Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy.
PLoS One. 2011;6(12):e28555. doi: 10.1371/journal.pone.0028555. Epub 2011 Dec 2.
The introduction of specific BCR-ABL inhibitors in chronic myelogenous leukemia therapy has entirely mutated the prognosis of this hematologic cancer from being a fatal disorder to becoming a chronic disease. Due to the probable long lasting treatment with tyrosine-kinase inhibitors (TKIs), the knowledge of their effects on normal cells is of pivotal importance.
We investigated the effects of dasatinib treatment on human bone marrow-derived mesenchymal stromal cells (MSCs).
Our findings demonstrate, for the first time, that dasatinib induces MSCs adipocytic differentiation. Particularly, when the TKI is added to the medium inducing osteogenic differentiation, a high MSCs percentage acquires adipocytic morphology and overexpresses adipocytic specific genes, including PPARγ, CEBPα, LPL and SREBP1c. Dasatinib also inhibits the activity of alkaline phosphatase, an osteogenic marker, and remarkably reduces matrix mineralization. The increase of PPARγ is also confirmed at protein level. The component of osteogenic medium required for dasatinib-induced adipogenesis is dexamethasone. Intriguingly, the increase of adipocytic markers is also observed in MSCs treated with dasatinib alone. The TKI effect is phenotype-specific, since fibroblasts do not undergo adipocytic differentiation or PPARγ increase.
Our data demonstrate that dasatinib treatment affects bone marrow MSCs commitment and suggest that TKIs therapy might modify normal phenotypes with potential significant negative consequences.
特定的 BCR-ABL 抑制剂在慢性髓性白血病治疗中的应用，彻底改变了这种血液学癌症的预后，使它从致命疾病转变为慢性疾病。由于可能需要长期使用酪氨酸激酶抑制剂（TKIs），因此了解它们对正常细胞的影响至关重要。
我们研究了达沙替尼治疗对人骨髓间充质基质细胞（MSCs）的影响。
我们的研究结果首次表明，达沙替尼诱导 MSCs 向脂肪细胞分化。特别是，当 TKI 被添加到诱导成骨分化的培养基中时，高比例的 MSCs 获得脂肪细胞形态，并过度表达脂肪细胞特异性基因，包括 PPARγ、CEBPα、LPL 和 SREBP1c。达沙替尼还抑制碱性磷酸酶的活性，这是一种成骨标志物，并显著减少基质矿化。在蛋白质水平上也证实了 PPARγ 的增加。达沙替尼诱导脂肪生成所需的成骨培养基的成分是地塞米松。有趣的是，单独用达沙替尼处理的 MSCs 也观察到脂肪细胞标志物的增加。TKI 作用是表型特异性的，因为成纤维细胞不会发生脂肪细胞分化或 PPARγ 增加。
我们的数据表明，达沙替尼治疗会影响骨髓 MSCs 的分化方向，并提示 TKI 治疗可能会改变正常表型，带来潜在的显著负面影响。
