Department of Hematology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province), The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China; Cancer Institute, Zhejiang University, Hangzhou 310009, China.
Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou310009, China.
Exp Cell Res. 2018 Oct 15;371(2):409-416. doi: 10.1016/j.yexcr.2018.08.035. Epub 2018 Sep 1.
Identifying and targeting oncogenic fusion genes have revolutionized the treatment of leukemia, such as PML-RARα fusion gene in acute promyelocytic leukemia. Here we identified an intrachromosomal fusion gene located on chromosome 19q.13 between UBA2 and WTIP gene in a case of acute myeloid leukemia. The UBA2-WTIP fusion gene contains the N-terminal E1_enzyme_family, VAE_Ubl domains of UBA2, and the C-terminal LIM domains of WTIP. The UBA2-WTIP fusion was detected by reverse transcriptase polymerase chain reaction and Sanger sequencing in 19 of 56 acute myeloid leukemia samples (33.9%). Ectopic expression of the UBA2-WTIP fusion in human acute myeloid leukemia KG-1a cells showed enhanced cell proliferation both in vitro and in vivo. The UBA2-WTIP fusion induced phosphorylation of STAT3, STAT5 and ERK1/2, and abrogates WTIP-mediated mammalian processing body formation. Finally, triptolide displayed selective cytotoxicity against KG-1a cells harboring the UBA2-WTIP fusion. Collectively, our findings suggest that the UBA2-WTIP fusion is an oncogenic fusion gene, as well as a promising therapeutic target for the treatment of acute myeloid leukemia.
鉴定和靶向致癌融合基因已经彻底改变了白血病的治疗方法，例如急性早幼粒细胞白血病中的 PML-RARα 融合基因。在这里，我们鉴定了一例急性髓系白血病中位于染色体 19q.13 上 UBA2 和 WTIP 基因之间的染色体内融合基因。UBA2-WTIP 融合基因包含 UBA2 的 N 端 E1_enzyme_family、VAE_Ubl 结构域和 WTIP 的 C 端 LIM 结构域。在 56 例急性髓系白血病样本中的 19 例（33.9%）中通过逆转录聚合酶链反应和 Sanger 测序检测到 UBA2-WTIP 融合。UBA2-WTIP 融合在人急性髓系白血病 KG-1a 细胞中的异位表达显示出体外和体内增强的细胞增殖。UBA2-WTIP 融合诱导 STAT3、STAT5 和 ERK1/2 的磷酸化，并取消 WTIP 介导的哺乳动物加工体形成。最后，雷公藤内酯甲对携带 UBA2-WTIP 融合的 KG-1a 细胞表现出选择性细胞毒性。总之，我们的研究结果表明，UBA2-WTIP 融合是一种致癌融合基因，也是治疗急性髓系白血病的有前途的治疗靶点。
