急性髓系白血病 (AML) 来源的间充质干细胞通过 IL-6/JAK2/STAT3 信号传导在 AML 中诱导化疗耐药和上皮-间质转化样程序,Cancer Science

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急性髓系白血病 (AML) 来源的间充质干细胞通过 IL-6/JAK2/STAT3 信号传导在 AML 中诱导化疗耐药和上皮-间质转化样程序
Cancer Science ( IF 4.5 ) Pub Date : 2023-06-04 , DOI: 10.1111/cas.15855
Jianle Lu ₁ , Qiaomei Dong ₂ , Shuling Zhang ₁ , Youfan Feng ₁ , Jincai Yang ₁ , Li Zhao _{1,

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Affiliation

由于治疗耐药性的增加，急性髓系白血病（AML）的治疗失败率很高。白血病微环境中的间充质干细胞（MSC）有助于AML的化疗耐药，但具体机制仍不清楚。上皮-间质转化（EMT）样谱在 AML 化疗耐药中的关键作用已逐渐被认识到。然而，迄今为止，尚无研究表明 AML 来源的骨髓间充质干细胞 (AML-MSC) 能诱导 AML 的 EMT 程序。我们分离了 AML-MSC，并将其与 AML 细胞共培养。我们发现，AML-MSCs 在耐药 AML 细胞中诱导显着的间质样形态，但在亲本 AML 细胞中很少见。在体外和体内存在或不存在化疗药物的情况下，AML-MSC 都能促进 AML 细胞的生长。急性髓系白血病 MSC 还诱导 AML 细胞中的 EMT 标志物表达，特别是在化疗耐药的 AML 细胞中。从机制上讲，AML-MSC 分泌丰富的白细胞介素 6 (IL-6)，并上调 AML 细胞中的 IL-6 表达。急性髓系白血病细胞反过来上调AML-MSCs中IL-6的表达。同时，AML-MSCs激活AML细胞中的JAK2/STAT3通路。两种 JAK/STAT 通路抑制剂抵消了 AML-MSC 诱导的 AML 细胞形态变化和 EMT 标志物表达。总之，AML-MSC不仅促进化疗耐药性的出现，而且一旦AML获得化疗耐药性，还会增强化疗耐药性。AML-MSC 在 AML 细胞中诱导 EMT 样特征；这种表型变化可能与化疗耐药进展有关。AML-MSC 通过 IL-6/JAK2/STAT3 信号传导在 AML 细胞中诱导 EMT 样程序，这为逆转 AML 化疗耐药提供了治疗靶点。

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Acute myeloid leukemia (AML)-derived mesenchymal stem cells induce chemoresistance and epithelial–mesenchymal transition-like program in AML through IL-6/JAK2/STAT3 signaling

Acute myeloid leukemia (AML) has a high rate of treatment failure due to increased prevalence of therapy resistance. Mesenchymal stem cells (MSCs) in the leukemia microenvironment contribute to chemoresistance in AML, but the specific mechanism remains unclear. The critical role of the epithelial–mesenchymal transition (EMT)-like profile in AML chemoresistance has been gradually recognized. However, there is no research to suggest that the AML-derived bone marrow mesenchymal stem cells (AML-MSCs) induce the EMT program in AML thus far. We isolated AML-MSCs and cocultured them with AML cells. We found that AML-MSCs induced a significant mesenchymal-like morphology in drug-resistant AML cells, but it was scarce in parental AML cells. The AML-MSCs promoted growth of AML cells in the presence or absence of chemotherapeutics in vitro and in vivo. Acute myeloid leukemia MSCs also induced EMT marker expression in AML cells, especially in chemoresistant AML cells. Mechanistically, AML-MSCs secreted abundant interleukin-6 (IL-6) and upregulated IL-6 expression in AML cells. Acute myeloid leukemia cells upregulated IL-6 expression in AML-MSCs in turn. Meanwhile, AML-MSCs activated the JAK2/STAT3 pathway in AML cells. Two JAK/STAT pathway inhibitors counteracted the AML-MSCs induced morphology change and EMT marker expression in AML cells. In conclusion, AML-MSCs not only promote the emergence of chemoresistance but also enhance it once AML acquires chemoresistance. AML-MSCs induce EMT-like features in AML cells; this phenotypic change could be related to chemoresistance progression. AML-MSCs induce the EMT-like program in AML cells through IL-6/JAK2/STAT3 signaling, which provides a therapeutic target to reverse chemoresistance in AML.

更新日期：2023-06-04

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