Migration arrest of chemoresistant leukemia cells mediated by MRTF-SRF pathway
Migration arrest of chemoresistant leukemia cells mediated by MRTF-SRF pathway
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DOI：
10.1186/s41232-020-00127-6
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发表时间：
2020-07-06
影响因子：
8.1
通讯作者：
Ishii, Masaru
中科院分区：
文献类型：
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作者：
Morimatsu, Maho;Yamashita, Erika;Ishii, Masaru
背景耐多柔比星化疗的白血病细胞在复发前可以存活很长时间。然而，体内化疗耐药性发展的机制仍不清楚。方法采用活体骨显像技术，观察阿糖胞苷化疗前后小鼠急性髓系白血病（AML）细胞（C1498）在骨髓中的行为。结果体外培养的C1498细胞在骨髓中具有较高的运动能力。阿糖胞苷处理损害了残余C1498细胞的运动性。然而，C1498细胞在复发后恢复了其迁移能力。RNA测序显示阿糖胞苷处理促进了MRTF-SRF通路的激活。使用CCG-203971的MRTF抑制增强了我们的AML小鼠模型中化疗的抗肿瘤作用，并抑制了耐药C1498细胞的迁移。结论这些结果为细胞迁移阻滞在AML化疗耐药发展中的作用提供了新的见解，并为调节细胞运动作为难治性AML的治疗靶点提供了强有力的理论基础。
Background Dormant chemotherapy-resistant leukemia cells can survive for an extended period before relapse. Nevertheless, the mechanisms underlying the development of chemoresistance in vivo remain unclear. Methods Using intravital bone imaging, we characterized the behavior of murine acute myeloid leukemia (AML) cells (C1498) in the bone marrow before and after chemotherapy with cytarabine. Results Proliferative C1498 cells exhibited high motility in the bone marrow. Cytarabine treatment impaired the motility of residual C1498 cells. However, C1498 cells regained their migration potential after relapse. RNA sequencing revealed that cytarabine treatment promoted MRTF-SRF pathway activation. MRTF inhibition using CCG-203971 augmented the anti-tumor effects of chemotherapy in our AML mouse model, as well as suppressed the migration of chemoresistant C1498 cells. Conclusions These results provide novel insight into the role of cell migration arrest on the development of chemoresistance in AML, as well as provide a strong rationale for the modulation of cellular motility as a therapeutic target for refractory AML.