文章：

RUNX1-ETO靶基因RASSF2抑制t(8;21)型急性髓系白血病的发展并调控Rac GTP酶信号通路

The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling

原文发布日期：2020-02-06

DOI: 10.1038/s41408-020-0282-9

类型: Article

开放获取: 是

英文摘要：

Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 (RASSF2) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2-proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia.
 

摘要翻译： 

大规模染色体易位是急性髓系白血病（AML）中常见的致癌驱动因素。这些易位常发生于关键转录/表观遗传调控因子中，通过改变正常基因表达促进恶性细胞生长。尽管已有此认知，导致白血病发生的关键基因表达改变仍未完全阐明。本研究通过解析RUNX1-ETO融合蛋白的转录调控机制，发现Ras关联结构域家族成员2（RASSF2）在t(8;21)相关AML中发生异常转录抑制。在多种模型中重新表达RASSF2能特异性抑制t(8;21)AML进展。生化与功能研究表明，RASSF2介导的功能依赖于与Hippo激酶MST1/MST2的相互作用，但不依赖于经典Hippo通路信号传导。通过邻近生物素标记技术，我们绘制了白血病细胞中RASSF2邻近蛋白质组图谱，揭示了其与Rac GTP酶相关蛋白（包括鸟嘌呤核苷酸交换因子DOCK2）的关联。重要的是，敲低RASSF2会损害Rac GTP酶活化，且在AML患者中RASSF2表达与Rac介导的信号转导广泛相关。这些发现揭示了RASSF2、Hippo激酶与Rac活性之间未被认知的机制关联，该关联可能在白血病中产生广泛的功能性影响。

原文链接：

The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling