Mesenchymal stromal cells confer chemoresistance to myeloid leukemia blasts through Side Population functionality and ABC transporter activation
Mesenchymal stromal cells confer chemoresistance to myeloid leukemia blasts through Side Population functionality and ABC transporter activation
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DOI：
10.3324/haematol.2018.214379
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发表时间：
2020-04-01
期刊：
影响因子：
10.1
通讯作者：
Anginot, Adrienne
中科院分区：
文献类型：
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作者：
Boutin, Laetitia;Arnautou, Pierre;Anginot, Adrienne
靶向化疗耐药的恶性细胞是肿瘤学当前的主要挑战之一。因此，必须改进这些细胞的特性，以监测它们的存活并开发适应性疗法。这在急性髓性白血病（AML）中特别令人感兴趣，无论预后如何，其5年生存率仅达到30%。微环境的作用越来越多地被报道是一个关键的调节器爆炸生存。在这种情况下，我们表明，接触间充质基质细胞促进了更好的生存在蒽环类抗生素的存在下，通过激活ABC转运培养的胚细胞。基质依赖性ABC转运蛋白激活通过α 4结合导致在原代白血病母细胞亚群中诱导侧群（SP）表型。基质促进效应是可逆的，并且在从健康供体或白血病患者分离的基质细胞中观察到。表达SP表型的胚细胞大多是静止的，并且在体外和体内在患者来源的异种移植小鼠模型中具有化学抗性。在转录组水平，来自SP的胚细胞在药物代谢程序中特异性富集。这种与间充质基质细胞接触的解毒特征代表了靶向AML细胞的基质诱导的化学抗性的有希望的方法。
Targeting chemoresistant malignant cells is one of the current major challenges in oncology. Therefore, it is mandatory to refine the characteristics of these cells to monitor their survival and develop adapted therapies. This is of particular interest in acute myeloid leukemia (AML), for which the 5-year survival rate only reaches 30%, regardless of the prognosis. The role of the microenvironment is increasingly reported to be a key regulator for blast survival. In this context, we demonstrate that contact with mesenchymal stromal cells promotes a better survival of blasts in culture in the presence of anthracycline through the activation of ABC transporters. Stroma-dependent ABC transporter activation leads to the induction of a Side Population (SP) phenotype in a subpopulation of primary leukemia blasts through alpha (alpha)4 engagement. The stroma-promoting effect is reversible and is observed with stromal cells isolated from either healthy donors or leukemia patients. Blasts expressing an SP phenotype are mostly quiescent and are chemoresistant in vitro and in vivo in patient-derived xenograft mouse models. At the transcriptomic level, blasts from the SP are specifically enriched in the drug metabolism program. This detoxification signature engaged in contact with mesenchymal stromal cells represents promising ways to target stroma-induced chemoresistance of AML cells.