CircZBTB46 predicts poor prognosis and promotes disease progression of myelodysplastic syndromes and acute myeloid leukemia.
CircZBTB46 predicts poor prognosis and promotes disease progression of myelodysplastic syndromes and acute myeloid leukemia.
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DOI：
10.1007/s10238-023-01243-6
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发表时间：
2023-11
影响因子：
4.6
通讯作者：
Shuang Li;Guangjie Zhao;Wanling Wu;Nianyi Li;Qian Wang;Wei Wang;Xianmin Song;Xiaoqin Wang
中科院分区：
文献类型：
--
作者：
Shuang Li;Guangjie Zhao;Wanling Wu;Nianyi Li;Qian Wang;Wei Wang;Xianmin Song;Xiaoqin Wang
环状RNA（circRNA）是近年来发现的一种重要的疾病调节因子，尤其是癌症。然而，circRNA在血液系统恶性肿瘤中的作用很少报道。本研究旨在鉴定骨髓增生异常综合征（MDS）和急性髓系白血病（AML）患者中特异性circRNA的表达谱，并评价circRNA在MDS和AML中的生物学作用，以了解其临床意义。进行逆转录-定量PCR以验证circZBTB 46的表达。采用Kruskal-Wallis检验、Kaplan-Meier曲线和考克斯回归模型分析circZBTB 46的临床意义。为了鉴定circZBTB 46的生物学功能，构建了circZBTB 46的两个特异性shRNA和一个慢病毒表达载体。使用细胞活力测定和流式细胞术分析证实了circZBTB 46对白血病细胞增殖、细胞周期分布和凋亡的影响。与对照组相比，circZBTB 46的表达在高危MDS和AML患者中逐渐增加。CircZBTB 46表达与MDS的重要临床参数显著相关，包括WHO分类、中性粒细胞绝对计数（ANC）、骨髓原始细胞、IPSS核型、IPSS/IPSS-R风险组和AML转化。CircZBTB 46表达还与AML患者的ANC、骨髓原始细胞、细胞遗传学风险组、FLT 3-ITD突变和治疗反应相关。此外，circZBTB 46过表达与MDS中较短的总生存期（OS，P= 0.0342，中位生存时间18.5 vs.45.4个月）和无白血病生存期（LFS，P= 0.0421）显著相关，还与AML中较短的OS（P= 0.0293，中位生存时间11.6 vs.16.9个月）显著相关。功能研究表明，沉默circZBTB 46表达显著抑制SKM-1，THP-1和K562细胞系的增殖并诱导凋亡，而拯救实验减轻了这些白血病细胞中siRNA介导的生长抑制和凋亡。目前的数据表明circZBTB 46作为MDS和AML中的进展和存活指标的基本致癌作用。
Circular RNAs (circRNAs) have been recently identified as important regulators of various diseases, especially cancer. However, the roles of circRNAs in hematologic malignancies have been rarely reported. This study aimed to identify a specific circRNA expression profile in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and to evaluate the biological roles of circRNA in MDS and AML for understanding their clinical significance. Reverse transcription-quantitative PCR was performed to validate the expression of circZBTB46. Kruskal–Wallis test, Kaplan–Meier curves, and the Cox regression model were employed to analyze the clinical significance of circZBTB46. Two specific shRNAs as well as an expression lentiviral vector of circZBTB46 were constructed to identify the biological function of circZBTB46. The impact of circZBTB46 on leukemia cell proliferation, cell cycle distribution, and apoptosis was confirmed using cell viability assay and flow cytometry analysis. The expression of circZBTB46 gradually increased in patients with higher-risk MDS and AML, as compared to controls. CircZBTB46 expression was significantly correlated with important clinical parameters of MDS, including WHO classification, absolute neutrophil count (ANC), marrow blast, IPSS karyotype, IPSS/IPSS-R risk groups, and AML transformation. CircZBTB46 expression was also associated with ANC, marrow blast, cytogenetic risk groups, FLT3-ITD mutation, and treatment response in AML patients. Furthermore, circZBTB46 overexpression was significantly correlated with shorter overall survival (OS,P= 0.0342, median survival time 18.5 vs. 45.4 months) and leukemia-free survival (LFS,P= 0.0421) in MDS, also with the shorter OS in AML (P= 0.0293, median survival time 11.6 vs. 16.9 months). Functional studies revealed that silencing circZBTB46 expression significantly inhibited proliferation and induced apoptosis in SKM-1, THP-1, and K562 cell lines, while rescue experiments alleviated the siRNA-mediated growth inhibition and apoptosis in these leukemic cells. The present data suggested the essential oncogenic role of circZBTB46, as a progression and survival indicator in both MDS and AML.