Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199
Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199
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DOI：
10.1038/s41401-023-01142-2
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发表时间：
2023-08-29
影响因子：
8.2
通讯作者：
Li，Qiu-bai
中科院分区：
文献类型：
--
作者：
Ren，Wen-xiang;Guo，Hao;Li，Qiu-bai
黏附分子在造血细胞的动态平衡调节和恶性转化中起着至关重要的作用。黏附分子在白血病细胞中的异常表达加速了疾病的进展和耐药的发展。因此，靶向黏附分子是一种有吸引力的抗白血病治疗策略。在本研究中，我们探讨了细胞粘附素-1(CytH1)在急性髓系白血病(AML)中的预后作用和功能意义。对来自GEPIA和血斑数据库的AML患者数据的分析表明，CyTH1在AML中显著过度表达，并与预后独立相关。使用AML细胞系和AML异种移植小鼠模型进行的功能分析证实，CyTH1耗竭显著抑制了白血病细胞的黏附、迁移、归巢和植入，延缓了疾病的进展，延长了动物的生存时间。CyTH1抑制剂SecinH3通过破坏白血病的黏附和生存程序，在体外和体内发挥抗白血病作用。与CyTH1基因敲除结果一致，SecinH3靶向CyTH1通过减少ITGB2的表达抑制了整合素相关的黏附信号。SecinH3有效地诱导了一组具有混合系白血病基因重排的AML细胞系(MOLM-13、MV4-11和THP-1)的凋亡并抑制其生长，部分原因是通过减少抗凋亡蛋白MCL1的表达。此外，我们还发现SecinH3与BCL2选择性抑制剂ABT-199(Ventoclax)有协同作用，抑制ABT-199耐药白血病细胞的增殖并促进其凋亡。综上所述，我们的结果不仅阐明了CyTH1在细胞黏附介导的白血病发生中的作用，而且还提出了一种治疗AML的新的联合治疗策略。
Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed thatCYTH1was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed thatCYTH1depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with theCYTH1knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML.