Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia.
Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia.
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通过基质半乳糖凝集素-3抑制克服急性淋巴细胞白血病中微环境介导的化学保护作用。
DOI：
10.3390/ijms222212167
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发表时间：
2021-11-10
影响因子：
5.6
通讯作者：
Heisterkamp N
中科院分区：
文献类型：
--
作者：
Tarighat SS;Fei F;Joo EJ;Abdel-Azim H;Yang L;Geng H;Bum-Erdene K;Grice ID;von Itzstein M;Blanchard H;Heisterkamp N
B细胞前体急性淋巴细胞白血病（BCP-ALL）中环境介导的耐药性显著促进复发。骨髓环境中的基质细胞通过分泌趋化因子作为BCP-ALL向基质迁移和粘附的线索来保护白血病细胞。基质细胞和BCP-ALL细胞通过基质半乳糖凝集素-3进行通讯。在这里，我们研究了基质半乳糖凝集素-3对BCP-ALL细胞的意义。我们使用CRISPR/Cas9基因组编辑来消除基质细胞中的半乳糖凝集素-3，并发现半乳糖凝集素-3对于稳态BCP-ALL增殖和活力是有利的。然而，有效的白血病迁移和粘附基质细胞显着依赖于基质半乳糖凝集素-3。重要的是，基质半乳糖凝集素-3的产生的损失使BCP-ALL细胞对常规化疗敏感。因此，我们测试了对半乳糖凝集素-3具有高特异性的新型基于碳水化合物的小分子化合物（Cpd 14和Cpd 17）。与使用半乳糖凝集素-3敲除基质细胞获得的结果一致，基质-BCP-ALL共培养物的处理抑制BCP-ALL迁移和粘附。此外，这些化合物在BCP-ALL细胞中诱导抗白血病应答，包括存活率和增殖的剂量依赖性降低、细胞凋亡的诱导以及重要的是药物抗性的抑制。总的来说，这些发现表明半乳糖凝集素-3通过白血病细胞和基质之间的相互作用调节BCP-ALL细胞对化疗的反应，并表明半乳糖凝集素-3抑制与常规药物的组合可以使白血病细胞对化疗敏感。
Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, the loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells, including a dose-dependent reduction of viability and proliferation, the induction of apoptosis and, importantly, the inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.
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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
影响因子：
28.5
作者：
Hu K;Gu Y;Lou L;Liu L;Hu Y;Wang B;Luo Y;Shi J;Yu X;Huang H
通讯作者：
Huang H
影响因子：
10.1
作者：
Kornblau SM;Ruvolo PP;Wang RY;Battula VL;Shpall EJ;Ruvolo VR;McQueen T;Qui Y;Zeng Z;Pierce S;Jacamo R;Yoo SY;Le PM;Sun J;Hail N Jr;Konopleva M;Andreeff M
通讯作者：
Andreeff M
影响因子：
20.3
作者：
Cheng, Chieh-Lung;Hou, Hsin-An;Tien, Hwei-Fang
通讯作者：
Tien, Hwei-Fang
影响因子：
4
作者：
Beckenkamp, Liziane R.;Souza, Lucas E. B.;Covas, Dimas T.
通讯作者：
Covas, Dimas T.
影响因子：
20.3
作者：
Gang, Eun Ji;Kim, Hye Na;Kim, Yong-Mi
通讯作者：
Kim, Yong-Mi