-RAR?). We demonstrate that in vitro both proteins have transforming potential, and recapitulate the main PML-RAR? biological properties, but CC-RAR? is uniquely able to disrupt PML nuclear bodies. Indeed, in vivo only the CC-RAR? chimera induces efficiently APL in a murine transplantation model. Thus, the PML CC domain represents the minimal structural determinant indispensable to transform RAR? into an oncogenic protein.
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