Our investigation uncovers that nanomolar concentrations of salinomycin, monensin, nigericin, and narasin (a group of potassium/sodium cation carriers) robustly enhance surface expression of CD20 antigen in B-cell-derived tumor cells, including primary malignant cells of chronic lymphocytic leukemia and diffuse large B-cell lymphoma. Experiments in vitro, ex vivo, and animal model reveal a novel approach of combining salinomycin or monensin with therapeutic anti-CD20 monoclonal antibodies or anti-CD20 CAR-T cells, significantly improving non- Hodgkin lymphoma (NHL) therapy. The results of RNA-seq, genetic editing, and chemical inhibition delineate the molecular mechanism of CD20 upregulation, at least partially, to the downregulation of MYC, the transcriptional repressor of the MS4A1 gene encoding CD20. Our findings propose the cation carriers as compounds targeting MYC oncogene, which can be combined with anti-CD20 antibodies or adoptive cellular therapies to treat NHL and mitigate resistance, which frequently depends on the CD20 antigen loss, offering new solutions to improve patient outcomes.

中文翻译：

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钾/钠阳离子载体通过靶向 MYC 稳健地上调 CD20 抗原，并与抗 CD20 免疫疗法协同作用以消除恶性 B 细胞。


我们的研究发现，盐霉素、莫能菌素、黑牙菌素和那拉辛（一组钾/钠阳离子载体）的纳摩尔浓度强烈增强了 B 细胞衍生的肿瘤细胞中 CD20 抗原的表面表达，包括慢性淋巴细胞白血病和弥漫性大 B 细胞淋巴瘤的原发性恶性细胞。体外、离体和动物模型实验揭示了一种将盐霉素或莫能菌素与治疗性抗 CD20 单克隆抗体或抗 CD20 CAR-T 细胞相结合的新方法，显着改善了非霍奇金淋巴瘤 （NHL） 治疗。RNA-seq、基因编辑和化学抑制的结果描述了 CD20 上调的分子机制，至少部分地下调了 MYC，MYC 是编码 CD20 的 MS4A1 基因的转录抑制因子。我们的研究结果提出阳离子载体作为靶向 MYC 癌基因的化合物，可以与抗 CD20 抗体或过继细胞疗法联合治疗 NHL 并减轻耐药性，这通常取决于 CD20 抗原的丢失，为改善患者预后提供新的解决方案。