PDF(Pubmed)
Abstract：
Knowledge of the molecular pathogenesis of acute myeloid leukemia has advanced in recent years. Despite novel treatment options, acute myeloid leukemia remains a survival challenge for elderly patients. We have recently shown that the triphosphohydrolase SAMHD1 is one of the factors determining resistance to Ara-C treatment. Here, we designed and tested novel and simpler virus-like particles incorporating the lentiviral protein Vpx to efficiently and transiently degrade SAMHD1 and increase the efficacy of Ara-C treatment. The addition of minute amounts of lentiviral Rev protein during production enhanced the generation of virus-like particles. In addition, we found that our 2nd generation of virus-like particles efficiently targeted and degraded SAMHD1 in AML cell lines with high levels of SAMHD1, thereby increasing Ara-CTP levels and response to Ara-C treatment. Primary AML blasts were generally less responsive to VLP treatment. In summary, we have been able to generate novel and simpler virus-like particles that can efficiently deliver Vpx to target cells.
摘要：
近年来，对急性髓系白血病的分子发病机制的认识有所提高。尽管有新颖的治疗选择,急性髓系白血病仍然是老年患者生存的挑战.我们最近表明，三磷酸水解酶SAMHD1是决定对Ara-C处理的抗性的因素之一。这里,我们设计并测试了掺入慢病毒蛋白Vpx的新型且更简单的病毒样颗粒,以有效和瞬时降解SAMHD1并提高Ara-C治疗的疗效.在生产过程中添加微量的慢病毒Rev蛋白增强了病毒样颗粒的产生。此外,我们发现,我们的第2代病毒样颗粒在SAMHD1水平高的AML细胞系中有效靶向和降解SAMHD1,从而提高Ara-CTP水平和对Ara-C治疗的应答.原发性AML母细胞通常对VLP治疗反应较小。总之,我们已经能够产生新型和更简单的病毒样颗粒，可以有效地将Vpx递送到靶细胞。
