多发性骨髓瘤（MM）是第二常见的血液恶性肿瘤。N6-甲基腺苷（m6A）是最丰富的RNA修饰。YTH结构域含家族蛋白2（YTHDF2）识别m6A含量高的RNA并促进其降解，以调节癌症进展。然而，YTHDF2在MM中的作用尚不清楚。我们研究了YTHDF2在MM中的表达水平和预后作用，并研究了YTHDF2对MM增殖和细胞周期的影响。结果表明，YTHDF2在MM中高度表达，并且是MM生存的独立预后因素。沉默YTHDF2抑制了细胞增殖并引起G1/S期细胞周期阻滞。RNA免疫共沉淀（RIP）和m6A-RIP（MeRIP）显示，YTHDF2依赖m6A加速EGR1 mRNA降解。此外，YTHDF2的过表达通过m6A介导的EGR1降解促进了MM的生长，无论是体外还是体内。此外，EGR1通过激活p21cip1/waf1转录和抑制CDK2-cyclinE1抑制了细胞增殖并延迟了细胞周期。EGR1沉默可以逆转YTHDF2沉默时被抑制的增殖和细胞周期阻滞作用。总之，YTHDF2的高表达通过EGR1/p21cip1/waf1/CDK2-cyclinE1轴介导的细胞周期转换促进了MM细胞的增殖，突显了YTHDF2作为有效的预后生物标志物和MM有望的治疗靶点的潜力。©2023年。作者（们）。

Multiple myeloma (MM) is the second most common hematological malignancy. N6-methyladenosine (m6A) is the most abundant RNA modification. YTH domain-containing family protein 2 (YTHDF2) recognizes m6A-cotaining RNAs and accelerates degradation to regulate cancer progression. However, the role of YTHDF2 in MM remains unclear. We investigated the expression levels and prognostic role of YTHDF2 in MM, and studied the effect of YTHDF2 on MM proliferation and cell cycle. The results showed that YTHDF2 was highly expressed in MM and was an independent prognostic factor for MM survival. Silencing YTHDF2 suppressed cell proliferation and caused the G1/S phase cell cycle arrest. RNA immunoprecipitation (RIP) and m6A-RIP (MeRIP) revealed that YTHDF2 accelerated EGR1 mRNA degradation in an m6A-dependent manner. Moreover, overexpression of YTHDF2 promoted MM growth via the m6A-dependent degradation of EGR1 both in vitro and in vivo. Furthermore, EGR1 suppressed cell proliferation and retarded cell cycle by activating p21cip1/waf1 transcription and inhibiting CDK2-cyclinE1. EGR1 knockdown could reverse the inhibited proliferation and cell cycle arrest upon YTHDF2 knockdown. In conclusion, the high expression of YTHDF2 promoted MM cell proliferation via EGR1/p21cip1/waf1/CDK2-cyclin E1 axis-mediated cell cycle transition, highlighting the potential of YTHDF2 as an effective prognostic biomarker and a promising therapeutic target for MM.© 2023. The Author(s).