Resistance to chemotherapy remains a major hurdle to the cure of Acute Myeloid Leukemia (AML) patients. Recent studies indicate a minority of malignant cells, termed drug-tolerant persisters (DTPs), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy without acquiring new genetic mutations. This chemoresistant state is transient and the cells return to baseline after removal of chemotherapy. Yet, the mechanisms employed by DTPs to resist chemotherapy are not well understood and it is largely unknown whether these mechanisms are also seen in patients receiving chemotherapy. Here, we used leukemia cell lines, primary AML patient samples and samples from patients with AML receiving systemic chemotherapy to study the DTP state. We demonstrated that a subset of AML cells transiently increases membrane rigidity to resist killing due to acute exposure to Daunorubicin and Ara-C. Upon removal of the chemotherapy, membrane rigidity returned to baseline and the cells regained chemosensitivity. Although resistant to chemotherapy, the increased membrane rigidity, rendered AML cells more susceptible to T-cell mediated killing. Thus, we identified a novel mechanism by which DTP leukemic cells evade chemotherapy and a strategy to eradicate these persistent cells.

中文翻译：

---

急性髓系白血病药物耐受的持久性细胞通过瞬时增加质膜刚度在化疗中存活，这也增加了它们对免疫细胞杀伤的敏感性。


对化疗的耐药性仍然是急性髓性白血病 （AML） 患者治愈的主要障碍。最近的研究表明，少数恶性细胞，称为耐药持久性 （DTP），在急性暴露于化疗时随机上调应激途径以逃避细胞死亡，而不会获得新的基因突变。这种化疗耐药状态是短暂的，去除化疗后细胞会恢复到基线水平。然而，DTP 用于抵抗化疗的机制尚不清楚，这些机制是否也出现在接受化疗的患者中，这在很大程度上是未知数。在这里，我们使用白血病细胞系、原发性 AML 患者样本和接受全身化疗的 AML 患者的样本来研究 DTP 状态。我们证明，由于急性暴露于柔红霉素和 Ara-C，AML 细胞亚群会瞬时增加膜刚性以抵抗杀伤。去除化疗后，膜硬度恢复到基线水平，细胞恢复化疗敏感性。尽管对化疗有耐药性，但膜硬度的增加使 AML 细胞更容易受到 T 细胞介导的杀伤。因此，我们确定了 DTP 白血病细胞逃避化疗的新机制以及根除这些持续细胞的策略。