Department of Hematology, Qilu Hospital of Shandong University, Jinan, P.R. China.
Mol Cancer Res. 2024 Oct 2;22(10):932-942. doi: 10.1158/1541-7786.MCR-23-0928.
The blast crisis (BC) of chronic myeloid leukemia (CML) has poor efficacy against existing treatments and extremely short survival. However, the molecular mechanism of CML-chronic phase (CP) transformation to CML-BC is not yet fully understood. Here, we show that Lin28B, an RNA-binding protein, acted as an activator enhancing the transformation to CML-BC by mediating excessive cell proliferation. The level of Lin28B expression was apparently elevated in patients with CML-BC compared with newly diagnosed patients with CML-CP. The overexpression of Lin28B promoted the proliferation of leukemia cells. Mechanistically, we identified Lin28B as a DNA-binding protein by binding to the promoter region of miR-181d and upregulating its expression, which inhibited the expression of programmed cell death 4 (PDCD4) by binding to the PDCD4 3'UTR region, thereby enhancing the proliferation of CML cells. Overall, the "Lin28B-miR-181d-PDCD4" regulatory axis promoted CML blast crisis. Implications: Our findings highlight the oncogenic role of Lin28B in CML blast crisis, acting as a DNA-binding protein that transcriptionally upregulates miR-181d expression.
慢性髓性白血病（CML）的急变期（BC）对现有治疗方法的疗效较差，生存时间极短。然而，CML-慢性期（CP）向 CML-BC 转化的分子机制尚不完全清楚。在这里，我们表明 RNA 结合蛋白 Lin28B 通过介导过度细胞增殖，充当增强向 CML-BC 转化的激活剂。与新诊断的 CML-CP 患者相比，CML-BC 患者的 Lin28B 表达水平明显升高。Lin28B 的过表达促进了白血病细胞的增殖。在机制上，我们通过结合到 miR-181d 的启动子区域并上调其表达，将 Lin28B 鉴定为一种 DNA 结合蛋白，通过结合到 PDCD4 的 3'UTR 区域抑制程序性细胞死亡 4（PDCD4）的表达，从而增强 CML 细胞的增殖。总体而言，“Lin28B-miR-181d-PDCD4”调控轴促进了 CML 急变期的发生。意义：我们的研究结果强调了 Lin28B 在 CML 急变期中的致癌作用，作为一种转录上调 miR-181d 表达的 DNA 结合蛋白。
