Laboratory of Transcriptional Regulation in Development and Cancer, Fondazione Istituto FIRC di Oncologia Molecolare, Milano, Italy.
PLoS One. 2012;7(10):e48353. doi: 10.1371/journal.pone.0048353. Epub 2012 Oct 25.
The Prep1 homeodomain transcription factor has recently been recognized as a tumor suppressor. Among other features, haploinsufficiency of Prep1 is able to strongly accelerate the B-lymphomagenesis in EμMyc mice. Now we report that this occurs concomitantly with a change in the type of B-cell lymphomas generated by the Myc oncogene. Indeed, the tumors generated in the EμMyc-Prep1(+/-) mice are much more immature, being mostly made up of Pro-B or Pre-B cells, while those in the EμMyc-Prep1(+/+) mice are more differentiated being invariably IgM(+). Moreover, we show that Prep1 is in fact required for the differentiation of Pro-B and Pre-B cells into IgM(+) lymphocytes and/or their proliferation, thus showing also how a normal function of Prep1 affects EμMyc lymphomagenesis. Finally, we show that the haploinsufficiency of Prep1 is accompanied with a major decrease of Myc-induced apoptosis and that the haploinsufficieny is sufficient for all these effects because the second allele of Prep1 is not lost even at late stages. Therefore, the tumor-suppressive activity of Prep1 is intertwined with both the interference with Myc-induced apoptosis as well as with natural developmental functions of the protein.
Prep1 同源结构域转录因子最近被认为是一种肿瘤抑制因子。除其他特征外，Prep1 的杂合不足能够强烈加速 EμMyc 小鼠中的 B 淋巴细胞瘤发生。现在我们报告说，这种情况与 Myc 癌基因产生的 B 细胞淋巴瘤类型的变化同时发生。事实上，在 EμMyc-Prep1(+/-) 小鼠中产生的肿瘤更加不成熟，主要由 Pro-B 或 Pre-B 细胞组成，而在 EμMyc-Prep1(+/+) 小鼠中产生的肿瘤则更加分化，始终为 IgM(+)。此外，我们表明 Prep1 实际上是 Pro-B 和 Pre-B 细胞分化为 IgM(+)淋巴细胞和/或其增殖所必需的，从而也显示了 Prep1 的正常功能如何影响 EμMyc 淋巴瘤的发生。最后，我们表明 Prep1 的杂合不足伴随着 Myc 诱导的细胞凋亡的大量减少，并且杂合不足足以产生所有这些效应，因为即使在晚期，Prep1 的第二个等位基因也没有丢失。因此，Prep1 的肿瘤抑制活性与干扰 Myc 诱导的细胞凋亡以及该蛋白的自然发育功能交织在一起。
