Chiarella Emanuela, Codispoti Bruna, Aloisio Annamaria, Cosentino Emanuela G, Scicchitano Stefania, Montalcini Ylenia, Lico Daniela, Morrone Giovanni, Mesuraca Maria, Bond Heather M
Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy.
Tecnologica Research Institute-Marrelli Health, 88900 Crotone, Italy.
Heliyon. 2020 Jun 5;6(6):e04020. doi: 10.1016/j.heliyon.2020.e04020. eCollection 2020 Jun.
A leukemic model produced by transducing Cord Blood derived-hematopoietic CD34 cells with the MLL-AF9 translocation resulting in the oncogenic fusion protein, is used to assess for sensitivity to Zoledronic acid. These cells are practically immortalized and are of myeloid origin. Proliferation, clonogenic and stromal co-culture assays showed that the MLL-AF9 cells were considerably more sensitive to Zoledronic acid than normal hematopoietic CD34 cells or MS-5 stromal cells. The MLL-AF9 cells were notably more inhibited by Zoledronic acid when cultured as colonies in 3 dimensions, requiring cell-cell contacts compared to suspension expansion cultures. This is coherent with the mechanism of action of Zoledronic acid inhibiting farnesyl diphosphate synthase which results in a block in prenylation of GTPases such that their role in the membrane is compromised for cell-cell contacts. Zoledronic acid can be proposed to target the MLL-AF9 leukemic stem cells before they emerge from the hematopoietic niche, which being in proximity to bone osteoclasts where Zoledronic acid is sequestered can be predicted to result in sufficient levels to result in an anti-leukemic action.
通过用导致致癌融合蛋白的MLL - AF9易位转导脐带血来源的造血CD34细胞产生的白血病模型，用于评估对唑来膦酸的敏感性。这些细胞实际上是永生化的，起源于髓系。增殖、克隆形成和基质共培养试验表明，MLL - AF9细胞对唑来膦酸的敏感性明显高于正常造血CD34细胞或MS - 5基质细胞。与悬浮扩增培养相比，当MLL - AF9细胞在三维空间中作为集落培养时，唑来膦酸对其抑制作用明显更强，这需要细胞间接触。这与唑来膦酸抑制法呢基二磷酸合酶的作用机制一致，该机制导致GTP酶的异戊二烯化受阻，从而使其在细胞膜中对细胞间接触的作用受到损害。可以提出唑来膦酸在MLL - AF9白血病干细胞从造血微环境中出现之前就对其起作用，由于唑来膦酸被隔离在靠近破骨细胞的骨部位，预计可以产生足够的水平从而产生抗白血病作用。
