The self-association coiled-coil domain of PML is sufficient for the oncogenic conversion of the retinoic acid receptor (RAR) alpha

In acute promyelocytic leukemia (APL) the retinoic acid receptor alpha (RAR alpha) 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 alpha, 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 alpha is still under investigation. In this work, we address this question using two different X-RAR alpha chimeras, where X represents the coiled-coil domain of PML (CC-RAR alpha) or the oligomerization portion of the yeast transcription factor GCN4 (GCN4-RAR alpha). We demonstrate that in vitro both proteins have transforming potential, and recapitulate the main PML-RAR alpha biological properties, but CC-RAR alpha is uniquely able to disrupt PML nuclear bodies. Indeed, in vivo only the CC-RAR alpha chimera induces efficiently APL in a murine transplantation model. Thus, the PML CC domain represents the minimal structural determinant indispensable to transform RAR alpha into an oncogenic protein. Leukemia (2011) 25, 814-820; doi: 10.1038/leu.2011.18; published online 18 February 2011