Department of Experimental Oncology, IFOM-IEO Campus, Milan, Italy.
Leukemia. 2011 May;25(5):814-20. doi: 10.1038/leu.2011.18. Epub 2011 Feb 18.
In acute promyelocytic leukemia (APL) the retinoic acid receptor alpha (RARα) 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 RARα, 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 RARα is still under investigation. In this work, we address this question using two different X-RARα chimeras, where X represents the coiled-coil domain of PML (CC-RARα) or the oligomerization portion of the yeast transcription factor GCN4 (GCN4-RARα). We demonstrate that in vitro both proteins have transforming potential, and recapitulate the main PML-RARα biological properties, but CC-RARα is uniquely able to disrupt PML nuclear bodies. Indeed, in vivo only the CC-RARα chimera induces efficiently APL in a murine transplantation model. Thus, the PML CC domain represents the minimal structural determinant indispensable to transform RARα into an oncogenic protein.
在急性早幼粒细胞白血病（APL）中，维甲酸受体 alpha（RARα）通过与几个伴侣融合成为致癌基因，其中大多数与早幼粒细胞白血病蛋白（PML）融合，它们都有一个共同点，即存在自我缔合结构域。因此，这些新的融合蛋白与野生型 RARα不同，后者仅与维甲酸 X 受体 alpha 形成异二聚体，也能够同型寡聚化。这种结构域的存在被认为是 APL 白血病细胞中发现的嵌合蛋白具有致癌潜力的关键。任何自我缔合结构域是否足以赋予 RARα致癌活性仍在研究中。在这项工作中，我们使用两种不同的 X-RARα嵌合体来解决这个问题，其中 X 代表 PML 的卷曲螺旋结构域（CC-RARα）或酵母转录因子 GCN4 的寡聚化部分（GCN4-RARα）。我们证明这两种蛋白在体外都具有转化潜力，并再现了 PML-RARα 的主要生物学特性，但 CC-RARα 独特地能够破坏 PML 核体。事实上，只有 CC-RARα 嵌合体在小鼠移植模型中能够有效地诱导 APL。因此，PML CC 结构域是将 RARα 转化为致癌蛋白所必需的最小结构决定因素。
