Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark.
Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
Leukemia. 2023 May;37(5):1113-1125. doi: 10.1038/s41375-023-01866-4. Epub 2023 Mar 15.
Mutations in U2AF1 are relatively common in myelodysplastic neoplasms (MDS) and are associated with an inferior prognosis, but the molecular mechanisms underlying this are not fully elucidated. Circular RNAs (circRNAs) have been implicated in cancer, but it is unknown how mutations in splicing factors may impact on circRNA biogenesis. Here, we used RNA-sequencing to investigate the effects of U2AF1 mutations on circRNA expression in K562 cells with a doxycycline-inducible U2AF1 mutation, in a mouse model with a doxycycline-inducible U2AF1 mutation, and in FACS-sorted CD34+ bone marrow cells from MDS patients with either U2AF1 or U2AF1 mutations. In all contexts, we found an increase in global circRNA levels in the U2AF1-mutated setting, which was independent of expression changes in the cognate linear host genes. In patients, the U2AF1 and U2AF1 mutations were both associated with an overall increased expression of circRNAs. circRNAs generated by a non-Alu-mediated mechanism generally showed the largest increase in expression levels. Several well-described cancer-associated circRNAs, including circZNF609 and circCSNK1G3, were upregulated in MDS patients with U2AF1 mutations compared to U2AF1-wildtype MDS controls. In conclusion, high circRNA expression is observed in association with U2AF1 mutations in three biological systems, presenting an interesting possibility for biomarker and therapeutic investigation.
U2AF1 突变在骨髓增生异常综合征 (MDS) 中相对常见，与预后不良相关，但其中的分子机制尚不完全清楚。环状 RNA (circRNA) 与癌症有关，但尚不清楚剪接因子的突变如何影响 circRNA 的生物发生。在这里，我们使用 RNA 测序来研究 U2AF1 突变对 K562 细胞中 circRNA 表达的影响，这些细胞具有诱导型 U2AF1 突变的诱导型 U2AF1 突变，在具有诱导型 U2AF1 突变的小鼠模型中，以及在 MDS 患者的 FACS 分选的 CD34+骨髓细胞中，这些患者具有 U2AF1 或 U2AF1 突变。在所有情况下，我们发现在 U2AF1 突变的情况下，全局 circRNA 水平增加，这与同源线性宿主基因的表达变化无关。在患者中，U2AF1 和 U2AF1 突变均与 circRNA 的总体表达增加相关。由非 Alu 介导的机制产生的 circRNAs 通常表现出表达水平的最大增加。几种已描述的与癌症相关的 circRNAs，包括 circZNF609 和 circCSNK1G3，在 U2AF1 突变的 MDS 患者中与 U2AF1 野生型 MDS 对照相比上调。总之，在三个生物系统中，与 U2AF1 突变相关的高 circRNA 表达表明这是一个有趣的生物标志物和治疗研究的可能性。
