Defined, serum/feeder-free conditions for expansion and drug screening of primary B-acute lymphoblastic leukemia
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Zhiwu Jiang1,2,3, Di Wu1,2, Wei Ye1,2, Jianyu Weng4, Peilong Lai4, Pengcheng Shi5, Xutao Guo5, Guohua Huang6, Qiuhua Deng6, Yanlai Tang7, Hongyu Zhao8, Shuzhong Cui9, Simiao Lin1,2, Suna Wang1,2, Baiheng Li1,2, Qiting Wu1,2, Yangqiu Li10, Pentao Liu11, Duanqing Pei1,2, Xin Du4, Yao Yao1,2,3 and Peng Li1,2,3
1Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
2Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
3Department of Abdominal Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510095, China
4Department of Hematology, Guangdong Provincial People’s Hospital, Guangzhou 510500, China
5Department of Hematology, Nanfang Hospital, Guangzhou 510500, China
6Department of Respiratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
7Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510500, China
8The First Affiliated Hospital, University of Zhengzhou, Zhengzhou 450000, China
9Affiliated Caner Hospital and Institute of Guangzhou Medical University, Guangzhou 510095, China
10Department of Hematology, Medical College, Jinan University, Guangzhou 510632, China
11Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, England, UK
Peng Li, email: [email protected]
Yao Yao, email: [email protected]
Keywords: B-ALL; microenvironment; growth factors; drug screening; kinase inhibitors
Abbreviations: B-ALL: B Acute lymphoblastic leukemia; OP9TA: OP9-derived adipocytes; CDK: cyclin-dependent kinase; FBS: fetal bovine serum; NSI: NOD/SCID/IL2Rg−/− mice
Received: June 21, 2017 Accepted: October 28, 2017 Published: November 15, 2017
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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