Section for Cancer Cytogenetics, Institute for Medical Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
PLoS One. 2012;7(6):e39354. doi: 10.1371/journal.pone.0039354. Epub 2012 Jun 22.
Rearrangement of chromosome band 6p21 is recurrent in endometrial stromal sarcoma (ESS) and targets the PHF1 gene. So far, PHF1 was found to be the 3' partner in the JAZF1-PHF1 and EPC1-PHF1 chimeras but since the 6p21 rearrangements involve also other chromosomal translocation partners, other PHF1-fusions seem likely. Here, we show that PHF1 is recombined with a novel fusion partner, MEAF6 from 1p34, in an ESS carrying a t(1;6)(p34;p21) translocation as the sole karyotypic anomaly. 5'-RACE, RT-PCR, and sequencing showed the presence of an MEAF6-PHF1 chimera in the tumor with exon 5 of MEAF6 being fused in-frame to exon 2 of PHF1 so that the entire PHF1 coding region becomes the 3' terminal part of the MEAF6-PHF1 fusion. The predicted fusion protein is composed of 750 amino acids and contains the histone acetyltransferase subunit NuA4 domain of MEAF6 and the tudor, PHD zinc finger, and MTF2 domains of PHF1. Although the specific functions of the MEAF6 and PHF1 proteins and why they are targeted by a neoplasia-specific gene fusion are not directly apparent, it seems that rearrangement of genes involved in acetylation (EPC1, MEAF6) and methylation (PHF1), resulting in aberrant gene expression, is a common theme in ESS pathogenesis.
6p21 号染色体带的重排是子宫内膜间质肉瘤（ESS）中反复出现的现象，其靶标是 PHF1 基因。到目前为止，已经发现 PHF1 是 JAZF1-PHF1 和 EPC1-PHF1 嵌合体的 3' 伴侣，但由于 6p21 重排还涉及其他染色体易位伙伴，因此其他 PHF1 融合似乎也有可能。在这里，我们展示了在携带 t(1;6)(p34;p21)易位作为唯一核型异常的 ESS 中，PHF1 与来自 1p34 的新型融合伙伴 MEAF6 发生重组。5'-RACE、RT-PCR 和测序显示，在肿瘤中存在 MEAF6-PHF1 嵌合体，MEAF6 的外显子 5 与 PHF1 的外显子 2 融合，从而使整个 PHF1 编码区成为 MEAF6-PHF1 融合的 3' 末端部分。预测的融合蛋白由 750 个氨基酸组成，包含 MEAF6 的组蛋白乙酰转移酶亚基 NuA4 结构域和 PHF1 的 tudor、PHD 锌指和 MTF2 结构域。虽然 MEAF6 和 PHF1 蛋白的具体功能以及为什么它们是肿瘤特异性基因融合的靶标尚不清楚，但似乎参与乙酰化（EPC1、MEAF6）和甲基化（PHF1）的基因重排导致异常基因表达，是 ESS 发病机制中的一个共同主题。
