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

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 Nakauchi, Yoshihiro Takihara, Yukio Kato, Akira Ooshima and Seong-Jin Kim ()
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Kazuhito Naka: Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan
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
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
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

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9039

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