Abstract：
Patients with multiple myeloma (MM) with chromosome 1q21 Gain (1q21+) are clinically and biologically heterogeneous. 1q21+ in the real world actually reflects the prognosis for gain/amplification of the CKS1B gene. In this study, we found that the copy number of prune exopolyphosphatase 1 (PRUNE1), located on chromosome 1q21.3, could further stratify the prognosis of MM patients with 1q21+. Using selected reaction monitoring/multiple reaction monitoring (SRM/MRM) analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS), transmission electron microscopy (TEM), confocal fluorescence microscopy, calculation of adenosine triphosphate (ATP), intracellular reactive oxygen species (ROS) and mitochondrial oxygen consumption rates (OCRs), we demonstrated for the first time that PRUNE1 promotes the proliferation and invasion of MM cells by stimulating purine metabolism, purine synthesis enzymes and mitochondrial functions, enhancing links between purinosomes and mitochondria. SOX11 was identified as a transcription factor for PRUNE1. Through integrated analysis of the transcriptome and proteome, CD73 was determined to be the downstream target of PRUNE1. Furthermore, it has been determined that dipyridamole can effectively suppress the proliferation of MM cells with high-expression levels of PRUNE1 in vitro and in vivo. These findings provide insights into disease-causing mechanisms and new therapeutic targets for MM patients with 1q21+.
摘要：
具有染色体1q21Gain(1q21+)的多发性骨髓瘤(MM)患者具有临床和生物学异质性。现实世界中的1q21+实际上反映了CKS1B基因的增益/扩增的预后。在这项研究中,我们发现修剪外聚磷酸酶1(PRUNE1)的拷贝数，位于1q21.3染色体上,可以进一步对1q21+MM患者的预后进行分层。使用选定的反应监测/多反应监测（SRM/MRM）分析，液相色谱-串联质谱(LC-MS/MS),透射电子显微镜（TEM），共聚焦荧光显微镜，三磷酸腺苷（ATP）的计算，细胞内活性氧（ROS）和线粒体耗氧率（OCR），我们首次证明PRUNE1通过刺激嘌呤代谢促进MM细胞的增殖和侵袭，嘌呤合成酶和线粒体功能，增强嘌呤体和线粒体之间的联系。SOX11被鉴定为PRUNE1的转录因子。通过对转录组和蛋白质组的综合分析，CD73被确定为PRUNE1的下游靶标。此外，已经确定，潘生丁在体外和体内均能有效抑制高表达PRUNE1的MM细胞的增殖。这些发现为患有1q21+的MM患者的致病机制和新的治疗靶标提供了见解。
