Galectin-3 mediates bone marrow microenvironment-induced drug resistance in acute leukemia cells via Wnt/β-catenin signaling pathway.
Galectin-3 mediates bone marrow microenvironment-induced drug resistance in acute leukemia cells via Wnt/β-catenin signaling pathway.
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Galectin-3通过Wnt/β-catenin信号通路介导骨髓微环境诱导的急性白血病细胞耐药
DOI：
10.1186/s13045-014-0099-8
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发表时间：
2015-01-27
影响因子：
28.5
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Hu K;Gu Y;Lou L;Liu L;Hu Y;Wang B;Luo Y;Shi J;Yu X;Huang H
急性白血病是目前血液系统恶性肿瘤死亡的主要原因。尽管新疗法发展迅速，但微小残留病（MRD）仍然持续发生并导致不良结果。骨髓微环境（BMM）中的白血病生态位被认为是造成这种 MRD 发展的原因，这可能导致白血病耐药性和疾病复发。因此，进一步研究白血病生态位与急性白血病细胞（ALC）相互作用的方式并开发阻断潜在过程的策略有望改善疾病预后。最近的研究表明半乳糖凝集素 3 (gal-3) 可能在此过程中发挥关键作用。因此，我们的目的是阐明 gal-3 在此过程中所发挥的确切作用并阐明其作用机制。我们使用人骨髓间充质干细胞（hBM-MSCs）在体外模拟白血病BMM，并研究其对ALCs耐药性的影响及其可能的机制，特别强调gal-3的作用。在我们的研究中，我们证明hBM-MSCs诱导gal-3上调，促进β-catenin稳定，从而激活ALC中的Wnt/β-catenin信号通路，这对于白血病的细胞毒性耐药性至关重要。添加 gal-3 短发夹 RNA (shRNA) 可以逆转这种效应。我们还发现 gal-3 的上调促进了 Akt 和糖原合酶激酶 (GSK)-3β 磷酸化，这被认为构成了 gal-3 和 Wnt 信号传导之间的跨桥。我们的结果表明，gal-3（介导 BMM 诱导的耐药性的关键因素）可能成为急性白血病的新治疗靶点。
Acute leukemia is currently the major cause of death in hematological malignancies. Despite the rapid development of new therapies, minimal residual disease (MRD) continues to occur and leads to poor outcomes. The leukemia niche in the bone marrow microenvironment (BMM) is thought to be responsible for such MRD development, which can lead to leukemia drug resistance and disease relapse. Consequently further investigation into the way in which the leukemia niche interacts with acute leukemia cells (ALCs) and development of strategies to block the underlying process are expected to improve disease prognosis. Recent studies indicated that galectin-3 (gal-3) might play a pivotal role in this process. Thus we aimed to elucidate the exact role played by gal-3 in this process and clarify its mechanism of action. We used human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) to mimic the leukemia BMM in vitro, and investigated their effects on drug resistance of ALCs and the possible mechanisms involved, with particular emphasis on the role of gal-3. In our study, we demonstrated that hBM-MSCs induced gal-3 up-regulation, promoting β-catenin stabilization and thus activating the Wnt/β-catenin signaling pathway in ALCs, which is critical in cytotoxic drug resistance of leukemia. This effect could be reversed by addition of gal-3 short hairpin RNA (shRNA). We also found that up-regulation of gal-3 promoted Akt and glycogen synthase kinase (GSK)-3β phosphorylation, thought to constitute a cross-bridge between gal-3 and Wnt signaling. Our results suggest that gal-3, a key factor mediating BMM-induced drug resistance, could be a novel therapeutic target in acute leukemia.
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影响因子：
20.3
作者：
Kamdje, Armel Herve Nwabo;Mosna, Federico;Krampera, Mauro
通讯作者：
Krampera, Mauro
影响因子：
56.9
作者：
CLARK, SS;MCLAUGHLIN, J;WITTE, ON
通讯作者：
WITTE, ON
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW
影响因子：
8
作者：
Crawford, HC;Fingleton, BM;Matrisian, LM
通讯作者：
Matrisian, LM
影响因子：
20.3
作者：
Clark, Mary C.;Pang, Mabel;Baum, Linda G.
通讯作者：
Baum, Linda G.