Division of Hematology/Oncology and Bone Marrow Transplant, The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA.
Int J Mol Sci. 2021 Nov 10;22(22):12167. doi: 10.3390/ijms222212167.
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.
骨髓微环境中细胞因子的分泌可作为 B 细胞前体急性淋巴细胞白血病（BCP-ALL）细胞迁移和黏附的趋化因子，从而介导肿瘤耐药，显著增加复发风险。骨髓基质细胞通过分泌细胞因子来保护白血病细胞，促进 BCP-ALL 细胞向骨髓基质细胞迁移并黏附。骨髓基质细胞和 BCP-ALL 细胞通过基质半乳糖凝集素-3 进行通讯。本研究旨在探讨基质半乳糖凝集素-3 对 BCP-ALL 细胞的意义。我们使用 CRISPR/Cas9 基因组编辑技术敲除基质细胞中的半乳糖凝集素-3，发现半乳糖凝集素-3 对半乳糖凝集素-3 缺失型 BCP-ALL 细胞的稳态增殖和活力没有影响，但对白血病细胞向基质细胞的迁移和黏附非常重要。重要的是，基质半乳糖凝集素-3 缺失可使 BCP-ALL 细胞对常规化疗敏感。因此，我们测试了新型糖基小分子化合物（Cpd14 和 Cpd17）对半乳糖凝集素-3 的高特异性。与使用半乳糖凝集素-3 敲除基质细胞得到的结果一致，这些化合物可抑制基质-BCP-ALL 共培养物中 BCP-ALL 细胞的迁移和黏附。此外，这些化合物可诱导 BCP-ALL 细胞发生抗白血病反应，包括细胞活力和增殖的剂量依赖性降低、细胞凋亡的诱导，更重要的是，抑制了耐药性。综上所述，这些发现表明，半乳糖凝集素-3 通过白血病细胞与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 抑制与常规药物联合使用可使白血病细胞对化疗更敏感。
