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Small-molecule inhibitors targeting INK4 protein p18INK4C enhance ex vivo expansion of haematopoietic stem cells

Author

Listed:
  • Yingdai Gao

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Peng Yang

    (Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute
    University of Pittsburgh)

  • Hongmei Shen

    (University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh)

  • Hui Yu

    (University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh)

  • Xianmin Song

    (Changhai Hospital, Secondary Military Medical University)

  • Liyan Zhang

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Peng Zhang

    (Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute
    University of Pittsburgh)

  • Haizi Cheng

    (Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute
    University of Pittsburgh)

  • Zhaojun Xie

    (Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute
    University of Pittsburgh)

  • Sha Hao

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Fang Dong

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Shihui Ma

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Qing Ji

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Patrick Bartlow

    (Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute
    University of Pittsburgh)

  • Yahui Ding

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Lirong Wang

    (Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute
    University of Pittsburgh)

  • Haibin Liu

    (Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute
    University of Pittsburgh)

  • Yanxin Li

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Hui Cheng

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Weimin Miao

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Weiping Yuan

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Youzhong Yuan

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Tao Cheng

    (State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Xiang-Qun Xie

    (Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Drug Abuse Research, Drug Discovery Institute
    University of Pittsburgh)

Abstract

Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel small-molecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.

Suggested Citation

  • Yingdai Gao & Peng Yang & Hongmei Shen & Hui Yu & Xianmin Song & Liyan Zhang & Peng Zhang & Haizi Cheng & Zhaojun Xie & Sha Hao & Fang Dong & Shihui Ma & Qing Ji & Patrick Bartlow & Yahui Ding & Liron, 2015. "Small-molecule inhibitors targeting INK4 protein p18INK4C enhance ex vivo expansion of haematopoietic stem cells," Nature Communications, Nature, vol. 6(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7328
    DOI: 10.1038/ncomms7328
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    Cited by:

    1. Marta Palafox & Laia Monserrat & Meritxell Bellet & Guillermo Villacampa & Abel Gonzalez-Perez & Mafalda Oliveira & Fara Brasó-Maristany & Nusaibah Ibrahimi & Srinivasaraghavan Kannan & Leonardo Mina , 2022. "High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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