2. Academic Validation
  3. Dipeptide species regulate p38MAPK-Smad3 signalling to maintain chronic myelogenous leukaemia stem cells

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

  • Nat Commun. 2015 Aug 20;6:8039. doi: 10.1038/ncomms9039.
Kazuhito Naka 1 2,  Yoshie Jomen 1,  Kaori Ishihara 1,  Junil Kim 3,  Takahiro Ishimoto 4,  Eun-Jin Bae 1 3,  Robert P Mohney 5,  Steven M Stirdivant 5,  Hiroko Oshima 6,  Masanobu Oshima 6,  Dong-Wook Kim 7,  Hiromitsu Nakauchi 8 9,  Yoshihiro Takihara 2,  Yukio Kato 4,  Akira Ooshima 3,  Seong-Jin Kim 3
Affiliations

Affiliations

  • 1 Exploratory Project on Cancer Stem Cells, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
  • 2 Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
  • 3 CHA Cancer Institute and Department of Biomedical Science, CHA University, CHA Bio Complex, 335 Pangyo-ro, Bundang-ku, Seongnam, Kyunggi-do 463-400, Republic of Korea.
  • 4 Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
  • 5 Metabolon, Inc., 617 Davis Drive Suite 400, Durham, North Carolina 27713, USA.
  • 6 Division of Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
  • 7 Department of Hematology, Seoul St Mary's Hospital, Cancer Research Institute, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea.
  • 8 Division of Stem Cell Therapy, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1 Shiroganedai, Minato-ku, Tokyo 108-8639, Japan.
  • 9 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA.
PMID: 26289811 DOI: 10.1038/ncomms9039
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.

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