Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Dis. 2021 Mar 19;12(4):297. doi: 10.1038/s41419-021-03566-2.
PU.1 (encoded by SPI1) is essential for myeloid development, and inhibition of its expression and activity can lead to acute myeloid leukemia (AML). The precise regulation of PU.1 expression is crucial for the development of AML, and the discovery of circular RNAs (circRNAs) can add a new layer of information on regulation. Here, we found that circSPI1, the circular RNA derived from the SPI1 gene, is highly expressed in AML but not in normal counterparts. Unlike SPI1, a tumor suppressor and being lowly expressed in AML, we demonstrate that circSPI1 acts as an oncogene, evidenced by the observation that circSPI1 knockdown induces myeloid differentiation and apoptosis of AML cells. We provide mechanistic evidence for multiple regulatory roles of circSPI1 in AML progression. On one hand, circSPI1 contributes to myeloid differentiation of AML cells by interacting with the translation initiation factor eIF4AIII to antagonize PU.1 expression at the translation level. On the other hand, circSPI1 contributes to proliferation and apoptosis by interacting with miR-1307-3p, miR-382-5p, and miR-767-5p; this role is uncoupled with SPI1. Finally, we illustrate the clinical significance of circSPI1 by showing that circSPI1-regulated genes are associated with the clinical outcome of AML patients. Our data provide new insight into the complex SPI1 gene regulation now involving circSPI1.
PU.1（由 SPI1 编码）对于髓系发育是必不可少的，其表达和活性的抑制可导致急性髓系白血病（AML）。PU.1 表达的精确调控对于 AML 的发展至关重要，而环状 RNA（circRNA）的发现可以为调控增加新的信息层。在这里，我们发现源自 SPI1 基因的 circSPI1 在 AML 中高度表达，但在正常对照中不表达。与作为肿瘤抑制因子且在 AML 中低表达的 SPI1 不同，我们证明 circSPI1 作为癌基因发挥作用，这一点可以通过观察到 circSPI1 敲低诱导 AML 细胞的髓样分化和凋亡来证明。我们提供了 circSPI1 在 AML 进展中多种调控作用的机制证据。一方面，circSPI1 通过与翻译起始因子 eIF4AIII 相互作用，拮抗翻译水平上的 PU.1 表达，促进 AML 细胞的髓样分化。另一方面，circSPI1 通过与 miR-1307-3p、miR-382-5p 和 miR-767-5p 相互作用，促进增殖和凋亡；这种作用与 SPI1 无关。最后，我们通过表明 circSPI1 调节的基因与 AML 患者的临床结果相关，说明了 circSPI1 的临床意义。我们的数据为涉及 circSPI1 的复杂 SPI1 基因调控提供了新的见解。
