The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou 510005, China; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Bioland Laboratory, Guangzhou 51005, China.
The Fifth Affiliated Hospital, State Key Laboratory of Respiratory Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou 510005, China; Bioland Laboratory, Guangzhou 51005, China.
Cancer Cell. 2022 Dec 12;40(12):1566-1582.e10. doi: 10.1016/j.ccell.2022.10.004. Epub 2022 Oct 27.
N-Methyladenosine (mA) modification and its modulators play critical roles and show promise as therapeutic targets in human cancers, including acute myeloid leukemia (AML). IGF2BP2 was recently reported as an mA binding protein that enhances mRNA stability and translation. However, its function in AML remains largely elusive. Here we report the oncogenic role and the therapeutic targeting of IGF2BP2 in AML. High expression of IGF2BP2 is observed in AML and associates with unfavorable prognosis. IGF2BP2 promotes AML development and self-renewal of leukemia stem/initiation cells by regulating expression of critical targets (e.g., MYC, GPT2, and SLC1A5) in the glutamine metabolism pathways in an mA-dependent manner. Inhibiting IGF2BP2 with our recently identified small-molecule compound (CWI1-2) shows promising anti-leukemia effects in vitro and in vivo. Collectively, our results reveal a role of IGF2BP2 and mA modification in amino acid metabolism and highlight the potential of targeting IGF2BP2 as a promising therapeutic strategy in AML.
N6-甲基腺苷（m6A）修饰及其调节剂在人类癌症中发挥着关键作用，并显示出作为治疗靶点的潜力，包括急性髓系白血病（AML）。IGF2BP2 最近被报道为一种 mA 结合蛋白，可增强 mRNA 的稳定性和翻译。然而，其在 AML 中的功能在很大程度上仍不清楚。在这里，我们报告了 IGF2BP2 在 AML 中的致癌作用和治疗靶点。IGF2BP2 在 AML 中表达较高，与不良预后相关。IGF2BP2 通过 mA 依赖性方式调节谷氨酰胺代谢途径中的关键靶标（如 MYC、GPT2 和 SLC1A5）的表达，促进 AML 的发展和白血病干细胞/起始细胞的自我更新。我们最近发现的小分子化合物（CWI1-2）抑制 IGF2BP2 在体外和体内显示出有希望的抗白血病作用。综上所述，我们的研究结果揭示了 IGF2BP2 和 m6A 修饰在氨基酸代谢中的作用，并强调了靶向 IGF2BP2 作为 AML 有前途的治疗策略的潜力。
