由MRTF-SRF途径介导的化疗耐药白血病细胞的迁移停滞
Migration arrest of chemoresistant leukemia cells mediated by MRTF-SRF pathway.
作者信息
Morimatsu Maho, Yamashita Erika, Seno Shigeto, Sudo Takao, Kikuta Junichi, Mizuno Hiroki, Okuzaki Daisuke, Motooka Daisuke, Ishii Masaru
机构信息
Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan.
WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan.
出版信息
Inflamm Regen. 2020 Jul 6;40:15. doi: 10.1186/s41232-020-00127-6. eCollection 2020.
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.
背景
休眠的化疗耐药白血病细胞在复发前可长期存活。然而，体内化疗耐药发生的机制仍不清楚。
方法
利用活体骨成像技术，我们对阿糖胞苷化疗前后小鼠急性髓系白血病（AML）细胞（C1498）在骨髓中的行为进行了表征。
结果
增殖性C1498细胞在骨髓中表现出高迁移率。阿糖胞苷治疗损害了残留C1498细胞的迁移率。然而，C1498细胞在复发后恢复了其迁移潜能。RNA测序显示，阿糖胞苷治疗促进了MRTF-SRF通路的激活。在我们的AML小鼠模型中，使用CCG-203971抑制MRTF增强了化疗的抗肿瘤作用，并抑制了化疗耐药C1498细胞的迁移。
结论
这些结果为细胞迁移停滞在AML化疗耐药发生中的作用提供了新的见解，并为调节细胞运动性作为难治性AML的治疗靶点提供了有力的理论依据。
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