广州生物院在急性B淋系白血病个性化药物筛选研究中获进展
近日,中国科学院广州生物医药与健康研究院李鹏研究组最新发现了间充质干细胞(MSCs)促进B型急性淋巴细胞白血病细胞生长的深层机制,以此确立原代B-ALL细胞体外培养体系,建立了个性化的药物高通量筛选平台。


本文转载自“广州生物医药与健康研究院”。

这一创新科研成果以Defined,serum/feeder-free conditions for expansion and drug screening of primary B-acute lymphoblastic leukemia为题,发表在Oncotarget上。

对化合物进行功能性筛选是B-ALL合理治疗方法发展的主要障碍。同时,由于细胞系在体外容易产生基因、表型漂移和丢失异质性,其作为药物筛选主流模型的可信性受到质疑。因此,解决原代细胞在体外培养和扩增困难的问题刻不容缓。

李鹏研究组发现,OP9细胞,而非OP9来源的脂肪细胞,能促进B-ALL原代细胞的体外生长,并通过RNA-Seq分析确定了支持这些细胞在体外生长的主要成分,据此建立了一种无血清培养体系FI76V。利用此体系可在体外培养和扩增一系列临床常见的原代细胞,且保持这些细胞最初的生物学特性。同时,研究人员基于此体系建立了一种高通量药物筛选平台,对378种激酶抑制剂进行筛选后,找到能在体外有效杀伤B-ALL细胞的17种激酶抑制剂。同时,该研究以此验证了dinaciclib和BTG226联合用药治疗B-ALL白血病的有效性。

研究工作获得中科院干细胞先导专项、国家自然科学基金、广东省自然科学杰出青年基金等的资助。

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  • Defined, serum/feeder-free conditions for expansion and drug screening of primary B-acute lymphoblastic leukemia

    Functional screening for compounds represents a major hurdle in the development of rational therapeutics for B-acute lymphoblastic leukemia (B-ALL). In addition, using cell lines as valid models for evaluating responses to novel drug therapies raises serious concerns, as cell lines are prone to genotypic/phenotypic drift and loss of heterogeneity in vitro. Here, we reported that OP9 cells, not OP9-derived adipocytes (OP9TA), support the growth of primary B-ALL cells in vitro. To identify the factors from OP9 cells that support the growth of primary B-ALL cells, we performed RNA-Seq to analyze the gene expression profiles of OP9 and OP9TA cells. We thus developed a defined, serum/feeder-free condition (FI76V) that can support the expansion of a range of clinically distinct primary B-ALL cells that still maintain their leukemia-initiating ability. We demonstrated the suitability of high-throughput drug screening based on our B-ALL cultured conditions. Upon screening 378 kinase inhibitors, we identified a cluster of 17 kinase inhibitors that can efficiently kill B-ALL cells in vitro. Importantly, we demonstrated the synergistic cytotoxicity of dinaciclib/BTG226 to B-ALL cells. Taken together, we developed a defined condition for the ex vivo expansion of primary B-ALL cells that is suitable for high-throughput screening of novel compounds.

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