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首页> 外文期刊>Experimental Hematology Oncology >Vincristine could partly suppress stromal support to T-ALL blasts during pegylated arginase I treatment
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Vincristine could partly suppress stromal support to T-ALL blasts during pegylated arginase I treatment

机译：长春新碱可部分抑制聚乙二醇精氨酸酶I治疗期间对T-ALL胚芽的基质支持

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Background Relapsed T-lineage acute lymphoblastic leukemia (T-ALL) has been an incurable disease. Recent reports showed that an L-arginine depleting enzyme, pegylated arginase (BCT-100) may be effective against T-ALL cells. On the other hand, studies including ours had shown the symbiosis of ALL blasts and human mesenchymal stromal cells (hMSCs) in bone marrow microenvironment during L-asparaginase treatment. As L-asparaginase and BCT-100 both act by depleting lymphoid cells of specific amino acid, we hypothesized that hMSCs may also protect T-ALL blasts from BCT-100 treatment in co-culture and such protection may be abrogated by pre-treating hMSCs with vincristine (VCR). Methods XTT assay was used to test sensitivities of T-ALL cell lines and hMSCs to BCT-100. Apoptosis of T-ALL cell lines with or without BCT-100 treatment were tested by annexin V / propidium iodide (AV/PI) assay using flow cytometer. Western blotting was performed to analyze the expression of ornithine transcarbamylase (OTC), an enzyme involved in L-arginine metabolism which may account for BCT-100 resistance. Results hMSCs were resistant to BCT-100 while CCRF-CEM, Jurkat and MOLT-4 were very sensitive to it. hMSCs could protect all the three cell lines from BCT-100 treatment in transwell co-culture. All the 3 T-ALL cell lines were also found to be rescued by an L-arginine precursor citrulline, while the breakdown product of BCT-100, ornithine only had limited salvaging effect on CCRF-CEM but not Jurkat and MOLT-4. Both hMSCs and 3 T-ALL cell lines express citrulline synthesis enzyme, ornithine transcarbamylase (OTC) at basal level while only hMSCs could express OTC at relatively higher level under BCT-100 treatment. Treating hMSCs with vincristine before co-culturing with T-ALL could resume the cytotoxicity of BCT-100 to CCRF-CEM and MOLT-4 cells. Conclusions Our results suggest a possible strategy to overcome resistance to BCT-100 from cancer microenvironments by suppressing hMSCs either in marrow or in the perivascular niche using vincristine.
机译：背景复发性T谱系急性淋巴细胞白血病（T-ALL）是一种无法治愈的疾病。最近的报道表明，一种L-精氨酸消耗酶，聚乙二醇化的精氨酸酶（BCT-100）可能对T-ALL细胞有效。另一方面，包括我们在内的研究表明，在L-天冬酰胺酶治疗期间，骨髓微环境中所有胚细胞与人间充质基质细胞（hMSCs）共生。由于L-天冬酰胺酶和BCT-100都通过消耗特定氨基酸的淋巴样细胞而起作用，因此我们假设hMSCs还可在共培养中保护T-ALL blasts免于BCT-100处理，并且这种保护作用可通过预处理hMSCs来废除长春新碱（VCR）。方法采用XTT法检测T-ALL细胞株和hMSCs对BCT-100的敏感性。使用流式细胞仪，通过膜联蛋白V /碘化丙啶（AV / PI）测定法检测经过或未经过BCT-100处理的T-ALL细胞凋亡。进行了蛋白质印迹分析以分析鸟氨酸转氨甲酰酶（OTC）的表达，该酶参与L-精氨酸代谢，可能是BCT-100耐药的原因。结果hMSCs对BCT-100有抗性，而CCRF-CEM，Jurkat和MOLT-4对此非常敏感。在跨孔共培养中，hMSC可以保护所有三个细胞系免受BCT-100处理。还发现所有3个T-ALL细胞系均由L-精氨酸前体瓜氨酸拯救，而BCT-100，鸟氨酸的分解产物仅对CCRF-CEM具有有限的挽救作用，而对Jurkat和MOLT-4则没有。 hMSCs和3个T-ALL细胞系均在基础水平上表达瓜氨酸合成酶，鸟氨酸转氨甲酰酶（OTC），而只有hMSC在BCT-100处理下可以表达相对较高水平的OTC。在与T-ALL共培养之前用长春新碱处理hMSC可以恢复BCT-100对CCRF-CEM和MOLT-4细胞的细胞毒性。结论我们的结果表明，通过使用长春新碱抑制骨髓或血管周围生境中的hMSC，可以克服癌症微环境对BCT-100的耐药性。

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