Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu, China.
Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu, China; Department of Hematology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, 120 Suzhi Road, Suqian 223812, Jiangsu, China.
Int Immunopharmacol. 2024 Jun 15;134:112212. doi: 10.1016/j.intimp.2024.112212. Epub 2024 May 9.
Chronic myeloid leukemia (CML) is a type of hematologic malignancies caused by BCR-ABL chimeric oncogene. Resistance to tyrosine kinase inhibitors (TKIs) leads to the progression of CML into advanced stages. Selinexor is a small molecule inhibitor that targets a nuclear transporter called Exportin 1. Combined with imatinib, selinexor has been shown to disrupt nuclear-cytoplasmic transport signal of leukemia stem cells, resulting in cell death. The objective of this study was to investigate the mechanism of drug resistance to selinexor in CML. We established K562 cell line resistant to selinexor and conducted single cell dynamic transcriptome sequencing to analyze the heterogeneity within the parental and selinexor resistant cell populations. We identified specific gene expression changes associated with resistance to selinexor. Our results revealed differential expression patterns in genes such as MT2A, TFPI, MTND3, and HMGCS1 in the total RNA, as well as MT-TW, DNAJB1, and HSPB1 in the newly synthesized RNA, between the parental and drug-resistant groups. By applying pseudo-time analysis, we discovered that a specific cluster of cells exhibited characteristics of tumor stem cells. Furthermore, we observed a gradual decrease in the expression of ferroptosis-related molecules as drug resistance developed. In vitro experiments confirmed that the combination of a ferroptosis inducer called RSL3 effectively overcame drug resistance. In conclusion, this study revealed the resistance mechanism of selinexor in CML. In conclusion, we identified a subgroup of CML cells with tumor stem cell properties and demonstrated that ferroptosis inducer improved the efficacy of selinexor in overcoming drug resistance.
慢性髓性白血病（CML）是一种由 BCR-ABL 嵌合癌基因引起的血液系统恶性肿瘤。对酪氨酸激酶抑制剂（TKIs）的耐药性导致 CML 进展为晚期。Selinexor 是一种小分子抑制剂，靶向一种称为 Exportin 1 的核转运蛋白。与伊马替尼联合使用，Selinexor 已被证明可破坏白血病干细胞的核质转运信号，导致细胞死亡。本研究的目的是研究 CML 对 Selinexor 耐药的机制。我们建立了对 Selinexor 耐药的 K562 细胞系，并进行了单细胞动态转录组测序，以分析亲本和 Selinexor 耐药细胞群体内的异质性。我们确定了与 Selinexor 耐药相关的特定基因表达变化。我们的结果显示，在总 RNA 中，MT2A、TFPI、MTND3 和 HMGCS1 等基因的表达模式存在差异，而在新合成的 RNA 中，MT-TW、DNAJB1 和 HSPB1 等基因的表达模式存在差异，在亲本和耐药组之间。通过应用伪时间分析，我们发现一个特定的细胞簇表现出肿瘤干细胞的特征。此外，我们观察到随着耐药性的发展，铁死亡相关分子的表达逐渐降低。体外实验证实，铁死亡诱导剂 RSL3 的组合可有效克服耐药性。总之，本研究揭示了 Selinexor 在 CML 中的耐药机制。总之，我们确定了具有肿瘤干细胞特性的 CML 细胞亚群，并证明铁死亡诱导剂可提高 Selinexor 克服耐药性的疗效。
