Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi 329-0498, Tochigi, Japan.
Int J Mol Sci. 2024 Mar 26;25(7):3693. doi: 10.3390/ijms25073693.
Chronic myeloid leukemia (CML) is induced by the expression of the fused tyrosine kinase BCR-ABL, which is caused by a chromosomal translocation. BCR-ABL inhibitors have been used to treat CML; however, the acquisition of resistance by CML cells during treatment is a serious issue. We herein demonstrated that BCR-ABL induced the expression of the RNA helicase DDX5 in K562 cells derived from CML patients in a manner that was dependent on its kinase activity, which resulted in cell proliferation and survival. The knockout of DDX5 decreased the expression of BIRC5 (survivin) and activated caspase 3, leading to apoptosis in K562 cells. Similar results were obtained in cells treated with FL118, an inhibitor of DDX5 and a derivative compound of camptothecin (CPT). Furthermore, FL118 potently induced apoptosis not only in Ba/F3 cells expressing BCR-ABL, but also in those expressing the BCR-ABL T315I mutant, which is resistant to BCR-ABL inhibitors. Collectively, these results revealed that DDX5 is a critical therapeutic target in CML and that FL118 is an effective candidate compound for the treatment of BCR-ABL inhibitor-resistant CML.
慢性髓性白血病（CML）是由融合酪氨酸激酶 BCR-ABL 的表达引起的，这种表达是由染色体易位引起的。BCR-ABL 抑制剂已被用于治疗 CML；然而，CML 细胞在治疗过程中获得耐药性是一个严重的问题。我们在此证明，BCR-ABL 通过其激酶活性诱导来自 CML 患者的 K562 细胞中 RNA 解旋酶 DDX5 的表达，这导致细胞增殖和存活。DDX5 的敲除降低了 BIRC5（存活素）的表达并激活了 caspase 3，导致 K562 细胞凋亡。在用 DDX5 的抑制剂 FL118 处理的细胞中也获得了类似的结果，FL118 是喜树碱（CPT）的衍生物化合物。此外，FL118 不仅在表达 BCR-ABL 的 Ba/F3 细胞中，而且在对 BCR-ABL 抑制剂耐药的表达 BCR-ABL T315I 突变体的细胞中，均能有效地诱导细胞凋亡。总之，这些结果表明 DDX5 是 CML 的一个关键治疗靶点，FL118 是治疗 BCR-ABL 抑制剂耐药性 CML 的有效候选化合物。
