Multiple myeloma (MM) patients with chromosome 1q gain (1q+) are clinically and biologically heterogeneous. The underlying molecular mechanisms are still under investigation, while the identification of targets for effective therapy of this subgroup of MM patients is urgently needed. We aimed to investigate the clinical significance and the regulatory mechanisms of insulin-like growth factor 2 messenger RNA (mRNA) binding protein 1 (IGF2BP1), a N6-methyladenosine (m⁶A) reader, in MM patients with 1q+. We found that MM patients with 1q+ exhibit a significantly higher level of IGF2BP1 mRNA than controls, while higher IGF2BP1 expression predicted a worse prognosis in MM patients with 1q+. IGF2BP1 overexpression promoted cell proliferation and G1-to-S phase transition of the cell cycle in NCI-H929 cells. Through comprehensive in silico analyses of existing public datasets and in-house generated high-throughput sequencing datasets, along with in vitro experiments, we identified CDC5L as a target of IGFBP1, which can bind to the m⁶A sites of CDC5L mRNA to up-regulate its protein abundance. Higher CDC5L expression also predicted a worse prognosis of MM patients with 1q+. Moreover, both knockdown and mutation of CDC5L attenuated the pro-proliferative effect of IGF2BP1. Furthermore, IGF2BP1 inhibitor BTYNB effectively inhibited CDC5L expression in MM cells with 1q+ and suppressed the proliferation of these cells in vitro and in vivo. Therefore, IGF2BP1 acts as a post-transcriptional enhancer of CDC5L in an m⁶A-dependent manner to promote the proliferation of MM cells with 1q+. Our work identified a novel IGF2BP1-CDC5L axis and provided new insight into developing targeted therapeutics for MM patients with 1q+.

染色体 1q 增益 (1q+) 的多发性骨髓瘤 (MM) 患者在临床和生物学上存在异质性。潜在的分子机制仍在研究中，同时迫切需要确定针对这一亚组 MM 患者的有效治疗靶点。我们的目的是研究胰岛素样生长因子 2 信使 RNA (mRNA) 结合蛋白 1 (IGF2BP1)（一种 N6-甲基腺苷 (m ⁶ A) 读数器）在 1q+ MM 患者中的临床意义和调节机制。我们发现 1q+ MM 患者的 IGF2BP1 mRNA 水平显着高于对照组，而较高的 IGF2BP1 表达预示 1q+ MM 患者预后较差。IGF2BP1过表达促进NCI-H929细胞中的细胞增殖和细胞周期G1至S期的转变。通过对现有公共数据集和内部生成的高通量测序数据集进行全面的计算机分析，以及体外实验，我们确定 CDC5L 是 IGFBP1 的靶标，它可以与 CDC5L mRNA 的 m ⁶ A 位点结合，从而向上-调节其蛋白质丰度。CDC5L 表达较高也预示着 1q+ MM 患者的预后较差。此外，CDC5L 的敲除和突变都会减弱 IGF2BP1 的促增殖作用。此外，IGF2BP1抑制剂BTYNB可有效抑制1q+ MM细胞中CDC5L的表达，并在体外和体内抑制这些细胞的增殖。^{因此，IGF2BP1以m 6} A依赖性方式作为CDC5L的转录后增强子，促进1q+的MM细胞的增殖。我们的工作确定了一个新的 IGF2BP1-CDC5L 轴，并为开发 1q+ MM 患者的靶向治疗方法提供了新的见解。