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

作者：Naka Kazuhito^*; Jomen Yoshie; Ishihara Kaori; Kim Junil; Ishimoto Takahiro; Bae Eun Jin; Mohney Robert P; Stirdivant Steven M; Oshima Hiroko; Oshima Masanobu; Kim Dong Wook; Nakauchi Hiromitsu; Takihara Yoshihiro; Kato Yukio; Ooshima Akira; Kim Seong Jin

来源：Nature Communications, 2015, 6(1): 8039.

DOI：10.1038/ncomms9039

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.

• 出版日期2015-8
• 单位河北医科大学