Multiple myeloma (MM) is a malignant plasma cell disorder in which the MYC oncogene is frequently dysregulated. Due to its central role, MYC has been proposed as a drug target; however, the development of a clinically applicable molecule modulating MYC activity remains an unmet challenge. Consequently, an alternative is the development of therapeutic options targeting proteins located downstream of MYC. Therefore, we aimed to identify undescribed MYC-target proteins in MM cells using Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) and mass spectrometry. We revealed a cluster of proteins associated with the regulation of translation initiation. Herein, the RNA-binding proteins Heterogeneous Nuclear Ribonucleoprotein C (hnRNPC) and La Ribonucleoprotein 1 (LARP1) were predominantly downregulated upon MYC depletion. CRISPR-mediated knockout of either hnRNPC or LARP1 in conjunction with redundant LARP family proteins resulted in a proliferative disadvantage for MM cells. Moreover, high expression levels of these proteins correlate with high MYC expression and with poor survival and disease progression in MM patients. In conclusion, our study provides valuable insights into MYC’s role in translation initiation by identifying hnRNPC and LARP1 as proliferation drivers of MM cells and as both predictive factors for survival and disease progression in MM patients.
多发性骨髓瘤是一种恶性浆细胞疾病，其中MYC癌基因常出现失调。鉴于其核心作用，MYC已被提议作为药物靶点；然而，开发能够调节MYC活性且适用于临床的分子仍是一个未解决的挑战。因此，另一种策略是开发针对MYC下游蛋白的治疗方案。为此，我们旨在通过细胞培养中氨基酸稳定同位素标记技术结合质谱分析，在多发性骨髓瘤细胞中鉴定尚未被描述的MYC靶蛋白。我们发现了一组与翻译起始调控相关的蛋白质簇，其中RNA结合蛋白异质核核糖核蛋白C和La核糖核蛋白1在MYC缺失时显著下调。通过CRISPR技术敲除hnRNPC或LARP1（同时敲除冗余的LARP家族蛋白）会导致多发性骨髓瘤细胞增殖能力下降。此外，这些蛋白的高表达水平与高MYC表达、多发性骨髓瘤患者不良生存及疾病进展相关。综上所述，本研究通过鉴定hnRNPC和LARP1作为多发性骨髓瘤细胞的增殖驱动因子，同时作为患者生存和疾病进展的预测因子，为理解MYC在翻译起始中的作用提供了重要见解。
肿瘤(癌症)患者之家