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Dipeptide species regulate p38MAPK–Smad3 signalling to maintain chronic myelogenous leukaemia stem cells

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  • Kazuhito Naka

    (Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan
    Research Institute for Radiation Biology and Medicine, Hiroshima University)

  • Yoshie Jomen

    (Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan)

  • Kaori Ishihara

    (Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan)

  • Junil Kim

    (CHA University, CHA Bio Complex, 335 Pangyo-ro, Bundang-ku, Seongnam, Kyunggi-do 463-400, Republic of Korea)

  • Takahiro Ishimoto

    (Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan)

  • Eun-Jin Bae

    (Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan
    CHA University, CHA Bio Complex, 335 Pangyo-ro, Bundang-ku, Seongnam, Kyunggi-do 463-400, Republic of Korea)

  • Robert P. Mohney

    (Metabolon, Inc.)

  • Steven M. Stirdivant

    (Metabolon, Inc.)

  • Hiroko Oshima

    (Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan)

  • Masanobu Oshima

    (Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan)

  • Dong-Wook Kim

    (Seoul St Mary’s Hospital, Cancer Research Institute, The Catholic University of Korea)

  • Hiromitsu Nakauchi

    (Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, The University of Tokyo
    Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine)

  • Yoshihiro Takihara

    (Research Institute for Radiation Biology and Medicine, Hiroshima University)

  • Yukio Kato

    (Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan)

  • Akira Ooshima

    (CHA University, CHA Bio Complex, 335 Pangyo-ro, Bundang-ku, Seongnam, Kyunggi-do 463-400, Republic of Korea)

  • Seong-Jin Kim

    (CHA University, CHA Bio Complex, 335 Pangyo-ro, Bundang-ku, Seongnam, Kyunggi-do 463-400, Republic of Korea)

Abstract

Understanding the specific survival of the rare chronic myelogenous leukaemia (CML) stem cell population could provide a target for therapeutics aimed at eradicating these cells. However, little is known about how survival signalling is regulated in CML stem cells. In this study, we survey global metabolic differences between murine normal haematopoietic stem cells (HSCs) and CML stem cells using metabolomics techniques. Strikingly, we show that CML stem cells accumulate significantly higher levels of certain dipeptide species than normal HSCs. Once internalized, these dipeptide species activate amino-acid signalling via a pathway involving p38MAPK and the stemness transcription factor Smad3, which promotes CML stem cell maintenance. Importantly, pharmacological inhibition of dipeptide uptake inhibits CML stem cell activity in vivo. Our results demonstrate that dipeptide species support CML stem cell maintenance by activating p38MAPK–Smad3 signalling in vivo, and thus point towards a potential therapeutic target for CML treatment.

Suggested Citation

  • Kazuhito Naka & Yoshie Jomen & Kaori Ishihara & Junil Kim & Takahiro Ishimoto & Eun-Jin Bae & Robert P. Mohney & Steven M. Stirdivant & Hiroko Oshima & Masanobu Oshima & Dong-Wook Kim & Hiromitsu Naka, 2015. "Dipeptide species regulate p38MAPK–Smad3 signalling to maintain chronic myelogenous leukaemia stem cells," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9039
    DOI: 10.1038/ncomms9039
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