ABSTRACT

WT1 has been reported to function as an oncogene and a tumor suppressor in acute myeloid leukemia (AML). The molecular mechanisms have not yet been fully elucidated. Here, we report that p53, served as a tumor suppressor, plays a critical role in regulating the function of WT1 in AML. For details, we performed a meta-analysis on 1131 AML cases, showing that WT1 gene mutation and TP53 gene exhibited a mutually exclusive predisposition in AML. p53 can be recruited to the promoter region of WT1’s target genes to modulate their expression by physically interacting with WT1. The AML-derived p53 mutation (p53^R248Q) can disrupt the interaction between WT1 and p53, resulting in the loss of modulation of WT1’s target genes. Furthermore, wild-type p53 maintained the anti-proliferation activity of WT1 in AML cells. In contrast, WT1 promoted AML cell proliferation in the absence of p53 (or mutated p53). In conclusion, we demonstrated a novel explanation of the controversial function of WT1 in AML. These results provided a mechanism by which WT1 inhibited AML cell proliferation in a p53-dependent manner.

摘要

据报道，WT1 在急性髓性白血病 (AML) 中起癌基因和肿瘤抑制因子的作用。分子机制尚未完全阐明。在这里，我们报告作为肿瘤抑制因子的 p53 在调节 AML 中 WT1 的功能中起关键作用。具体而言，我们对 1131 例 AML 病例进行了荟萃分析，显示 WT1 基因突变和 TP53 基因在 AML 中表现出相互排斥的易感性。p53 可以被招募到 WT1 靶基因的启动子区域，以通过与 WT1 物理相互作用来调节它们的表达。AML 衍生的 p53 突变（p53 ^R248Q) 可以破坏 WT1 和 p53 之间的相互作用，导致 WT1 靶基因的调节丧失。此外，野生型 p53 维持 WT1 在 AML 细胞中的抗增殖活性。相反，WT1 在没有 p53（或突变的 p53）的情况下促进 AML 细胞增殖。总之，我们对 WT1 在 AML 中的有争议的功能进行了新的解释。这些结果提供了WT1以p53依赖性方式抑制AML细胞增殖的机制。