State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematological Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Mol Cancer Res. 2020 Jul;18(7):1063-1073. doi: 10.1158/1541-7786.MCR-19-0852. Epub 2020 Apr 20.
Multiple myeloma remains incurable due to the persistence of a minor population of multiple myeloma cells that exhibit drug resistance, which leads to relapsed and/or refractory multiple myeloma. Elucidating the mechanism underlying drug resistance and developing an effective treatment are critical for clinical management of multiple myeloma. Here we showed that promoting expression of the gene for polycomb-like protein 3 (PHF19) induced multiple myeloma cell growth and multidrug resistance and . was overexpressed in high-risk and drug-resistant primary cells from patients. High levels of were correlated with inferior survival of patients with multiple myeloma, in the Total Therapy 2 cohort and in the Intergroup Francophone du Myeloma (IFM) cohort. Enhancing expression levels increased , and expression in multiple myeloma cells. PHF19 also bound directly with EZH2 promoted the phosphorylation of EZH2 through PDK1/AKT signaling. miR-15a is a small noncoding RNA that targeted the 3'UTR of . We found that downregulation of led to high levels of in multiple myeloma cells. These findings revealed that served a crucial role in multiple myeloma proliferation and drug resistance and suggested that the pathway made a pivotal contribution to multiple myeloma pathogenesis, offering a promising approach to multiple myeloma treatment. IMPLICATIONS: Our findings identify that mediates EZH2 phosphorylation as a mechanism of myeloma cell drug resistance, providing a rationale to explore therapeutic potential of targeting in relapsed or refractory patients with multiple myeloma.
多发性骨髓瘤仍然无法治愈，因为存在一小部分具有耐药性的多发性骨髓瘤细胞，这导致多发性骨髓瘤复发和/或难治。阐明耐药性的机制并开发有效的治疗方法对于多发性骨髓瘤的临床管理至关重要。在这里，我们发现促进多梳样蛋白 3（PHF19）基因的表达可诱导多发性骨髓瘤细胞生长和多药耐药性，并且在患者的高危和耐药性原代细胞中过表达。高水平的 与多发性骨髓瘤患者的生存不良相关，在 Total Therapy 2 队列和 Intergroup Francophone du Myeloma（IFM）队列中均如此。增强 表达水平增加了 和 在多发性骨髓瘤细胞中的表达。PHF19 还与 EZH2 直接结合，通过 PDK1/AKT 信号通路促进 EZH2 的磷酸化。miR-15a 是一种小的非编码 RNA，靶向 的 3'UTR。我们发现下调 导致多发性骨髓瘤细胞中 水平升高。这些发现表明 在多发性骨髓瘤增殖和耐药性中起关键作用，并表明 途径对多发性骨髓瘤发病机制有重要贡献，为治疗复发性或难治性多发性骨髓瘤提供了一种有前途的方法。
我们的发现确定了 作为骨髓瘤细胞耐药的一种机制，介导了 EZH2 的磷酸化，为探索靶向 在复发性或难治性多发性骨髓瘤患者中的治疗潜力提供了依据。
