The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
Biochem Pharmacol. 2024 Jul;225:116262. doi: 10.1016/j.bcp.2024.116262. Epub 2024 May 3.
Chemotherapy alone or in combination with allogeneic stem cell transplantation has been the standard of care for acute myeloid leukemia (AML) for decades. Leukemia relapse with limited treatment options remains the main cause of treatment failure. Therefore, an effective and safe approach to improve treatment outcomes is urgently needed for most AML patients. Mesenchymal stem cells (MSCs) have been reported to efficiently induce apoptosis and shape the fate of acute myeloid leukemia cells. Here, we identified LG190155 as a potent compound that enhances the antileukemia efficiency of MSCs. Pretreatment of MSCs with LG190155 significantly provoked differentiation in both AML patient-derived primary leukemia cells and AML cell lines and reduced the tumor burden in the AML mouse model. Using the quantitative proteomic technique, we discovered a pivotal mechanism that mediates AML cell differentiation, in which autocrine bone morphogenetic protein 6 (BMP6) in MSCs boosted IL-6 secretion and further acted on leukemic cells to trigger differentiation. Furthermore, the activity of the BMP6-IL6 axis was dramatically enhanced by activating vitamin D receptor (VDR) in MSCs. Our data illustrated an effective preactivated approach to reinforcing the antileukemia effect of MSCs, which could serve as an effective therapeutic strategy for AML.
化疗单独或与同种异体干细胞移植联合已成为急性髓系白血病（AML）几十年的标准治疗方法。治疗失败的主要原因是白血病复发且治疗选择有限。因此，大多数 AML 患者迫切需要一种有效且安全的方法来改善治疗效果。间充质干细胞（MSCs）已被报道可有效诱导急性髓系白血病细胞凋亡并决定其命运。在这里，我们鉴定出 LG190155 是一种有效增强 MSCs 抗白血病效率的化合物。LG190155 预处理 MSCs 可显著诱导 AML 患者来源的原代白血病细胞和 AML 细胞系分化，并降低 AML 小鼠模型中的肿瘤负担。通过定量蛋白质组学技术，我们发现了一种介导 AML 细胞分化的关键机制，其中 MSC 中的自分泌骨形态发生蛋白 6（BMP6）增强了白细胞介素 6（IL-6）的分泌，并进一步作用于白血病细胞以触发分化。此外，MSCs 中维生素 D 受体（VDR）的激活显著增强了 BMP6-IL6 轴的活性。我们的数据说明了一种增强 MSCs 抗白血病效果的有效预激活方法，可作为 AML 的有效治疗策略。
