BCR-ABL1融合基因来源的环状RNA在慢性粒细胞白血病中的功能及作用机制研究

CircRNAs derived from fusion genes have been shown to play important roles in tumors, and studies on the function and mechanism of fusion-circRNAs have attracted widespread attention. Approximately 95% of patients with chronic myeloid leukemia (CML) are positive for the BCR-ABL1 fusion gene, which plays a key role in the development of CML. However, whether BCR-ABL1 fusion gene can generate functional circRNAs have not been reported. Our previous study identified for the first time that a new circRNA which we named circ-BA1, produced by the BCR-ABL1 fusion gene, are mainly located in the cytoplasm and inhibit the proliferation of CML cells. However, the molecular mechanisms involved in this progression remains unclear. Bioinformatics analysis revealed that circ-BA1 contains an open reading frame that encodes a peptide, suggesting that circ-BA1 may inhibit the proliferation of CML cells through its encoded peptide. Therefore, this project aims to reveal the biological functions and mechanisms of circ-BA1 and to deepen the study of fusion-circRNAs and BCR-ABL1 fusion gene in CML. Moreover, we will also explore the clinical relevance of circ-BA1 and provide new ideas for the clinical treatment of CML.

融合基因产生的环状RNA在肿瘤中发挥重要作用，其功能及其作用机制的研究已成为新的热点。BCR-ABL1融合基因在CML的发生发展中起着关键作用，但其能否产生环状RNA尚无报道。我们的前期研究发现BCR-ABL1融合基因产生的新环状RNA circ-BA1，定位于细胞质中且抑制CML细胞增殖，但具体机制尚不明确。生物信息学分析发现circ-BA1含有可以编码多肽的开放阅读框，推测circ-BA1可能通过其编码的多肽抑制CML细胞的增殖。本项目拟在前期研究的基础上，采用Northern blot、荧光原位杂交、动物模型等分子、细胞、动物生物学实验，揭示circ-BA1在CML中的生物学功能及其作用机制，深化融合环状RNA及BCR-ABL1融合基因在CML中的研究。此外，我们还将探明circ-BA1的临床相关性，为CML的临床治疗提供新的思路。

融合基因所产生的环状RNA与肿瘤的进程密切相关。BCR-ABL1融合基因在慢性粒细胞白血病（CML）的发生发展中起着关键性的作用，但BCR-ABL1融合基因是否能够产生融合环状RNA，以及其来源的环状RNA是否参与CML的进展尚不明确。项目鉴定了BCR-ABL1这一重要的融合基因产生的circRNA，并系统开展了融合环状RNA在CML中的研究，取得了多项研究成果：1）鉴定了BCR-ABL1融合基因能够产生环状RNA circ-BA；2）证明了circ-BA1在CML中的生物学功能；3）发现circ-BA1通过诱导细胞周期阻滞抑制CML；4）在携带BCR-ABL1融合基因的CML患者中验证了circ-BA1的存在。本项目的研究丰富了对融合环状RNA的认识，为融合环状RNA及BCR-ABL1融合基因的研究提供了新的思路，同时也为临床中CML患者的诊疗提供了新的策略。本项目已顺利完成既定目标，在Cancer Communications（IF:15.283）、Hepatology（IF:17.298）、Cell Stress等国际期刊发表论文3篇（已标注基金号81900156）；培养博士1名，硕士2名。