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Oncogene v.37 no.21, 2018년, pp.2837 - 2849   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

Targeting PFKFB3 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitor

Zhu, Yu (Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu Province, PR China. zhuyu@jsph.org.cn ) ; Lu, Luo (Key Laboratory of Hematology of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, Jiangsu Province, PR China. zhuyu@jsph.org.cn ) ; Qiao, Chun (Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Province Hospital, Nanjing, 210029, Jiangsu Province, PR China. zhuyu@jsph.org.cn ) ; Shan, Yi (Division of Hematology Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA. zhuyu@jsph.org.cn ) ; Li, Huapeng (Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu Province, PR China ) ; Qian, Sixuan (Key Laboratory of Hematology of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, Jiangsu Province, PR China ) ; Hong, Ming (Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Province Hospital, ) ; Zhao, Huihui ; Li, Jianyong ; Yang, Zhongfa ; Chen, Yaoyu ;
  • 초록  

    Resistance to the BCR-ABL tyrosine kinase inhibitor (TKI) remains a challenge for curing the disease in chronic myeloid leukemia (CML) patients as leukemia cells may survive through BCR-ABL kinase activity-independent signal pathways. To gain insight into BCR-ABL kinase activity-independent mechanisms, we performed an initial bioinformatics screen and followed by a quantitative PCR screen of genes that were elevated in CML samples. A total of 33 candidate genes were identified to be highly expressed in TKIs resistant patients. Among those genes, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), controlling the limiting step of glycolysis, was found to be strongly associated with TKIs resistance. PFKFB3 knockdown or pharmacological inhibition of its kinase activity markedly enhanced the sensitivity of CML cells to TKIs. Furthermore, pharmacological inhibition of PFKFB3 inhibited CML cells growth and significantly prolonged the survival of both allograft and xenograft CML mice. ChIP-seq data analysis combined with subsequent knockdown experiment showed that the Ets transcription factor PU.1 regulated the elevated expression of PFKFB3 in TKIs-resistant CML cells. Therefore, our results showed that targeting PFKFB3 sensitizes CML cells to TKIs and PFKFB3 may be a potential BCR-ABL kinase activity-independent mechanism in CML.


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