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Targeting PFKFB3 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitor

Oncogene volume 37, pages 2837–2849 (2018)Cite this article

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Abstract

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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Acknowledgements

The authors thank the patients who donated bone marrow samples that made this work possible. The authors specially thank Dr. Alan G. Rosmarin from the University of Massachusetts, Division of Hematology/Oncology (Worcester, MA) for suggestions and support for this research.

Funding

This work was supported by the National Natural Science Foundation of the People’s Republic of China (Nos. 81070437, 81270614, 81300379, 81570134, 81570141, 81522001, 81200362), National Public Health Grand Research Foundation (No. 201202017), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institute (No. JX10231801) and Key Project of Jiangsu Province Health Agency (K201107).

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  1. Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu Province, PR China

    Yu Zhu, Luo Lu, Chun Qiao, Sixuan Qian, Ming Hong, Huihui Zhao, Jianyong Li & Yaoyu Chen

  2. Key Laboratory of Hematology of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, Jiangsu Province, PR China

    Yu Zhu, Luo Lu, Chun Qiao, Sixuan Qian, Ming Hong, Huihui Zhao, Jianyong Li & Yaoyu Chen

  3. Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Province Hospital, Nanjing, 210029, Jiangsu Province, PR China

    Yu Zhu, Luo Lu, Chun Qiao, Sixuan Qian, Ming Hong, Huihui Zhao, Jianyong Li & Yaoyu Chen

  4. Division of Hematology Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Yu Zhu, Yi Shan, Huapeng Li & Zhongfa Yang

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Zhu, Y., Lu, L., Qiao, C. et al. Targeting PFKFB3 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitor. Oncogene 37, 2837–2849 (2018). https://doi.org/10.1038/s41388-018-0157-8

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